THE ADHESION MOLECULE
FactsBook Second Edition
THE ADHESION MOLECULE
FactsBook Second Edition
Other books in the FactsBook Series: Robin Callard and Andy Gearing The Cytokine FactsBook Steve Watson and Steve Arkinstall The G-Protein Linked Receptor FactsBook Shirley Ayad, Ray Boot-Handford, Martin J. Humphries, Karl E. Kadler and C. Adrian Shuttleworth The Extracellular Matrix FactsBook, 2nd edn Grahame Hardie and Steven Hanks The Protein Kinase FactsBook The Protein Kinase FactsBook CD-Rom Edward C. Conley The Ion Channel FactsBook h Extracellular Ligand-Gated Channels Edward C. Conley The Ion Channel FactsBook Ih Intracellular Ligand-Gated Channels Edward C. Conley and William J. Brammar The Ion Channel FactsBook IV: Voltage-gated Channels Kris Vaddi, Margaret Keller and Robert Newton The Chemokine FactsBook Marion E. Reid and Christine Lomas-Francis The Blood Group Antigen FactsBook A. Neil Barclay, Marion H. Brown, S.K. Alex Law, Andrew J. McKnight, Michael G. Tomlinson and P. Anton van der Merwe The Leucocyte Antigen FactsBook, 2nd edn Robin Hesketh The Oncogene and Tumour Suppressor Gene FactsBook, 2nd edn Jeffrey K. Griffith and Clare E. Sansom The Transporter FactsBook Tak W. Mak, Josef Penninger, John Rader, Janet Rossant and Mary Saunders The Gene Knockout FactsBook Bernard J. Morley and Mark J. Walport The Complement FactsBook Steven G.E. Marsh, Peter Parham and Linda Barber The HLA FactsBook Hans G. Drexler The Leukemia-Lymphoma Cell Line FactsBook
THE ADHESION MOLECULE
FactsBook Second Edition
Clare M. Isacke Imperial College of Science, Technology and Medicine, London, UK
Michael A. Horton University College London, London, UK
ACADEMIC PRESS A Harcourt Science and Technology Company
San Diego San Francisco New York Boston London Sydney Tokyo
This book is printed on acid-free paper. Copyright 9 2000 by ACADEMIC PRESS All Rights Reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Academic Press A Harcourt Science and Technology Company Harcourt Place, 32 Jamestown Road, London NW1 7BY http://www.hbuk.co.uk/ap/ Academic Press 525 B Street, Suite 1900, San Diego, California 92101-4495, USA h ttp://www, apnet, com ISBN 0-12-356505-7 Library of Congress Catalog Card Number: 00-104879 A catalogue for this book is available from the British Library
Typeset by Mackreth Media Services, Hemel Hempstead, UK Printed in Great Britain by Redwood Books, Trowbridge, Wiltshire 00 01 02 03 04 05 RB 9 8 7 6 5 4 3 2 1
Preface
vii ...
Abbreviations
Vlll
Chapter 1 Introduction
2
Chapter 2 Adhesion Molecule Families
7
Chapter 3 Accessing Information on the World Wide Web
Cadherins E-Cadherin ................................. N-Cadherin ................................. P-Cadherin R-Cadherin ................................. VE-Cadherin .............................. .......................... OB-Cadherin ..............................
33
CD33 .......................................
97
CEACAM family ..................... Contactin- 1 ICAM- 1 .................................... ICAM-2 .................................... ICAM-3 .................................... ICAM-4 ...................
103 108 111 114
43 46 51 53 57
59
116
Cadherin- 14 .......... Ksp-Cadherin ..............................
69
.............. 133 Desmocollin 3 ........................... Desmoglein 1 ....... Desmoglein 2 .............................. Desmoglein 3 .............................. Immunoglobulin superfamily ALCAM .................................... CD22a and p .............................. CD31 .......................................
78 80 83 85 89 91 94
Sialoadhesin ..............................
138
Integrins Integrin aL................................. Integrin aM .............................. Integrin ax .............................. Integrin a” ..............................
149 152 155 157
Integrin a1.................................
159
CD6 .................. CD23 .......................................
23 7 239
CD39 .......................................
247
CD42c ....................................
254
Integrin a3................
Integrin Integrin Integrin Integrin Integrin Integrin Integrin Integrin Integrin Integrin Integrin Integrin
ah................................. a , ................................. a8.... ag.... a , ..............................
173 176
P3................................. P4.................................
182 184 187 190 192 195 198 20 1
Integrin P, ................................. Integrin Ps
208 210
Selectins E-Selectin ...... L-Selectin ................................. P-Selectin .................................
21s 218 220
Syndecans Syndecan-1 .............................. Syndecan-2 .......... Syndecan-3 .............................. Syndecan-4
225 227 229 23 1
aIlb.............................. av
aE.................................
PI ................................. PI .................................
Other molecules AMOG
..................235
CD43 ........... CD57 .......................................
264
Claudin-1 ................................. Claudin-3 Claudin-4 .................................
271 273 275
Collagen type XI11 (a1 chain) ......280 Collagen type XVII (a1 chain) Dystroglycan ..................... E48 .......................................... 288 ESL-1 290 Galectin 3 ................................. 292 GlyCAM-1 .............................. 294 HSA ....................................... 296 LYVE- 1 298 Occludin ................................. 300 PCLPl .................................... 302 PSGL-1 304 VAP-1 .................................... 307
Index .......................................
309
The authors acknowledge all those who have helped in the completion of this book. In particular we would like to thank Chau Chong for excellent secretarial help, our laboratories for their patience while the book was being written and members of the UK Adhesion Group who filled in questionnaires suggesting molecules that should be included. Many colleagues were invaluable in checking entries and providing unpublished information. We would particularly like to thank Ann Ager, Chris Buckley, Paul Crocker, Pat Doherty, Kurt Drickamer, Nancy H o g , Gudrun Ihrke, David Jackson, Sirpa Jalltanen, Clive Landis, Tony Magee, Fiona Watt, Sue Watt and Lisa Williams. Writing this book was greatly helped by the recent publication of The Leucocyte Antigen FactsBook, and we would like to acknowledge Neil Barclay, Marion Brown, Alex Law, Andrew McKnight, Michael Tomlinson and Anton van der Merwe whose hard work made our task much easier. With the published literature on adhesion molecules increasing by several thousand papers per annum and the various mammalian genome projects sequencing apace, a book will inevitably contain omissions and inaccuracies, and the references have a danger of being superseded. For this we apologize. However, with access to electronic databases on the World Wide Web (see Chapter 3 ) , this is relatively easy to remedy and the reader is asked to bear with us and make their own updates relating to a favourite molecule.
Acquired immunodeficiency syndrome B lymphocyte B cell antigen receptor Complement control protein Cluster of differentiation Cadherin-related neuronal receptor Chondroitin sulphate cs Extracellular matrix ECM Epidermal growth factor EGF Ezrin/radixin/moesin ERM Embryonic stem ES Expressed sequence tag EST Focal adhesion kinase FAK Fibroblast growth factor FGF Glycosaminoglycan GAG N-Acetylgalactosamine GalNAc N-Acetylglucosamine GlcNAc Gly cosyl-phosphatidylinositol GPI Glycogen synthase kinase GSK High endothelial venule HEV Interferon IFN Immunoglobulin Ig Immunoglobulin superfamily IgSF Interleukin IL Immunoreceptor tyrosine-based inhibitory motif ITIM Kilobase pairs kb Kilodalton kDa Leucocyte adhesion deficiency LAD Lipopoly saccharide LPS Leucine-rich repeat LRR Mitogen-activated protein kinase MAPK Mouse Genome Informatics MGI Major histocompatibility complex MHC Natural killer NK Nuclear magnetic resonance NMR Online Mendelian Inheritance in Man OMIM Phosphatidylinositol PI SDS-PAGE Polyacrylamide gel electrophoresis in sodium dodecyl sulphate Src homology domain 2 SH2 Src homology domain 3 SH3 Sialyl-Lewis* sLeA Sialyl-LewisX sLeX T lymphocyte T Transmembrane TM
AIDS B BCR CCP CD CNR
TM4SF
TNF WFl
www
Tetraspan supcrfamily Tumour nccrosis factor Wingless Wnrld Widc Wch
Size (approximate
Type
8
amino acids)
Cadherin repeat
Collagennus domain
Complement control protein (CCPF
Drsrnoglein repeat
Epidermal growth
factor (EGF)
D h
0 @ p
T 10
Vatisblc length
Lectin C-type
Size (approximate amino acids)
120
Galccrin or Lectin S-type
LRR repeats
140
a
24
"r' 60
Link
90
p +
30
70-90
Scavenger receptor
110
40
OTHER SYMBOLS USED Fihronectin type 111 /FnN
N-g Iycory lation si teP
Q-linked glymwlation Glrcmoam inoglvcan
GPI anchor in lipid hilayer
Jrn munoglohulin (Ig) C2 set
Site of propeptide cleavage [c.R.in cad herins! Unknown nr unclear molecular cnnfnrrnation nr membrane attnchrnent/linkajy
Figure 1 Icons used for the protein domains and repeats that are present in adhesion molecules.
h
/
-SJ
7
This Page Intentionally Left Blank
THE INTRODUCTORY CHAPTERS
AIMS OF THE BOOK The primary aim of this book is to provide a compendium of the major cell surface adhesion molecules. The entries have been designed to allow the reader to establish the main structural and functional features of a molecule quickly and to provide sufficient information for accessing further information. A detailed explanation of the organization of the entries is included in this chapter. In addition there are two further chapters preceding the individual entries. Chapter 2 provides a background to the main adhesion molecule families and Chapter 3 provides information as to how to access information on adhesion molecules on the World Wide Web.
CRITERIA FOR SELECTION Deciding on which molecules should be included in this book was a difficult task and many researchers may be offended to find the subject of their work missing. The difficulties arise in several areas. First, the majority of adhesion receptors belong to a family group based on recognizable structural features. With the rapid advances in cloning and proteomics, new molecules which contain these structural features are frequently appearing in the literature and databases. However, for many of these new molecules there is no information as to whether they function as adhesion molecules. Unless such information has been obtained, these molecules have not been given individual entries but they are discussed in the relevant sections in Chapter 2. Second, some molecules have been shown to be bona fide adhesion molecules but have been omitted unless a mammalian orthologue has been established. In the majority of cases these molecules have been identified in Drosophila melanogaster or in Caenorhabditis elegans. Both these organisms have extensive databases associated with them that can be accessed for further information (see Chapter 3 and C . elegans: http://www.sanger.ac.uk/Projects/C-elegansl; http://www.wormbase.org/; D. melanogaster: http://flybase.bio.indiana.edu/). Third, molecules which function in cell recognition rather than cell adhesion have been omitted. These include components of the immune recognition complexes such as the T and B cell receptors, receptor:ligand pairs such as Notch and Jagged/Serrate. Although not easy to assess, recognition molecules are judged as those that play a crucial role in mediating cel1:cell interactions but do not alone mediate adhesion. Similarly, in the past few years, the distinction between adhesion molecules and signalling receptors has become increasingly blurred, and indeed many adhesion and signalling receptors act in concert to mediate their biological effects. Again, unless such receptors have been demonstrated themselves to have adhesive properties, they have been omitted. Finally, there is an increasing number of transmembrane molecules that associate with adhesion molecules and in many cases modulate their function. However, these association molecules, such as members of the tetraspan
superfamily (TM4SF) do not alone mediate adhesion. Similarly, intracellular components which associate with adhesion molecules have not been included.
ORGANIZATION OF THE DATA Name The most commonly used name for each molecule has been used and other names that are currently still in use are given also. Many of the adhesion molecules originally were given different names but gradually a consensus of nomenclature has arisen. As will be discussed in Chapter 2, cadherins, integrins, selectins and syndecans have family names. An equivalent situation does not exist for the immunoglobulin superfamily (IgSF),which reflects the diversity of function within this family. However, within the IgSFs, nomenclature for subfamilies, such as the siglecs and ICAMs, is becoming more common. Many of the adhesion molecules are expressed by leucocytes and consequently they have a CD (cluster of differentiation) nomenclature (see Leucocyte Antigen FactsBook'). In some cases this is the most commonly used name, especially for those molecules that were originally characterized in different laboratories and hence given different names. In other cases, molecules have a CD nomenclature but an earlier consensus for another name means that the CD number is not commonly used.
Family The family to which the adhesion molecule belongs is given. Some families are further divided and, in these cases, the subfamily is also provided. Further information into the organization of families and subfamilies is given in Chapter 2. The 'other molecule' section contains those proteins that we decided to include on the basis of functional information but which again do not fit into the major adhesion molecule families.
Molecular diagram Many of the adhesion molecules are expressed by leucocytes and are therefore listed in the Leucocyte Antigen FactsBook'. To aid cross-referencing, we have used the same icons for the protein domains and repeats. In addition, new icons have been used to represent domains not found in leucocyte antigens. The aim of the diagram is to provide a visual representation of the molecule indicating the subunit composition, how it is attached to the membrane, its orientation, the number and type of protein domains, the degree and type of glycosylation and the position of any proteolytic cleavage sites. The icons and symbols are shown in Fig. 1. The cytoplasmic domains of the majority of adhesion molecules do not contain recognizable protein domains and therefore these are represented by squiggly lines, the length of which is proportional to the sequence length. Nuclear magnetic resonance (NMR)and crystallographic data are increasingly available for domains present within some of the families of adhesion molecules (e.g. IgSF, cadherins, integrins). We have not attempted to discuss or illustrate detailed atomic structural data for any of the molecules; we do though discuss and reference this in general terms in Chapter 2 and the individual molecule entries.
Size of the receptor The number of amino acids and calculated relative molecular weight (M,) of the entire polypeptide backbone (includingthe signal sequence) is given. The M,of the fully processed molecule obtained from sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE)under reducing conditions is given in kilodaltons (kDa).Where relevant, sizes under non-reducing conditions are also listed. As all the adhesion molecules are processed through the rough endoplasmic reticulum and Golgi apparatus, this value reflects the size of the glycosylated protein. In the case of the type I proteins this reflects the loss of the N-terminal signal sequence and for the classical cadherins, desmocollins and desmogleins, the additional loss of the propeptide sequence.
Glycosylation All of the adhesion molecules are glycosylated, but in the majority of cases the extent and nature of the carbohydrate modification is not known. N-linked carbohydrates are attached to Asn residues within the consensus motif Asn-X-Ser or Asn-X-Thr, where X is any amino acid except Pro. The number of these motifs present in the polypeptide backbone is given and the approximate positions shown in the diagram. It should be noted that not all potential N-linked sites are necessarily occupied. 0-linked sugars are attached to Ser or Thr residues but there is no consensus sequence for this modification. In most molecules, 0-linked glycosylation is found in stretches of sequence with a preponderance of Ser, Thr and Pro amino acids, where specificity depends on a combination of sequence context, secondary structure and accessibility. It should be noted that the acceptor sequence context for 0-glycosylation of serine is different from that of threonine. A programme for the prediction of 0-glycosylation sites is available at the web site: http://www.cbs.dtu.dk/services/. The approximate predicted positions of the 0-linked sugars are indicated in the diagrams and the following terms are used to describe the extent of 0glycosylation: No entry
0
+ to + + +
There are no data from sequence or biochemical studies to indicate the level of 0-glycosylation. The absence of 0-glycosylation is indicated by biochemical analysis. Biochemical data indicate that 0-glycosylation occurs a low (+), moderate (++) or high (++ + ) level.
Glycosaminoglycans (GAG) have been identified on syndecans 1-4, CD44 and dystroglycan. With the exception of keratan sulphate, which is not found on any of the adhesion molecules listed here, GAGS are attached via a xylose residue linkage to specific serine residues in the protein core. Attachment requires the presence of a C-terminal Gly; however, not all Ser-Gly sites are GAG modified.
Gene location and size The chromosome location of the human gene is given together with the gene size and number of exons, where known. As indicated in the text, where the genomic
structure has been established in non-human species, the gene size and number of exons for that species is given. Due to the rapidly changing information on the ‘human genome’ we have not attempted to provide a gene structure diagram which inevitably is likely to be superceded.
Alternative forms Many of the adhesion molecules are subject to alternative splicing and other modifications and this section summarizes what is known about the different isoforms. Where relevant, the position of sequences encoded by alternatively spliced exons or the position of exon insertion is indicated in the amino acid sequence.
Structure Biochemical and structural data are summarized in this section.
Ligands This section describes the ligands characterized for each adhesion molecule. In many cases the ‘ligand’ is another membrane-bound molecule and therefore may be more properly described as a ’counter receptor’. In some cases a physiological ligand has not been identified but molecules have still been included in the book where their structure or function strongly suggests that they are adhesion molecules.
Function Functional data are summarized in this section. In some cases a physiological function can only be predicted.
Distribution The tissue and cellular distribution of the adhesion molecule is described in this section. It should be noted that in many cases a full analysis of tissue distribution has not been undertaken and therefore may be wider than described. Where relevant the subcellular distribution of the molecule is also discussed.
Disease association The OMIM (Online Mendelian Inheritance in Man) accession number for each molecule is given (information as to how to access information from the OMIM databases is given in Chapter 3).Where relevant the association of a molecule with a particular disease is described. In addition, the use of reagents directed against these molecules for disease prediction or in therapy is also indicated.
Knockout The MGI (Mouse Genome Informatics) accession number is given. As described in Chapter 3, accessing knockout mouse databases provides a large amount of information about the function of the murine homologue of the adhesion molecule. Where a knockout has been generated, the phenotype is described.
Amino acid sequence Amino acid sequences are shown in the single-letter code (Table 1). If it is known, the human amino acid sequence is given. The initiating methionine is amino acid 1. The predicted signal sequence is show in bold and the predicted transmembrane domain is underlined. Any further information is described for individual entries.
Table 1. Single-letter and three-letter amino acid codes Amino acid
Single-letter code
Three-letter code
Alanine Arginine Asparagine Aspartic acid Cysteine Glutamic acid Glutamine Glycine Histidine Isoleucine Leucine Lysine Methionine Phenylalanine Proline Serine Threonine Tryptophan Tyrosine Valine
A R N D C E
Ala Arg Asn ASP CYS Glu Gln GlY His Ile Leu
Q G H I L K M F P S T
W Y
V
LYS
Met Phe Pro Ser
Thr Trp TYr Val
Database accession The accession numbers are given for the nucleic acid sequences in the GenBankIEMBL databases and for the amino acid sequences in SwissProt databases. Where there is no SwissProt entry, the TrEMBL database accession number is given. Unless otherwise stated, these accession numbers refer to the human molecules. Information as to how to retrieve information from the databases is given in Chapter 3 .
References It is not feasible to give a comprehensive list of references. The references given are recent ones, which, together with the databases accession information described in Chapter 3, will allow access to the rest of the literature.
References Barclay, A.N. et al. (1997)The Leucocyte Antigen FactsBook, 2nd edn. Academic Press, London.
The majority of adhesion molecules can be grouped into families. In the case of cadherins, integrins, selectins and syndecans, this grouping is based both on structural and functional similarities of the family members. The immunoglobulin superfamily (IgSF)represents a more diverse group of proteins that have structural similarity but a variety of different functions, and consequently subfamilies with functional similarity are arising. Finally, a large number of adhesion molecules do not fit into any of these families and these have been listed as ‘others’. Some of the ‘other’ adhesion molecules can be divided into subfamilies. It is anticipated that many of the remaining ’other’ molecules are the first identified members of a family, and that other members will be isolated and characterized within the next few years.
CADHERINS
Introduction The cadherin proteins now comprise a very large superfamily which can be divided into two subfamilies, the classic cadherins and the protocadherins, each of the subfamilies is further subdivided (Fig. 1). Only the classic cadherins are given individual entries in this book but, as is discussed in this section, it is anticipated that in this rapidly moving field many of the protocadherins will prove to mediate cell adhesion in vivo.
Structure Classic cadherins The classic cadherins can be subdivided into four subfamilies, the type I classic cadherins, the type 11 classic cadherins, the desmosomal cadherins and the modified or other classic cadherins. The first cadherin to be identified was E-cadherin (cadherin-1),which acts as the prototype for the type I classic cadherins, namely N-cadherin (cadherin-2), Pcadherin (cadherin-3)and R-cadherin (cadherin-4).In each case the letter indicates the tissue in which the cadherin was first identified. A number of features characterize the type I classic cadherins. They are synthesized as precursor polypeptides with an N-terminal propeptide sequence being proteolytically removed intracellularly. This event is a necessary step in the activation of cadherins to generate adhesion-competent molecules. In their extracellular domains, the type I classic cadherins have five tandemly arranged cadherin repeats of approximately 110 amino acids in length, also called extracellular cadherin JEC) domains, in between which are located four calcium binding pockets. Structural analysis of the N-terminal cadherin repeat of E-cadherin and N-cadherin show a barrel-like structure composed of seven antiparallel p-strands with the N- and C-termini located at the top and bottom, respectively. Although there is no sequence similarity, this structure is similar to the immunoglobulin domains found in the immunoglobulin superfamily (IgSF) members (see
Classic cadherins
1 S Pro
R Type11
4 Cd
Cd
Cd
Cd 1
Cd
E3
cyto
Cd
gs
cyto
Cd
F:
cyto
Cd
$ 3 Cons ~
j
I
pro
S
n
y
Cd
Cd
Cd
Cd I
I
Desmocollins
n
S 'Pro
4 Cd
Cd
Cd
Cd
1
Desmogleins
pro
Pmtocadherlns
S Cd
Cd
Cd
Cd
Cd
non-HAV
RGD
Figure 1 Structure of the cadherin family members. As described i n the text, cadherins can be divided into classic cadherins and protocadherins. Within the classic cadherins there is a further subdivision into type I classic cadherins, type II classic cadherins, desmosomal cadherins, and other or modified classic cadherins. The desmosomal cadherins fall into t w o groups, the desmocollins and the desmogleins. The characteristics of each cadherin type are described i n the text. (S, signal sequence; Pro, propeptide sequence; Cd, extracellular cadherin repeats; cyto, cytoplasmic domain; D, desmoglein repeats; V , variable cytoplasmic domain sequence; Cons, conserved cytoplasmic domain sequence). Arrow indicates position of propeptide cleavage to generate the mature form of the classic cadherins. Amino acid motifs within the N-terminal cadherin repeat indicate the adhesion recognition sequence. Note (a) other or modified classic cadherins: the three otherlmodified classic cadherins covered i n this book are not shown i n this diagram as these are described individually i n the text and i n
’Immunoglobulin superfamily’). One major difference is that the IgSF are not calcium binding proteins, whereas in the cadherins the five domains assume a rodshape that is stabilized by the binding of calcium ions between successive repeat domains. Located within the N-terminal domain of the classic type I cadherins is the conserved HAV motif which is part of the active site for interaction with cadherins on neighbouring cells. Other residues within the active site provide the specificity for homophilic interaction. The exceptions are N- and R-cadherin which have almost identical amino acids at the homophilic binding interface and can interact with each other. In addition, a tryptophan residue in the +2 position after removal of the propeptide sequence is required for this trans interaction. Within domain 1, on the opposite side to the adhesive or trans-face, is the cis face which mediates homophilic association with cadherins in the plane of the membrane. This cis interaction is dependent on calcium being bound between domains 1 and 2, and is necessary for the subsequent trans interaction and hence cel1:cell adhesion’-30. The cytoplasmic domain of the type I class cadherins is 150-160 amino acids in length and is required for their adhesive function as it is this domain that mediates the association with the actin cytoskeleton. Binding to actin is not direct but via linker proteins known as catenins. The arrangement of the catenin binding is as follows: cadherin-p-catenin-a-catenin-actin. Originally three catenins were identified but it is now established that the desmosomal component plaltoglobin (previously called y-catenin), like p-catenin, can bind to both cadherins and acatenin, and that the inclusion of p-catenin and plakoglobin in the cadherin/catenin complex is mutually exclusive. However, as evidenced by the different phenotypes associated with the knockout of p-catenin (MGI:88276) and plaltoglobin (MGI:96650) in vivo”6, these two components have different physiological roles and are not functionally redundant. As discussed below, pcatenin is considered to have a dual role in that it is not only required for cadherin association with the cytoslteleton but it also has an important signalling function. The type I1 classic cadherins include VE-cadherin (cadherin-5), K-cadherin (cadherin-6),cadherin-8, OB-cadherin (cadherin-111, cadherin-14 and M-cadherin (cadherin-15)and are structurally similar to the type I subfamily in that they have a propeptide sequence, five cadherin repeats and, where it has been examined, they have been shown to mediate homophilic binding and to associate intracellularly with catenins. The notable differences are that the propeptide sequence tends to be
their separate entries. (b) Desmogleins: the structure shown here corresponds t o desmoglein 1 . Desmoglein 2 and desmoglein 3 have six and t w o desmoglein repeats, respectively, in their cytoplasmic domains. (c) Protocadherins: protocadherins are shown w i t h six extracellular domain repeats. However, as described in the text, protocadherins with seven repeats have been isolated. The position of the variable and conserved protocadherin cytoplasmic sequences are shown. As described in the text, the conserved sequences are conserved between members of a protocadherin subfamily but not between members of different subfamilies. In the CNR protocadherins (a subset of the protocadherina subfamily) there is an R G D motif in t h e N-terminal cadherin repeat. This is not conserved between all protocadherins. Finally, i t is anticipated that more protocadherins will be identified and it remains t o be determined whether t h e y all conform to the protocadherin structure as shown here.
shorter and the HAV motif on the adhesive face of the N-terminal cadherin domain is not conserved. It is known that additional type 11 cadherins exist and it is anticipated that these will be cloned and further characterized in the near future. For example, full length cadherin-7 (GenBank AB035301), cadherin-9 (GenBank AB035302) and cadherin-10 (GenBank AF039747)’ have recently been isolated but as there are no functional data available on these molecules, they have not been given individual entries. Included in this book are three modified or other classical type cadherins; Hcadherin (T-cadherin, cadherin- 13), Ksp-cadherin (cadherin-16) and LI-cadherin (cadherin 17).H-Cadherin has not conserved the HAV motif but has retained a long propeptide sequence. However, the major difference between this cadherin and the type I/type 11 classic cadherins is that it does not have a cytoplasmic domain, rather it is held in the membrane via a glycosyl-phosphatidylinositol (GPI) anchor. Kspand LI-cadherin are the most diverged in that they have no propeptide sequence, the extracellular domain contains seven cadherin repeats, the HAV motif is not conserved and the cytoplasmic domain is much shorter. The desmosomal cadherins, the desmocollins and desmogleins, mediate adhesion in desmosomes, which are intercellular contacts that are linked on their cytoplasmic face to intermediate filaments&l1.The three desmocollins show overall homology to the classic type I cadherins with a long N-terminal propeptide sequence and five extracellular cadherin repeats. Unlike the type I cadherins, the adhesion recognition sequence is F/YAT/S rather than HAV. The three desmogleins differ from type I classic cadherins in having a short, approximately 29-amino-acid, propeptide sequence, only four cadherin repeat domains and a R/YAL rather than HAV adhesion motif. The intracellular domains of the desmogleins have diverged substantially from other cadherins and contain between two and six, 28-30-aminoacid, desmoglein repeat sequences. Although these desmoglein repeats are smaller, they show some homology to cadherin repeats. The cytoplasmic domains of desmosomal cadherins interact with intermediate filaments (keratin in skin and desmin in heart) via plakoglobin (y-catenin) and other desmosome-associated proteins, such as desmoplakins and plectin.
Protocadherins Structurally the protocadherins differ from the classic cadherins in that they do not have propeptide sequences and the extracellular domains contain more than five cadherin repeats (usually six or ~ e v e n ) ~ ~Recently J3. it has become clear that there are a very large number of protocadherins. This first became apparent with the identification of a family of approximately 20 murine genes in a screen for receptors coupled to the Fyn signalling pathway in the brainl4. These cadherins were named the CNR (cadherin-related neuronal receptor) cadherins. Examination of eight members of this subfamily revealed six extracellular cadherin repeats with conserved calcium binding sequences. Most notable about the structure was the presence in the N-terminal cadherin repeat of a conserved RGD motif and within the 220-230-amino-acid cytoplasmic domains, the presence of four PXXP motifs and the complete conservation of the C-terminal 153 amino acidsl4. The presence of these 3‘ identical sequences led to the suggestion that the CNR protocadherins might arise from the joining of diverse 5’ exons to a common set of 3’ exons. Support for this hypothesis has come from the identification of 52 human protocadherin genes arranged in three tandemly linked clusters in the 5q31 region
of chromosome 5. These three clusters have been named protocadherin (Pcdh)a, Pcdhp and Pcdhy with the Pcdha genes being the probable human orthologues of the murine CNR protocadherins. Strikingly, within each cluster there is a tandem array of large exons each of which encodes for the extracellular, transmembrane and membrane proximal cytoplasmic domain of the different protocadherins. To generate a functional protocadherin, one of the 'variable' 5' exons must be joined to the conserved C-terminal cytoplasmic domain portion which is encoded for by three 'constant' 3' exons. In this manner protocadherins with differing extracellular domains (and hence presumably differing binding specificity) and a common Cterminal cytoplasmic domain are generated in a manner that can be regarded as a simplified version of the generation of antibodies and T cell receptor~'~J~. Cytoplasmic domain components associated with the Pcdhp and Pcdhy gene products have not been identified but, given that there is no cytoplasmic domain conservation between the Pcdh protocadherin subfamilies, it is unlikely that the Pcdhp and Pcdhy receptors will associate with Fyn. It should be noted that these three gene clusters do not encode all of the protocadherins. Human protocadherins with a gene structure similar to that of the Pcdha, Pcdhp and Pcdhy protocadherins, have been identified. These include the Pcdh8 gene (chromosome 13)'7 and the Pcdhl2 gene (chromosome 5q31). In addition, protocadherins with different gene and predicted protein structures such as two homologues of the Drosophila fmi gene, hFlarningo1 (chromosome3)and hFlarningo2 (chromosome 22q13),'70 and a human homologue of the Drosophila fat gene (hFat2, chromosome 5q33) have been described. Although these latter protocadherins differ in their number of cadherin and transmembrane domains and the presence of additional extracellular domain motifs, they contain the typical protocadherin feature of a very large first exon encoding multiple cadherin domains170.
Ligands and regulation of ligand binding The characteristic feature of the classic cadherins is their ability to mediate Ca2+dependent homophilic adhesion with specificity being generated by sequence differences at the adhesive face of the N-terminal domain. As discussed above, structural studies combined with mutagenesis suggest that binding can be regulated by the cadherins switching between non-binding monomers and adhesive competent dimers in the plane of the membrane. However, this is probably not the only form of binding regulation and there is increasing evidence for a regulatory role both for the cytoplasmic domains and by the cis-association of the cadherins with other receptors18J9. It should be noted that although a robust ce1l:cell adhesive function has been demonstrated for the type I classic cadherins, a similar role for many of the other classic cadherins has yet to be demonstrated'o. In addition, the demonstration that E-cadherin can bind the a$, and azpl integrinszl,zzraises the possibility that other classic cadherins may have additional ligands. Less is known about the ligand binding properties of the protocadherins, however, despite the differences in extracellular domain organization, at least some of the protocadherins can mediate Caz+-dependent homophilic cell adhesion'2J38'3. In addition the CNR protocadherins contain an RGD motif in their N-terminal cadherin repeat, which is predicted to be located on a protruding loop thereby implicating this subclass of Pcdha protocadherins as counter-receptors for integrins on neighbouring cell~"f~~4.
..
1
Signal transduction As with the majority of adhesion molecules, there is evidence that the cadherins act in concert with signal transduction pathways to provide a coordinated regulation of cell behaviour and gene expression. In the case of the type I classic cadherins, this linking of signalling and adhesive function is particularly strong owing to the dual role of 6-catenin as both a structural component of the adhesive complexes and as a potent transcriptional cofactor. p-Catenin is a key component in the Wnt/wingless (Wg) pathway. In the absence of Wnt/Wg signalling, free cytoplasmic p-catenin is phosphorylated by the cytoplasmic enzyme glycogen synthase kinase 3p (GSK) and in its phosphorylated state is recognized by the ubiquitin-proteosome system and targeted for degradation. Activation of the Wnt/Wg pathways results in inhibition of GSK, accumulation of stable nonphosphorylated p-catenin, which is able to associate with the lymphoid enhancer binding factor (LEF)/T cell specific factor (TCF) transcription factor and activate gene e x p r e s s i ~ nThis ~ ~ ~pathway ~ ~ ~ . is conserved throughout evolution; however, it is now clear that it much more complex than the simplified scheme outlined here. For example, the interaction of GSK and p-catenin involves a number of other components, including the tumour suppressor gene product APC (adenomatous polyposis coli) and the scaffolding protein axin/conductin, and these play a key role in regulating p-catenin signalling. In addition, the relationship between pcatenin in the cadherin adhesive complexes and p-catenin as a signalling molecule has yet to be fully elucidated5~6~25~26. More recently, evidence has been accumulating that the cis-association of cadherins with growth factor receptors plays an important role in regulating N-cadherin-mediated neural outgrowth18#19.Whether similar growth factor receptor interactions are found in non-neural tissues with other classic cadherins has yet to be determined. Little is known about putative signal transduction pathways associated with the protocadherins except that at least a subclass of the protocadherins, the CNR cadherins, were identified on the basis of their interaction with the non-receptor tyrosine kinase, Fyn. The demonstration that subfamilies of Pcdha, p and y protocadherins contain a common 3’ cytoplasmic domain indicates that they will activate common signalling pathways, although it should be noted that differences in the membrane proximal portions of their cytoplasmic domains, and indeed in their transmembrane and extracellular domains, allows the possibility of individual protocadherins to activate individual pathways in addition to common pathwaysI”16.
Function The first identified cadherins, the type I classic cadherins, were characterized by their ability to mediate Cax+-dependent homophilic adhesion and by their differential cell type distribution. It is these features that underlie the ability of cadherins to regulate the cell type specific adhesion required for the arrangement and rearrangement of cells during morphogenesis27. At least in the case of Ecadherin, which is localized to the adherens junctions in epithelial cells, and the desmosomal cadherins, cadherins also play a crucial role in establishing the intercellular junctions5. The finding that desmocollins and desmogleins are linked to intermediate filaments in desmosomes suggests a functional role in maintaining tissue integrity at sites undergoing mechanical stress as would be found, for example, in the heart and skin. In addition, the discovery that components of the
type I classic cadherin adhesive complex have a signalling role in the cell suggests that these cadherins function as more than just molecular glue, and that they also serve to regulate cel1:cell interactions and provide information to the cell as to its extracellular milieu. Currently the most exciting development in cadherin research is the recent demonstration of the large subfamilies of protocadherins. The unique genomic arrangement of these protocadherins, which allows variable extracellular domains to be joined to a constant cytoplasmic domain portion suggests a mechanism for tightly controlling cel1:cell interactions by cell-specific expression of adhesion molecules which would activate a common signalling pathway. Consequently it has been speculated that protocadherins may provide the molecule code for specifying neuronal connections in the brain. Whether this is indeed a physiological function of protocadherins, and whether they have additional roles both in neural and non-neural tissues remains to be determined.
IMMUNOGLOBULIN SUPERFAMILY Introduction The immunoglobulin superfamily (IgSF)represents a large group of proteins with the common feature that they all contain one or more extracellular Ig domains. All cells in the body express such molecules and in leucocytes, where the cell surface proteins have been most thoroughly characterized, 34% of the transmembrane and membrane-associated proteins are IgSF members. However, it should be noted that not all IgSF members function as adhesion molecules and therefore the leucocyte IgSF molecules given entries in this book only represent a subset of those found in The Leucocyte Antigen FactsBook.z8
Structure General Ig domains are 70-110 amino acids in length with a distinct overall structure referred to as the Ig fold. This fold consists of two p sheets each made up of short antiparallel p strands. In the majority of Ig domains, the two p sheets are joined by a disulphide linkage. Sequence and structural comparisons have shown that there is highest conservation in the in-pointing p sheet residues, i.e. those that are packed face:face and variation at the out-pointing p sheet residues and the loops that connect the p strands. Originally Ig domains were characterized as V-type or C-type based on features shared in common with the Ig and T cell receptor Vdomains and the Ig, T cell receptor and major histocompatibility complex (MHC) C-domains, respectively. In V-type domains the two p sheets are made up of three and four p strands (the ABED and GFC strands), and lying between these sheets are the C’ and C” additional strands. These two additional strands are missing in the C-type domains. Subsequently, sequence and structural analysis of more IgSF members revealed a group of domains which were similar to C-type domains but with some sequence patterns found in V-type domains. This new group are referred to as C2 domains, and are characterized by the lack of the D strand but the presence of the C’ strand. The original C-type domains, which contain only the ABED and GFC strands, have been renamed C1 domain^^^,^^. Further structural
analysis has demonstrated that the C2-type domains in fact represent two distinct sets, which have been termed C2 and I domain^^^,^^. However, as structural information is not available for many of the IgSF members described in this book, the term C2 will be used here for both C2 and I domains. As discussed under ‘Cadherins’, structural analysis of cadherin domains gave the surprising finding that, despite no sequence similarity, these repeats showed an overall structural arrangement similar to that found in the Ig domains, particularly I-type members of the C2 domains. It has been proposed that this similarly results from convergent evolution owing to the favourable stability of protein folds generated by two p sheets3’. In support of this theory is the fact that similar arrangements are found in other protein domains. For example, fibronectin type I11 (Fn3) repeat^,^^,^^ such as those found in the IgSF members L1 and NCAM (see individual entries), again have a fold generated by two p As illustrated by the entries in this book, the number of Ig domains within the IgSF members is variable and, in addition, it should be noted that many IgSF members also contain non-Ig domains. The only common features are that, with the exception of CD147, in molecules with V-type domains, these domains are N-terminal to the C2type domains and the Ig domains are N-terminal to non-Ig domains.
Subfamilies The IgSF can be grouped into subfamilies but in many cases this represents an artificial grouping as individual molecules can belong to more than one subfamily. For example, the five ICAMs can be grouped together on the basis of sequence similarity and their ability to bind integrins. However, VCAM, MAdCAM-1 and CD31, which are not closely related to the ICAMs, have functional overlap in that they also act as integrin counter-receptors. Consequently we have not divided the IgSF entries into subgroups but a few relevant issues will be discussed here.
Siglecs The siglecs are functionally characterized by their ability to bind sialic acid. The now agreed nomenclature of this group of molecules is sialoadhesin (siglec-1), CD22 (siglec-2), CD33 (siglec-3),MAG ( myelin-associated glycoprotein; siglec-4a) and SMP (Schwann cell myelin protein; sigle~-4b).3~ All the siglecs are transmembrane proteins with extracellular domains consisting of an unusual Nterminal V-type Ig domain followed by a variable number of C2-type domains. It is now clear that these five molecules do not represent the full siglec subfamily. Cloning of siglec-51~~, ~iglec-63~, ~ i g l e c - and 7 ~ ~~ i g l e c - has 8 ~ ~recently ~ been reported, and it is likely that other siglecs will be identified.
Neural IgSF members In this book individual entries are included for the following IgSF members found in neural tissues: ALCAM, contactin-1, ICAM-5, MAG, L1, NCAM, P(0)and TAG1. This discussion will concentrate on contactin-1, L1, NCAM and TAG-1. NCAM and L1 are type I transmembrane adhesion molecules whereas contactin-1 and TAG-1 are GPI anchored. One of the difficulties in classifying these four molecules is that, over the past decade, a large number of related molecules have been cloned from different species and consequently there is some controversy as to whether different molecules are species orthologues of each other or different
subfamily members. In general it is agreed that NCAM is the mammalian orthologue of Drosophila fasciclin 11. TAG-1, originally cloned in mice, is the product of the human TAX-1 gene and is the orthologue of chicken axonin-1. Human contactin-1 is the orthologue of rodent F3 and chicken F1 1. The situation for L1 is more controversial. L1 (previously known as NILE) shows sequence similarity to two chicken adhesion molecules, NgCAM and NrCAM. NgCAM is considered to be a probable L1 orthologue, whereas NrCAM together with the murine CHLl (close homologue of L1) and neurofascin are regarded as vertebrate L1 family members. It has yet to be determined whether Drosophila neuroglian and leech tractin represent invertebrate orthologues or other L1 family members41. The second area of controversy is in the ligands for these four molecules and this will be discussed below. Finally, there is an increasing number of other IgSF molecule that are predicted to function as neural adhesion molecules. Owing to the limited functional data on these molecules or their ligands, or the fact that they have only been characterized in invertebrates, they have not been given individual entries in this book. Of particular note are DCC (deleted in colorectal carcinoma; SwissProt P43 146; OMIM 120470),which is probably the mammalian orthologue of Drosophila frazzled and Caenorhabditis elegans Unc40 genes, and the DCC-related protein neogenin (OMIM 601907).It is now well established that DCC and neogenin are structurally related type I transmembrane proteins which bind to members of the netrin family. Netrins play a key role in axon guidance but, as they are secreted molecules, they and their receptors have not been included in this book. However, it is likely that the netrins are in some way tethered to the extracellular matrix and it remains to be determined whether binding of the netrins to their receptors represents an ‘adhesive’ interaction42.
Ligands and signal transduction Unlike the cadherins, which essentially mediate homophilic interactions via the antiparallel binding of the N-terminal cadherin repeats with the equivalent domain on neighbouring cells, the IgSF members show a broad range of ligand interactions. These include integrins (e.8. ICAMs), sialic acid (members of the siglec subfamily), extracellular matrix components (e.g. contactin- 1) and homophilic interactions (e.g. CD31, P(O), CEACAM family). In some cases, more than one ligand has been identified. For example, in addition to binding integrins, ICAMs act as receptors for various viruses and parasites, CD31 can also mediate homophilic interactions and MAdCAM additionally binds L-selectin. The IgSF ligands are discussed in the individual entries. However, of particular interest in the past few years has been the lessons learnt from the neural IgSF members. One of the curiosities in this field was how molecules such as TAG-1 and contactin might mediate adhesive interactions when they are linked to the membrane via GPI anchors. Some clues as the mechanisms operating have come from the demonstration that these GPI-anchored molecules can associate in the plane of the membrane with other neural IgSF members. For example, both contactin and TAG-1 bind in cis to L1 family members. Furthermore, both L1 and NCAM can interact in cis with each other and growth factor receptors. Importantly these different interactions can modulate ligand binding and downstream signal transduction path~ays4~,43-45. It has yet to be determined whether similar cis interactions regulate non-neural IgSF members.
INTEGRINS Cell adhesion molecules of focal adhesion contacts Integrins are so called because they ‘integrate’ the extracellular matrix with the intracellular cytoskeleton46 and hence deliver ‘outside-in’signals from the external environment to the cell to modify cellular structure and functions: cell adhesion, motility, proliferation, apoptosis, induction of gene transcription and differentiation. To achieve this, integrins are recruited into complex structures, focal adhesion contacts (or related structures at cel1:cell contacts, which can involve integrins interacting with counter-receptors, such as a&, and alp1with Ecadherin - see entries). The function of the integrin receptor is itself modulated by signals from within the cell delivered via other receptor systems (‘inside-out’ signalling) through complex cytoskeletal interactions with their cytoplasmic tail+@. The intracellular proteins that interact with integrins at focal adhesion contacts5@52include cytoslteletal elements and link proteins, such as a-actinin, talin and paxillin, and associated non-receptor tyrosine kinases as c-Src and focal adhesion kinase (FAK). Other transmembrane proteins (e.g. syndecan-4 and dystroglycan; see individual entries) and cell junction-specific components (such as dystrophin in neuromuscular junctions; see dystroglycan entry) are also concentrated in these adhesion c0mplexes5~.
Integrin structure A wide range of other proteins have been shown from biochemical, immunological and cDNA and genomic cloning approaches in a large number of species from all phyla53254 to be structurally and functionally related. The original integrin family (also called gpIIbIIIa, included the a and p subunits of platelet glycoprotein aIIbP3 which shares its p3 chain with the a,& vitronectin receptor), the PI matrix receptors and the leucocyte a L (LFA-l),aM (Mac-1) and ax (p150/95) molecules, which share a common p? chain. Seventeen a and 8 p chains have now been characterized. We have excluded those ‘integrins’ that have been only defined as EST sequences or which exist only in non-mammalian species. An additional collagen-binding integrin alpha chain, a1 1540J4b, has recently been cloned. Integrins are heterodimers and form 23 a p associations as shown in Fig. 2. Some chains associate widely (e.g. the p1 and av subunits having several partners) whereas Additional complexity is generated others show no promiscuity (e.g. a#,, by several subunits undergoing mRNA splicing55;some of these isoforms differ in their tissue distribution, developmental regulation and ligand binding specificity. Biochemical, molecular and physical analyses have revealed the protein structure of the subunits (see Fig. 3). The a and p subunits are both transmembrane, N-glycosylated glycoproteins with large extracellular domains, a single hydrophobic transmembrane region, and short cytoplasmic domain, apart from p4. Rotary shadowing electron microscopy of a number of purified integrin receptors has revealed that they are extended structures of - 10 x 20 nm, with an N-terminal globular ’head’, formed by the association of the two subunits, linked to the membrane by two extended ‘rod’ structure^^^. a Subunits are between 120 and 180 kDa and comprise a large N-terminal extracellular domain, a 20-30 amino acid transmembrane region and a short,
Figure 2 The integrin family i s composed o f a series o f alp dimers. The various combinations that have been observed are illustrated. Thus, for example, PI chains are associated with a large number o f a chains, whereas a,,, only combines with p,. Proteolyltc cleavage s~tes a4a9 c r 3 ~ . 5 1 ~ 6 ( r 7 c r 8 a I l b n v
Homo!ogous repeats t
4
Divalent cation binding domains 4
I[ [!I 1Y Y YI VII
1
-
I 1.
t
h
r RI
Subunit A
i
_J
Ls-s\
\ l dorna~n
a1 a2 a10 orE crL nM n X nD Signal sequence
+
L~gand-bmd~ng Extracellular doma~n 'Omarn
\ -
Transmembrane domaln
Cysteine-rich domains
r
Cytoplasmic domaln
.
r
p Subunit
Figure 3 Integrin subunit structures. The general features of an integrin heterodimer are shown. In addition, RNA splice variants exist (see text) that modify the structure o f integrin subunits a,, a,, aIIt,and P, i n their extracellular domains, and the cytoplasmic tails o f a,, a,, a,, P,, P, and P,. The cytoplasmic tail of the p chain is shown as an 'average' for all p subunits except p,, which has a unique, approximate 1000 amino acid long, intracellular extension (see entry for integrin P,) Glycosylation sites vary between individual integrins and are omitted.
usually hydrophilic, cytoplasmic tail. All a chains contain seven homologous, approximately 60 amino acids long, tandem repeat sequences; the C-proximal three or four contain putative divalent cation binding sites, which are critical in ligand binding and subunit association. Some integrin a chains contain an inserted, or ‘I,, domain of -200 amino acids between the second and third repeats. These include the four a subunit partners of the p2 integrins and a l , a2,a I oand aE.The I domain has sequence homology with several molecules, including cartilage matrix protein, type VI collagen and the von Willebrand factor ‘A‘ domains7, all of which can all interact with collagen, and is involved in ligand bindings8. The a l p l and a2P1integrins have been shown to be collagen receptors; however, none of the pz heterodimers bind collagen suggesting that the I domain here has other roles. The other a subunits, without I domains, are post-translationally cleaved near to the transmembrane domain, the resultant fragments being disuphide bonded. The a4 and a8 subunits are, however, cleaved within the middle of the chain into two non-disulphide bonded components; the different forms of the a4pI dimer have altered ligand binding (see entry for ad).The cytoplasmic domains of the a subunits show little sequence similarity with the exception of the conserved amino-acid motif GFFKR, which is involved in the transmission of signals into the cell, possibly via its ability to bind calretic~lin4~49+Q. The p subunits are usually smaller than a subunits and are between 90-1 10 kDa, apart from the 210 kDa p4 chain. The C-terminal halves of all p subunits have a high cysteine content (e.g. 56 in the p3 chain), grouped into four, 40 amino acid cysteine-rich regions, which are internally disulphide bonded. The cytoplasmic tails are usually short (40-50 amino acids), although the p4is unique with a 1018 amino acid long cytoplasmic domain, which contains four fibronectin type 111 repeats. A three amino acid sequence (TTT)is found within the cytoplasmic tail of several p subunits and in a& it is essential for ligand binding. Further functional domains have been defined4749#sz, frequently by mutational analysis. These include the binding site for a-actinin in the cytoplasmic tail of PI which mediates linkage between the integrin and actin cytoskeleton and focal contact localization sequences in (via the ’Cyto-1’ motif - REFAKFAKEK - and other sequences). More globally, integrin cytoplasmic tails are key to the establishment of the twoway linkage between the ‘outside-in’ and ‘inside-out‘ signal transduction processes; however, conserved linear amino-acid sequence motifs that mediate the signalling processes have not been identifiedsq-64.
Three-dimensionalmodels of integrins Various structural models for integrin a-subunit domains have been proposed based upon sequence modelling of the ct and p chains, and the solution of the crystal structure of several examples of ‘I’ domains65-68. To date, studies have been insufficient to take account of the impact of the known effects of cation and ligand binding upon protein con for ma ti or^^^.^^-^^; this will have to await analysis of the integrin dimer in its membrane environment when this becomes technically feasible. The seven-fold repeats seen in the N-terminal extracellular part of all the a chains of integrins have been predicted to take up a radial arrangement, giving a ‘ppropellar fold’72. Divalent cation-binding domains, containing the consensus
sequence DXD/NXDGXXD (which is similar to the EF-hand loop structure of calmodulin) are found within the C-proximal three to four repeats (numbers IV, V, VI and VII); different binding locations are predicted for calcium and magnesium ions, the latter being positioned such that it can co-ordinate with a donated negative charge (Glu or Asp) from a bound protein ligand72-74. The crystal structures of several ’I’ domains have now been solved (aL, aM, a l , a2; see individual entries J with different protein conformations observed in the presence of co-crystallized divalent cations. The I domain also contains a divalent cation binding site (metal ion-dependent adhesion site or ‘MIDAS’), which has homology to the dinucleotide-binding (Rossmann) fold first identified in lactic dehydrogenase. It consists of a conserved DxSxS motif together with distally placed Thr and Asp residues; this leaves one metal coordination site free and this is proposed to be involved in ligand binding, possibly by accepting the acidic LDV sequence ligand motif75. Finally, an analysis of the p chain has been performed using the conserved DxSxS motif seen in the a chain as a probe sequence. An ’I domain-like’ structure has been identified at its N-terminus and this is suggested to serve similar cationand ligand-binding f u n ~ t i o n s ~ 6 , ~ ~ .
Alternative forms of integrins - RNA splice variants An increasing number of RNA splice variants of both integrin subunits are being identifiedS5; these increase further the structural diversity of integrins and thus their functional complexity. Alternate extracellular domains have been identified for two p, integrins, a6 and a7, and (YIlh. a6 and a7 isoforms are created by mutually exclusive utilization of alternative exons between the N-terminal repeats I11 and IV, whereas variation in the light chain of a I [ h is due to variable exon splicing. A truncated, soluble 60 kDa form of p3with a unique C-terminus is due to use of a cryptic donor splice site. Alternate forms of cytoplasmic tails also exist for both a and p integrin subunits. Variable C-termini have been described for a?, a6 and a7, and there is good evidence for variation in tissue distribution and regulation in embryonic development for the a6 and a7 isoforms (see entries). Likewise, several forms of p, (five isoforms), p3 and pi have been identified. Again there is clear evidence for functional importance in such variation; only the subunit is localized in focal adhesion contacts, and the p,C variant has altered adhesion properties (see entries).
Integrin ligand specificity Physicochemical analysis of integrins in conjunction with cross-linking studies with radioactively labelled RGD and other peptide probes has revealed that the ligand binding site of the functional integrin heterodimer resides in its globular head and includes the cation-binding region of the a subunit and the N-terminal portion of the p subunit78.Other studies have shown that the I domain of the a chains of pz i n t e g r i n ~ and ~ ~ , its homologous region in the N-terminal part of the p chain, also are invloved in interaction with ligands. Thus, ligand binding by integrins, and hence their specificity, is likely to depend on the particular ap subunit combination utilized. However, the influence of receptor activation via conformational changes following signalling cannot be underestimated, for
example, p2 and pi integrins generally require activation before they can recognize ligand, whereas PI receptors are usually constitutively acti~ated66.6~-~~. In the main, integrins act as cell surface receptors for ECM proteins; the range of ligands recognized by individual integrin dimers are given in the individual molecule entries. Some integrins are promiscous and can bind a number of ligands (e.g. a& can recognize vitronectin, fibrinogen, fibronectin, denatured collagen and other proteins], whereas others show a more restricted binding pattern (e.g. a5pI and alp,). Conversely, several ECM proteins are recognized by a number of different integrin receptors. Thus, laminin is bound by alpl, a,pI, a3p1,a&,, a7Pl, a& and asp4. Added complexity is produced by different integrins recognizing different regions of the same molecule (e.g. avp3 and aIlbP3bind distinct sites on fibrinogen79)and splice variants (e.g. p3, a3 and a6)show differing ligand affinities. Integrins can also serve as cel1:cell adhesion molecules by recognizing counterreceptors on other cells, for example, a4p, for VCAM-1, the p2 integrins with ICAMs and E-cadherin for some PI integrins. The recognition of microbial coat proteins by the p2 subfamily probably reflects ancestral functions of the integrin genes together with molecular mimicry and selection by prokaryotic pathogens. Important insights into the interaction between integrins and their ligands will come from an understanding of the three-dimensional structure of recognition sequences in ligands, in addition to knowledge of binding pockets of the integrins themselves (as discussed above). Thus, the structure of RGD sequence containing fibronectin type 111 repeats (FNIII)from fibronectin and tenascin have been solved. The RGD tripeptide is presented at the end of a flexible loop8b8z, whereas the binding surface for the IgSF ligand ICAM-283-85 is flat, lacking the protruding loop seen with VCAM-1.
Integrin-associatedproteins Integrins are associated with intracellular and cell surface molecules, ’integrinassociated protein~’~6387. Early observations were that the platelet integrin aI& interacted with CD9, a tetraspan family member (TM4SFIs8, and CD47 with p3 integrin~~~. The cytoplasmic tails of integrins have been shown to interact directly both with general intracellular signalling proteins (e.g. PI3 ltinase) and also with those exhibiting specific integrin-linked functions - integrin-linked kinase (ILK), focal adhesion kinase (FAK),pi endonexin and ICAP- 159-644,90. There is also an ever-expanding list of membrane proteins that have been shown to associate directly with integrins at the cell s ~ r f a c e ~ These ~ J ~ . modify the activation status of integrins, and hence their adhesive functions, and also participate in integrin-mediated signal transduction by activating a different set of signalling molecules (e.g. activation of PI4 kinase via TM4SF proteins] to those associated with cytoslteletal proteins (eg. FAK and MAP kinases in association with the actin cytoskeleton). These associations include: PI integrins (a3,ad, a6), and a4p7interacting with members of the TM4SF (including CD9, CD53, CD63, CD81, CD151); avp3 with growth factor receptors; and CD87/urokinase type plasminogen activator receptor (uPAR)with p2 and some PI integrins (details of the cited C D molecules not found in this FactsBook can be found in The Leucocyte Antigen FactsBook”). Finally, there is also evidence supporting the functional interaction between
CD147 (see individual entry for details) and some PI integrins ( a , and a 6 ) 9 2 , between aI&, and CD36 (see entry)Y3,and between CD98 (see entry) and PI integrins94. Some integrins interact with IgSF proteins. This has been best characterized between P3 integrins and CD47, an ubiquitous hybrid protein predicted to have five transmembrane domains and a single extracellular Ig domains’. It modifies avPi integrin adhesive function in some cell-types and directly transmits signals via G proteins; recent evidence suggests that it may also bind thrombospondin directly’5.
Integrin peptide recognition motifs and the clinical use of integrin antagonists The first integrin binding site defined was the Arg-Gly-Asp (RGD) sequence96, identified as the minimal binding site in fibronectin capable of supporting cell adhesion’’ (summarized in Table 1). Several hundred RGD sequences exist in protein and DNA databases; the majority of extracellular matrix proteins isolated to date seem to contain RGD or homologous sequences, although only a minority have been shown to be biologically active and many are so only after ‘denaturation’. Progressive truncation and mutation of parent matrix molecules, and adhesion inhibition and competition studies with various synthetic peptides, have confirmed that many integrins recognize the RGD motif in their ligands. Further well-characterized motifs include the [HHLGGAIKQAGDV from and the LDV sequence from fibronectin (for a4P1)(Table 1). fibrinogen (for Identification of these peptide sequences has formed the basis for the development of adhesion-based therapeutics for use in a wide range of clinical indications and some of these are mentioned in the individual molecule entries. and a4P1in, for example, These include modification of the function of a,P,, aIl,,P3 osteoporosis, vascular disorders, cancer, transplant rejection, autoimmune disorders and infection, by the use of modified peptides, non-peptidic chemicals and function-blocking antireceptor antibodie~~~8-~~~~*04~~104b,104c.
Table 1. Some well-characterized peptide recognition sequences identified for in tegrins RGD
KQAGDV
LDV, REDV
KRLDGS
DGEA, RKK
SELECTINS Introduction The three selectins, E-selectin (CD62E), L-selectin (CD62L) and P-selectin (CD62P), are related both structurally and functionally. They have been extensively studied due to their role in the inflammatory response and their potential use as therapeutic targets. These three molecules have been the subject of recent reviews1~5-~~~, which should be consulted for greater detail.
Structure All three selectins are type I transmembrane proteins with an N-terminal C-type lectin domain followed by an EGF repeat and a variable number of complement control protein (CCP) domains. The human E-selectin, L-selectin and P-selectin have six, two and nine CCP domains, respectively. However, the number of CCP domains in E- and P-selectin varies from four to six and from six to nine, respectively, in other species. The C-type lectin domain is so called because it requires Ca2+ to bind carbohydrate'07J09 and it is this domain in the selectins which mediates ligand binding. Within the C-type lectin domain, all three selectins contain four correctly spaced cysteine residues required for nested disulphide bond formation, key residues for Ca2+ binding and other conserved residues necessary for packing of the hydrophobic core109J10.Structural analysis of this domain from L-selectin, togcther with the structural analysis of other C-type lectin domains engineered to introduce selectin-ligand interactions, has identified residues involved in cation coordination and oligosaccharide binding106J1'.EGF domains"' are found in a wide variety of proteins and are characterized by the presence of two antiparallel p strands with connecting loops. X-ray crystallography has shown that the EGF domain in E-selectin has a similar structure to EGF domains found in other The precise role of this domain in the functioning of selectins is not known but certainly it is necessary as its deletion results in loss of E-selectin-mediated adhesion"3. Most probably, the EGF domain is required as part of the selectin binding site by interacting with protein components on the ligand and/or for the correct spacing or orientation of the C-type lectin domain. CCP domains are so named because they are commonly found in proteins that control the complement cascade. By NMR analysis of the complement control protein Factor H, CCP domains have been shown to consist of two segments of antiparallel p sheet and a short triple-stranded p sheet"4. The function of the selectin CCP domains is not known but it has been speculated that they may optimize the interaction with ligand by extending the C-type lectin/EGF domains away from the cell membrane and increasing the flexibility of the molecule.
Ligands and regulation of ligand binding Selectins, as their names indicate, bind carbohydrates with all three selectins binding to the tetrasaccharide sialyl-Lewisx ( sLex)and its stereoisomer, sLe*, in which the positions of the linkages of fucose and galactose are exchanged. In
addition, both E- and P-selectin can bind sulpho-LeX and sulpho-LeA and Lselectin binds with high efficiency to sulphated sLeXepitopes in which additional sulphate residues are attached to the galactose and N-acetylglucosamine residues (Fig. 4). In all cases these ligands contain fucosylated core trisaccharides with a negative charge due to the addition of a sialic acid or sulphate residuejs), and are generally found at the termini of 0-linked sugars (Fig. 4f07,108). To date the main identified physiological selectin ligands are as follows: E-selectin, which is predominantly expressed on endothelial cells can bind ESL-1, PSGL-1, and L-selectin on leucocytes. P-selectin expressed on endothelial cells is more restricted in its interaction, showing a preference for leucocyte PSGL-1 as a ligand. Leucocyte L-selectin in turn recognizes three main endothelial cell ligands, GlyCAM- 1, CD34 and MAdCAM- 1 and leucocyte PSGL-1 (see individual entries for details). It should be noted that although these represent the bestcharacterized selectin ligands, a number of other glycoprotein and glycolipid ligands have been identified. The identification of selectin ligands raises the issue as to how binding selectivity is achieved. For example, PSGL-1, which by a variety of criteria represents the major leucocyte P-selectin ligand in vivo, carries less than 1% of the cell surface sLex. It is now clear that the molecules on which the carbohydrate is presented, other modifications to the carbohydrate ligand and to the core protein, and the cell type in which the ligand is expressed all play an important role in determining selectin-ligand interactions. The biochemical nature of the selectin ligands has been extensively reviewed elsewheref08 and will not be further discussed here.
Function Both in vivo and in vitro studies have clearly established that selectins play an important role in mediating the rolling of leucocytes on endothelium and that this is a necessary component of leucocyte extravasation during recirculation and entry into inflamed t i s s u e ~ ~ ~Leucocyte ~ - ” ~ . extravasation requires multiple molecular interactions and it is the function of the selectins to provide their initial tethering to the endothelial wall. As the leucocytes are under flow, this tethering causes them to roll along the endothelium, which allows them to sense their local environment. This in turn leads to activation of the leucocyte integrins, which then mediate firm adhesion and subsequent extravasation. Previously it was thought that this integrin activation was mediated by chemokines released from the endothelium; however, there is increasing evidence that the selectins and their ligands are an additional important component in this event. In the case of the leucocyte selectin, L-selectin, its interaction with GlyCAM-1 has been demonstrated to result in the activation of the p2 leucocyte integrinff9.The mechanism by which this is achieved is less clear. Although the cytoplasmic domain of L-selectin is very short, this domain is required for leucocyte rolling”0. Ligation of L-selectin stimulates a signalling cascade via the non-receptor tyrosine kinase p56Ick, which results in the activation of mitogen-activated protein kinase (MAPKfzfJzz).It has yet to be determined whether this signalling pathway is directly responsible for p2 integrin activation and how L-selectin might interact with p56lCk.In the case of P-selectin and its ligand PSGL-1, it is PSGL-1 on leucocytes which can activate the integrins. Again the mechanism by which this occurs is not clear. In
mouse neutrophils there is evidence that this process is direct and does not require co-stimulatory components123, but, in human neutrophils, ligation of PSGL- 1 alone is not sufficient for integrin activation. The selectin-mediated signal transduction pathways have been reviewed recentlylo6 and will not be discussed further here.
NeuAc
NeuAc
a2
a2
k 3
‘u3
Fuc
Gal P1
Gal Pl
i Jal 4
Fuc
Jal
i
3
3
GlcNAc
4
GlcNAc I
3’-sialyl-LewisA
3’-sialyl-LewisX
so4 \ 3
\ 3
Gal P1
Fuc
Gal Pl
JU1
\ 4
Fuc
Jal
\ 3
3
4
GlcNAc
GlcNAc
I
I
3’-sulpho-LewisA
3’-sulpho-LewisX
NeuAc
NeuAc
a2
a2
i
3
Gal Pl
io4 Fuc
Jal
‘u
4 ‘ 3
GlcNAc I 6’-sulpho-3’-sialyl-LewisX
4
3
GlcNAc I 6’-sulpho-3’-sialyl-LewisA
Figure 4 Oligosaccharide ligands for the selectins. Structure of the core trisaccharide ligands for the selectins (Fuc, fucose; Gal, galactose; GlcNAc, N acetylglucosamine; NeuAc, N-acetylneuraminic acid).
SYNDECANS Introduction The syndecans are a group of heparan sulphate proteoglycans that participate in a range of cellular events including cellular signalling, cel1:matrix and cel1:cell adhesion.
Structure and ligand binding Syndecans are all type I transmembrane molecules with the characteristic feature that all four family members are modified by the addition of heparan sulphate glycosaminoglycan (GAG) chainsfz4.This modification occurs in the Golgi apparatus when a linkage tetrasaccharide is added to a serine residue which is N-terminal to a glycine (Fig. 5). The majority of syndecan Ser-Gly sequences that are heparan sulphate modified are surrounded by regions that contain acidic residues and are devoid of basic amino acids. In addition, many of the sites reside in Ser-Gly repeatszz5.An N-acetylglucosamine (GlcNAc) is then added to the tetrasaccharide and heparan sulphate chain elongation proceeds by the sequential addition of alternating glucuronic acid and GlcNAc sugars (Fig. 5). Importantly, some of the sugars are then further modified. First individual GlcNAc residues are N-deactylated and N-sulphated, then adjacent glucuronic acid residues are epimerized to form iduronic acid and finally 0-sulphation occurs at various sites. These thrcc reactions are carried out sequentially and result in blocks of modified sugars within the GAG chain that are required for high-affinity binding of ligands (see below). In addition to heparan sulphate, syndecan-1 also contains chondroitin sulphate chains, which are added to the membrane proximal GAG acceptor sitesfz6. Although syndecan-4 can be modified by chondroitin sulphate, the attachment sites are the same as those for heparan sulphate and, in the majority of cells, heparan sulphate is the dominant GAGzz7.At least for syndecan-1, the extent and type of GAG modification is dependent on cell typefz8 and this variability almost certainly has functional consequences. It should be noted that syndecans are not the only GAG-modified
[GlcNAc * GlcUA]
n>50
heparan sulphate repeats
Xyl-
+
GlcUA * Gal
--
linker
Gal
Xyl
I
Ser
+
I GlY
Figure 5 Heparan sulphate modification of syndecans. Linkage of heparan sulphate to core syndecan protein occurs via a tetrasaccharide linker, GlcUA-GalGal-Xyl. In the Golgi apparatus, the heparan sulphate sugars are further modified as described in the text. (Gal, galactose; GlcNAc, N-acetylglucosamine; GlcUA, glucuronic acid; Xyl, xylose).
1
adhesion molecules, and the modification of CD44 and dystroglycan (see individual entries) by heparan and chondroitin sulphate occurs in a similar manner as described here. Syndecans have been reported to bind a wide variety of different ligands. As these have recently been extensively reviewed124, they will only be briefly summarized here. Key to the functioning of syndecans is their ability to bind extracellular ligands via their heparan sulphate chains and to date a very large number of heparan sulphate-binding proteins have been identified. These include polypeptide growth factors, enzymes, extracellular matrix proteins, cell adhesion molecules, lipid-binding proteins, blood coagulation factors, viruses and toxins. Given the array of potential ligands, it is important to consider how binding specificity might be generated. Clearly, there are cell-type-specific modifications of the heparan sulphate chains in terms of the extent and positioning of the 0sulphation. Thus, the number and type of GAG chains decorating the syndecans can vary. These differences can modulate both ligand specificity and binding efficiency. Apart from the sites required for heparan sulphate addition, the extracellular domains of the syndecans show little sequence similarity. This is in contrast to their transmembrane and cytoplasmic domains, which are highly conserved both between family members and between syndecans isolated from mammals, chicken, Xenopus, Drosophila and C. e l e g a n ~ ~ ~ ! ’ -Examination ~3~. of the cytoplasmic domains show two regions of exact conservation, termed conserved regions 1 and 2 (C1 and C2) separated by a variable (V)region.
Signal transduction Given the high conservation in the cytoplasmic domains of all syndecans, it is unsurprising that they have a common function in mediating the association of syndecans with the cytoskeleton and downstream signal transduction pathways124J30-’32. The sequence of the C-terminal C2 domain of syndecans predicts that is will act as a binding site for proteins with type I1 PDZ domains. Recently, association of two such proteins, syntenin and CASK, has been d e m o n ~ t r a t e d l ~CASK ~ ~ ~ ~additionally . contains a binding site for band 4.1 proteins134,which include the ERM (ezrin, radixin, moesin) subfamily and these proteins are known to act as membrane:cytoskeletal linkers by interacting between transmembrane proteins and the actin cytoskeleton. Consequently, the association of such PDZ-containing proteins with the syndecans potentially provides a mechanism for linkage to the cytoskeleton, the recruitment of signalling components and, given the demonstrated interaction of ERM proteins with CD44 and ICAM-2 (see individual entries), the clustering with other adhesion molecules. Less information is available on the role of the conserved membrane proximal C1 domain, although peptides from this region can compete with the ability of syndecan-3 to associate with both signalling and structural components, such as Src, Fyn, cortactin and tubulin136. Unlike the other family members, the V region in the syndecan-4 cytoplasmic domain can bind activated protein kinase C a (PKCa)and PIP,137J38.By definition, the V domain in syndecan-4 is not conserved in other family members. It will therefore be of interest to determine whether
the other syndecans bind unique cytoplasmic components to mediate individual functions.
Function As described above, the syndecan ligands include a wide array of heparan sulphatebinding proteins. The role of syndecans in binding to growth factors has been extensively studied and it is generally accepted the syndecans themselves do not act as growth factor receptors. Rather they are regarded as co-receptors and thus may play a variety of overlapping roles. First, they may sequester growth factors at the cell surface, thereby increasing their local concentration or bringing them into closer proximity to their signalling receptors. Second, binding to heparan sulphate can change the conformation of the growth factors which increases their affinity for their receptors. Finally, this interaction can promote ligand oligomerization which enhances the activation of the receptor~"~.Of particular interest with respect to this FactsBook is the role of syndecans in mediating cell adhesion. Cel1:matrix adhesion is primarily mediated by the binding of integrins to extracellular matrix (ECM)components. However, many of these ECM molecules additionally bind heparan sulphate proteoglycans. In the case of fibronectin, it has been demonstrated that both integrin and heparan sulphate binding is required for cell adhesion'39 and cells which cannot synthesize heparan sulphate cannot form focal adhesionsl40. Owing to its widespread distribution and localization to focal adhesions, it has been proposed that syndecan-4 may play a role in the formation of these adhesive complexes'40o,possibly via its ability to recruit protein kinase C. In addition there is increasing evidence that other syndecan family members may have cell-type-specific roles both in cel1:matrix and cel1:cell adhesion124,130-'32. In conclusion, syndecans appear to function as co-receptors both in growth factor signalling and in cell adhesion. It will be of interest to determine the molecular mechanisms that regulate these two functions and how interactions between these dual roles may act to co-ordinate cellular responses.
OTHER MOLECULES
Introduction The 'other molecules' section contains a heterogeneous group of molecules that cannot be grouped solely by structural homology or by functional characteristics. The common factor connecting them is that there is good evidence for involvement in cell adhesion. Thus, we have included three enzymes with additional adhesive functions (AMOG, CD39, VAP-1), several ligands for the selectins not included elsewhere JESL-1, GlyCAM-1, HSA, PSGL-1), two hyaluronan receptors (CD44 and L W E - 1), two scavenger receptors (CD6, CD36), four leucine-rich repeat domain containing proteins of the CD42 family, two lectins (CD23, galectin-3),six mucins JCD34, CD43, CD164, GlyCAM-1, PCLP1, PSGL-1) and three unclassified molecules (CD57, CD98, E48). We have also included entries for integral membrane proteins (claudins, occludin) associated
with epithelial and endothelial 'tight junctions', and dystroglycan, a protein which was orignally found at neuromuscular junctions but which appears to have much broader adhesive functions. Clearly the 'other molecules' formed the most difficult section to compose in that the only selection criterion used was evidence for an adhesive function. Consequently, this is the part of the FactsBook in which errors of omission are most likely to have occurred; for this, we apologise. Detailed discussion on these molecules is included in their individual entries. However, a brief review is given below on those adhesion molecules which belong to a larger family group of homologous proteins and where the majority of family members have no adhesive function.
Leucine-rich repeat (LRR) molecules The LRR proteins form a diverse family that includes extracellular matrix, cytoplasmic and membrane molecules involved in signal transduction and protein-protein interactions in development, in addition to cell adhesion. They are defined by the presence of one or more 22-28 amino acid long 'flank-centre (leucine-rich region)-flank' sequence motifs ( LRRs)I4', which were originally identified in leucine rich a2-glyprotein. Thus the LRR family includes: matrix glycoproteins and proteoglycans with structural roles ( e g decorin, biglycan, fibromodulin)"J2; adhesive platelet glycoproteins of the CD42 family (first identified in the sequences of platelet gpIb and gpIX that bind von Willebrand factor)'43,144; hybrid membrane molecules, such as the neuronal tyrosine kinase receptor (trk)'45, mucins (e.g. densin- 180)'46, and neural IgSF members LIG-1147 and NLRR148iand a series of Drosophila melanogaster proteins involved in nervous system development - connectin'49, chaoptin'50 and TOLLIS'.
CD36 family The CD36 family of proteins consist of molecules that are class B1 scavenger receptors that bind native and modified lipoprotein^^^^ and are involved in the recognition and phagacytosis of apoptotic cells1532 '54. As such, these macrophage receptors probably play an important role in, for example, the pathogenesis of atherosclerosis'55. The gene encompasses CD36, which has additional adhesive functions as: a collagen/thrombospondin receptor (see entry); the human scavenger receptor, CLA-1 (CD36 and LIMP I1 Analogous-l)158; LIMP 11, a lysosomal integral membrane protein of ubiticus distribution; and Croquemort, a Drosophila melanogaster receptor involved in macrophage recognition of apoptotic cells during de~elopment'5~2 '6O.
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Selectins 105 Frenette, P.S. and Wagner, D.D. (1997)Thromb. Haemost. 78, 60-64. 106 Crockett-Torabi, E. (1998)J. Leukocyte Biol. 63, 1-14. 107 Weis, W.I. et al. (1998)Immunol. Rev. 163, 19-34. 108 Vestweber, D. and Blanks, J.E. (1999)Physiol. Rev. 79, 181-213. 109 Drickamer, K. (1993)Curr. Opin. Struct. Biol. 3, 393-400. 110 Weis, W.I. et al. (1991)Science 254, 1608-1615. 111 Graves, B.J. et al. (1994)Nature 367, 532-538. 112 Campbell, I.D. and Bork, P. (1993)Curr. Opin. Struct. Biol. 3, 385-392. 113 Pigott, R. et al. (1991)J. Immunol. 147, 130-135. 114 Barlow, P.N. et al. (1993)J. Mol. Biol. 237, 268-284. 115 Imhof, B.A. and Dunon, D. (1995)Adv. Immunol. 58,345-416. 116 Lasky, L.A. (1995)Ann. Rev. Biochem. 64, 113-139. 117 McEver, R.P. et al. (1995)J. Biol. Chem. 270, 11025-1 1028. 118 Tedder, T.F. et al. (1995)FASEB J. 9, 866-873. 119 Hwang, S.T. et al. (1996)J. Exp. Med. 184, 1343-1348. 120 Kansas, G.S. et al. (1993)J. Exp. Med. 177, 833-838. 121 Waddell, T.K. et al. (1995)J. Biol. Chem. 270, 15403-15411. 122 Brenner, B. et al. (1996)Proc. Natl Acad. Sci. USA 93, 15376-15381. 123 Blanks, J.E. et al. (1998)Eur. J. Immunol. 28, 433-443. Syndecans lZ4 Carey, D.J. (1997)Biochem. J. 327, 1-16. lZ5 Zhang, L. et al. (1995)J. Biol. Chem. 270, 27127-27136. lZ6 Kokenyesi, R. and Bernfield, M. (1994)J. Biol. Chem. 269, 12304-12309. lz7 Shworak, N.W. et al. (1994)J. Biol. Chem. 269, 21204-21214. lZ8 Sanderson, R.D. and Bernfield, M. (1988) Proc. Natl Acad. Sci. USA 85, 9562-9566. lz9 Rapraeger, A.C. and Ott, V.L. (1998)Curr. Opin. Cell Biol. 10, 620-628. 130 Woods, A. and Couchman, J.R. (1998)Trends Cell Biol. 8, 189-192. Couchman, J.R. and Woods, A. (1996)J. Cell. Biochem. 61, 578-584. 132 Zimmermann, P. and David, G. (1999)FASEB J. 13 (Suppl.),S91-S100.
Grootjans, J.J. et al. (1997)Proc. Natl Acad. Sci. USA 94, 13683-13688. Cohen, A.R. et al. (1998)J. Cell Biol. 142, 129-138. 35 Hsueh, Y.P. et al. (1998)J. Cell Biol. 142, 139-151. 36 Kinnunen, T. et al. (1998)J. Biol. Chem. 273, 10702-10708. 37 Oh, E.S. et al. (1998)J. Biol. Chem. 273, 10624-10629. 38 Lee, D. et al. (1998)J. Biol. Chem. 273, 13022-13029. 39 Woods, A. et al. (1993)Mol. Biol. Cell 4, 605-613. 40 LeBaron, R.G. et al. (1988)J. Cell Biol. 106, 945-952. 4oa Couchman, J.R. and Woods, A. (1999)J. Cell Sci. 112,3415-3420.
33 ‘34
3ther molecules 41 Kobe, B. and Deisenhofer, J. (1995)Nature 374, 183-186. 42 Hocking, A.M. et al. (1998)Matrix Biol. 17, 1-19. 43 Lopez, J.A. et al. (1987)Proc. Natl Acad. Sci. USA 84, 5615-5619. 44 Hickey, M.J. et al. (1989)Proc. Natl Acad. Sci. USA 86, 6773-6777. 45 Schneider, R. and Schweiger, M. (1991)Oncogene 6, 1807-1811. 46 Apperson, M.L. et al. (1996)J. Neurosci. 16, 6839-6852. 47 Suzulti, Y. et al. (1996)J. Biol. Chem. 271, 22522-22527. 48 Taguchi, A. et al. (1996)Brain Res. Mol. Brain Res. 35, 31-40. 49 Nose, A. et al. (1992)Cell 70, 553-567. 50 Krantz, D.E. and Zipursky, S.L. (1990)EMBO J. 9, 1969-1977. 51 Gay, N.J. et al. (1991)FEBS Lett. 291, 87-91. 52 Calvo, D. et al. (1998)Lipid Res. 39, 777-788. 53 Platt, N. et al. (1998)Trends Cell Biol. 9, 365-372. 54 Yamada, Y. et al. (1998)Cell Mol. Life Sci. 7, 628-640. 55 Hirano, K. et al. (1999)Circ. Res. 85, 108-116. 56 Calvo, D. and Vega, M.A. (1993)J. Biol. Chem. 268, 18929-18935. 57 Calvo, D. et al. (1995)Genomics 25, 100-106. 58 Murao, K. et al. (1997)J. Biol. Chem. 272, 17551-17557. 59 Franc, N.C. et al. (1999)Science 284, 1991-1994. 60 Franc, N.C. et al. (1996)Immunity 4, 431-443.
We have made extensive use of the following World Wide Web (WWW)-based databases in the preparation of this book. For literature surveys, we utilized either or Medline on BioMedNet PubMed (http://www.ncbi.nlm.nih.gov/PubMed/) (http://www.biomednet.com/);the advantage of the former is that an increasing number of journal articles can be downloaded electronically as ’pdf files’ without resource to the library. For certain molecules that have attained ’CD’ status as leucocyte proteins, then an initial step was to examine the ‘CD’ database posted at NCBI (http://www.ncbi.nlm.nih.gov/prow/cd/index-molecule.htm). For the majority of ‘CD’ molecules this contains information on the individual protein and direct links to protein sequences and the Online Mendelian Inheritance of Man (OMIM) database (see later). Other information can be obtained from the human leucocyte differentiation antigen (HLDA) workshop For our specific sequence entries, database at: http://mol.genes.nig.ac.jp/hlda/. we used information obtained from the GenBank (hosted by NCBI: http://WWW.NCBI.NLM.NIH.GOV/) and SwissProt (http://www.expasy.ch/) sequence databases. Brief ‘how to use’ information is given later in this chapter. Knockout and mutation analysis in mice is becoming increasingly important in understanding the function of adhesion molecules and there are some useful databases containing this information (see Table 1).Likewise, there are a large and expanding number of web sites that can be bookmarlted to cover additional information, for example on ESTs, protein motifs and glycosylation sites. We have included a list of our favourite web sites in Table 1. Their use is largely intuitive and they all have good homepage listings of contents, on-line help sections and e-mail addresses for queries. One surprise, though, is that there were very few really valuable sites specifically orientated towards adhesion molecules; those we have found are listed in Table 1.
NCBI SERVER FOR GENBANK AND OTHER DATABASES A homepage for GenBank (http://WWW.NCBI.NLM.NIH.GOV/) enables a variety of searches to be formulated. The most commonly used is likely to be the Entrez browser, which then links to search engines for DNA (GenBank),protein and other databases. Entering the nucleotide or protein databases enables the simple keyword search function to be operated which then links to the citationjs) for the sequence requested. For ’nucleotide’ sequences this will produce a GenBank report, which contains information on key references, accession numbers, the nucleotide sequence and its derived amino acid sequence with some information on structural motifs. Medline references are directly linked to those cited in the report. The report form also enables the information to be displayed in different formats and access to be made to a variety of related databases, such as Medline, GenPept (protein) reports, lists of related sequences in the database, etc. The ’protein’ search reveals similar information in an identical format but only contains the amino acid sequence of the molecule.
Table 1 Useful databases
Cell adhesion molecule web resources OCD Molecules: http://www.ncbi.nlm.nih.gov/prow/cd/index-molecule. htm HLDA Homepage: http://mol.genes.nig.ac.jp/hlda/ Cell adhesion Domain: http://www.cell-adhesion.net/ Adhesion proteins in drosophila: http://flybase.bio.indiana.edu/allied-datallklinteractivefly/airnain/btransm.htm#dafka2 Adhesion proteins in neurobiology: http://www.neuro.wustl.edu/neuromuscular/lab/adhesion.htm Useful bioresource search engine: http://www.expasy.ch/BioHunt
Gene knockout resources ”Mouse Genome Informatics homepage at Jackson Laboratory: http://www.informatics.jax.org/ aSearchable knockout and transgenic mouse database (TBASE): http:/Itbase.j ax.org/ Mouse gene knockout listing: http://www.bioscience.org/knockout/alphabet.htm BioMedNet (Mouse Knockout and Mutation Database) listing: http://research.bmn.com/mkmd Internet transgenic resource links: http://tbase.jax.org/docs/databases.html
Quick sequence searches (GenBank and SwissProt and links) “NCBI server:
http://WWW.NCBI.NLM.NIH.GOV/ “Swiss Institute of Bioinformatics server: http://www.expasy.ch/
Human genetic diseases “OMIM (Online Inheritance in Man): http://www.ncbi.nlm.nih.gov/Omim/ Human Gene Mutation Database (HGMD): http://www.uwcm.ac.uk/uwcm/mg/hgrndO.html
EST databases NCBI EST search:
http://WWW.NCBI.NLM.NIH.GOV/dbEST/index.html
Human EST project: http://genome.wustl.edu/est/esthmpg.html EST projects at Washington University: http://genome.wustl.edu/gsc/est/navest .pl
Molecular biology, protein modelling and other links Databases and search engines Resources at the Sanger Centre: http://www.sanger.ac.uk/ The Genome Database: http://gdbwww.gdb.org/ UK Human Genome Mapping Project resources: http://www.hgmp.mrc.ac.ulz/ European Bioinformatics Institute (database access, sequence search tools, etc.): http://www.ebi.ac.uk/ Sequence searches at EMBL: http://www.embl-heidelberg.de/Services/index.html Other useful sites for databases, etc. DNA and protein analysis tools: http://www.roclzefeller.edu/rucs/toolkit/toolkit.html Protein and biological databases at Johns Hopkins University: http://www.bis.med. jhmi.edu/ Molecular biology and protein links: http://www.cbs.dtu.dk/biolinlz.html Bioinformatics at the Weizmann Institute: http://bioinformatics.weizmann.ac.il/ Harvard links: http://mcb.harvard.edu/BioLinks.html TIGR database: http://www.tigr.org/tdb/ TIGR human gene index: http://www.tigr.org/tdb/hgi/hgi.html Nucleotide and protein analysis including structural motifs. The Protein Data Bank (protein modelling resource): http://www.rcsb.org/pdb/ Swiss Institute of Bioinformatics server (including 2D gel electrophoresis): http://www.expasy.ch/ The Protein Domain Database: http://www.toulouse.inra.fr/prodom.html
Table 1 Continued Protein modelling and motifs listing: http://guitar.rockefeller.edu/modbase/databases.html Nucleotide and protein structure prediction resources (Center for Biological Sequence Analysis): http://www.cbs.dtu.dk/services/ Current Biology’s Macromolecular Structures Database (searchableby keywords): http://research.bmn.com/msd Protein modelling at UCL: http://www.biochem.ucl.ac.uk/bsm/biocomp/index.html
DNA clone access I.M.A.G.E. DNA clones: http://www-bio.llnl.gov/bbrp/image/image.html Glycosylation analysis OSugars, proteoglycans and GAGS: http://bssv0 1.lancs.ac.uk/gig/pages/toppage.htm 0-glycosylation sites:
http://www.cbs.dtu.dk/services/NetOGlyc/ “www sites found to be particularly useful in the preparation of this FactsBook.
SWISSPROT PROTEIN SEQUENCE DATABASE Entry is made through the ExPAsy molecular biology server (http://www.expasy.ch/), which provides lists of databases and tools on its homepage. Click SwissProt and TrEMBL under ’databases’ to enter the SwissProt database. This is accessed by clicking on SRS (‘sequence retrieval system’) and then the ‘start button’ on the Sequence Retrieval System homepage, which then allows you to select individual sequence databases to search. Press the ‘query form’ button and enter the keyword to be searched. This will result in the downloading of individual sequence-related information in a standardized form (NiceProt view). This contains key references (which are directly linked to Medline abstracts), a description of the molecule and its function, its amino acid sequence and accession number, including those for the GenBank DNA sequence, and descriptions of the location of basic motifs (e.g. signal sequence, transmembrane domain, glycosylation sites, cleavage sites) and specific motifs (e.g. Ig domains, repetitive amino acid sequences, etc.) within the molecule. Further information on domain structure and homologous sequences can be downloaded via two interactive ‘domain viewers’, ’FT table viewer‘ and ‘Domain structure’ with simple online instructions.
OMIM Enter the database (http://www.ncbi.nlm.nih.gov/Omim/) via the use of the ‘search the OMIM database’ prompt, and enter keywords or OMIM accession number into the search section. The search will yield a page where individual
entries are given by their OMIM number, which can be accessed directly to yield text and references concerning the item of interest. The text also contains linked PubMed and OMIM accession numbers, which can be directly sourced from the body of the database entry. Furthermore, a variety of related links are provided to other databases as listed: Medline Protein DNA HGMD LOCUS GenMap GDB Nomenclature
Linked references on PubMed. Access to GenPept protein sequence database. Link to GenBank DNA information on molecule. Link to Human Gene Mutation Database entry. Link to chromosomal information and derived resources. Link to genetic locus, which can be further accessed to the MIM GenMap giving chromosomal locations and adjacent genes. A series of linked genetic and sequence resources and their accession numbers. A searchable database to definitions of correct usage of gene and nomenclature symbols.
MOUSE KNOCKOUT DATABASES A resource that can be utilized to access information is held by the Mouse Genome Informatics JMGI) database at the Jackson Laboratory (http://www.informatics.jax.org/). Here, entry is via the MGI homepage and entering a keyword term either in the ‘quick gene search’ box or the MGI number (in correct format, for example enter MGI:88354 for E-cadherin) and subsequent links to enter the relevant results page. For more refined searches enter details via the ’Genetic and Phenotypic Data’ section. Clicking on the highlighted gene symbol in the results page enters a subfile that contains details of the mouse chromosomal location of the gene, links to accession numbers in GenBank, SwissProt and other databases. Clicking on the ‘phenotype’ gives details of the knockout mouse; general information on gene structure and protein function are also included. These are all linked by a unique accession number, the MGI number (quoted in the individual molecule entries under ‘Knockout’). Again, unfortunately, the MGI number cannot be used as a unique identifier for a gene on the MGI homepage search engine. Another way to access knockout information is to enter the TBASE database (Transgenic/Targeted Mutation Database) on mouse knockout phenotypes is to access the ‘citation database’ (http://tbase.jax.org/), enter a keyword and search. The search reveals related links to the published literature, which can then be further investigated by a series of clickable links, which finally produces the full TBASE printout containing information on the mouse knockout mice, details of the DNA constructs used, information on the host mouse strain, linked references and, of course, its phenotype. This is given in further detail via a link within the ’phenotype results’ section, which can be clicked to provide full details, including unpublished data. Files are identified by a unique TBASE accession number.
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CELL ADHESION MOLECULES
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Cadherins
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- .- -
Cadherin-1, epithelial cadheda, uvornorulin ~
0
.
Family Cadherin (typc I subfamily)
Structure
Molecular weights Amino acids Polypcptidc
882
97456
1
. ,
Cd
SDS-PAGE reduced
120 kDa
Carbohydrate N-linkcd sitcs Q-linkcd sites
2
Gene location
1hq22.1
Gene structure
-100 kh, 16 exnns
Alternative forms
C=TGOH
Alternativcly spliced isoforrns have been detected in some tumours.
Structure Like all classical typc I cadherins, E-cadherin is expressed initially as a precursor with a n N-terminal propeptide domain, which is cleaved off insidc the cell during protein maturation. The mature form of the protein forms a homodimer with adjacent moleculcs at the ccll sudacc. Thc extracellular domain contains fivc cadherin repcats of approximately 110 amino acids separated by four calcium hinding sites. The N-terminal domain contains the conserved HAV motif required fox hornophilic binding to E-cndhcrin cxpresscd on ncighhouring cclls'. Thc cytoplasmic domain associates with p-catcnin, which in turn binds to a-catcnin or phkoglohin, thcrchy linking E-cadhcrin to thc actin cytoskclcton'. The solution structure of thc N-tcrrninal domain2 and crystal structure of the two N-terminal domains? havc hccn solvcd. Thc stnicturc of rhe cadhcrms is discusscd furthcr in Scction I.
c0
Ligands
E-cadherrn mediates Ca>--dcpcndcnthomotypic adhesion. In addition, Ecadhcrin is a ligand for the aFP,and m?@, integrins and this binding is to a site in the E-cadhcrin N-tcrminal domain which is distinct from the homotypic binding site*5 .
Function E-cadhcrin is a key mcdiator nf epithelial ccllxell adhesion in cmlbryonic and adult tissucs. It functions both in the formation of organized ce1l:cell
---.. -- .... . . --
Cadherin Family . ..
contacts" and in tiwue rnorphnjicncsis and thc maintcnancc nf the cpithclium7. Antibody blocking or dominant ncgativc cxpcrimcnts demonstrate that loss of functlc~nalE-cadhcrin results In the loss of a polarlzcd cpithclial phcnorypc. Thcsc cxpcrimcnts togcthcr with in vrvo data (scc hclow) dtmonstratc that E-cadhcrin can act as a tumour suppressor. In addition, thc binding of E-cadhcrin to lcucocytc intcgrins mediates thc interaction hctwccn T cclls and mucosal cpithelium,
Distribution E-cadhcrin is widcly cxprcsscd in non-ncural epithcl~alcclls, whcrc it is localized to ccll:cell contact arcas and particularly to the arlherens junctions. During devdopmcnt, E-cadhcrin i s cxprcsscd very carly on cmhryonic cclls, is switched off in the mesoderm forming at gastrulation snri is thcn rc-oxprcsscd during mcscnchymal to cpithclial transitionR.Loss of E-cadhcrin cxprcssic~nis found in many tumours (see hclow).
Disease association OMIM 192090 Using in vitro and In vrvo svstcms rt has hecn dcmonstratcd that loss of E-cadherin expression in tumour cclls is associatcd with a Inore invasive phcnorypc and that rc-cxpscssion can rcsult in rcvcrsion to a morc benign phenotype*. Conscql~ently,E-cndhcrin has btcn implicnttd to function as a tumour suppressor. Using a lnousc model oh pancrcatlc P-cclE carcinogcncsis, Per1 ct al. havc directly dcmonstratcd that loss of E-cadhcrin has a causal mlc in the transition froin adcnoma to carcinomain".Lrws o r reduction in Ecadhcrin cxprcssion m tumours can rcsult from: (a1 allclic dclction or Toss or heterozygosity on chromosome 16; (hF missensc or nonsensc mutations; (c) altcmativc splicing rcsultrng in loss of rhc cxtracollu!ar or intraccllular domains; (dl protcolysis of thc cxtraccllular doma~n;or Icl suppression of cxprcs~ion~~-~.
Knockout MGr:88354 Tl-re Gene Knockout Fncr~Hook'~,plOI E-cadhcrin -/- crnhryos dcvclop normally ta blastula stagc and compact duc to the prcsencc of maternal E-cadherin. Suhscquently cclls do not propcrly polarize resulting in the ahscncc of a hlastocyst cavity and trophcctndurmnl cpithelium, and the inability t o implant"""'.
Amino acid sequence of human E-cadherin 1 MGPWSRSLSA LLLLLQVSSW LCQEPEPC;!~'c:F':J.,-~.:,.:' :!':';.':'
:';'?.:?;!,:!.':?ir.'!
:.,&,I
...............................
;;'~,;~;-;':-,',:..':".-<;
;;c;>!:'.;?,:[;(;;> rb
'G I[;?
]
9 1 !;\::!?:!.::;;:';!('.;
:;l':'<;y ;;.,:?:
;;
: ;:-:?:-: ,:.,i;-:;AK',,.''y!-::>]A [>E[.:U,L;!'r!''r:, [-'~H,:k~:s~~j~:~[ P :TO--.;? v:i;r -7: .:!:;L P(;TS -.j:.:r7..7~:y~ 7 : ~ nn!-!:yy.;,; T [>'.,<;-.';.'
2 1. 1 .;-;].:3 p b : ~ L, 1 T:.'T~o!:o"~L:: 3 D 1 .L,'!TT l m Y O n ? - JmPI3r?:?<7TT?;? ~ : T G ~ . ~ T ! : ~ TC[,3-35??T . ~ ~ . ~,.7 ,.
'
The propeptide sequence underlined and in italics is cleaved tn form the maturc protein.
Database accession EMRL/Genl3ank SwissProt
21.3009 P12830
References Yap, A.S. ct al. (1997)Annu. Rcv. Cell Dcv. Riol. 13, 1 19-146. Overduin, M. et al. (19951 Science 267,386,389. Nagar, R. ct al. (1996)Naturc ,?PO,360-364. Ccpck, K.L. ct al. (1994)Naturc A72, 190-19.3. Karccla, P.1. ct al. (199h)J. Riol. Chcm. 271, 30909-30915. '. Adams, C.L. and Nelson, W.J. (1998)Curr. Opin. Cell R~ol.10, 572-577. ' Takc~chl,M. (14951 Curr. O p ~ nCell . Riol. 7, 614-627. W u h c r , 0. et al. (19961 Gun. Opin. Cell Riol. 8, 685-691. Takcrchl, M. (19931 Curr. Opln. Cell Riol. 5, 806-81 1. Pcrl, A.K. ct al. (1998)Naturc 392, 190-193. Rirchmcicr, W. and Rehrens, J. (1994) Riochern. Riophys. Actn 1 198, 11-16. ** Rerx, G. et al. (19981Hum. Mutat. 12, 22c-237. * I Guilford, P. ct al. (1998)Natutc 392, 402-405. IJ Richards, F.M. et al. (1999)Hum. Mol. Genet. H, 607-610. Mak, T.W. (19981 The Gcnc Knockout FactsRook. Acadcm~cPress, London. l6 Riethmacher, D. et al. (19951 Proc. Natl Acad. Sci. USA 92, 855-859. I' Lan~c,L. ct al. ( 19941 Pmc. Natl Acad. Sci. USA 9 1, 8263-8267.
Cadherin-2, neural cadhetin -
Family Cadherin (type I subfamily]
Structure Molecular weights Amino acids Polypeptide SDS-PAGE reduced
Carbohydrate N-linked sites 0-linked sites
Gene location Gene structure
>200 kb, 16 exons
4
COOH
Alternative forms Structure Like all classical type I cadherins, N-cadherin is expressed initially as a precursor with an N-tcrminal propcptidc domain, which is cleaved off inside the cell during protein maturation. The mature form of the protein forms a homodimer with adjacent molecules at the cell surface. The extracellular domain contains five cadherin repeats of approximately 110 amino acids separated by four calcium binding sites. The N-terminal domain contains the conscrvcd HAV motif required for homophilic binding to N-cadhcrin cxprcsscd on ncighbouring cellst. The cytoplasmic domain associates with catenins, thereby linking N-cadherin to the actin cytoskeleton2. This interaction is promoted hy thc non-receptor protein tyrosine phosphatase PTP-IR, which when associated with N-cadherin can dephosphorylate p-cateninJ. Crystal structure from the N-terminal domain of N-cadherin4 led to the proposal that classic cadherins form strand dimers whereby cadherin dimers on apposing cells interact to form a linear 'zipper'4.5. The structure of thc cadherins is discussed further in Section I.
Ligands N-cadherin mediates Gala-dependent homotypic adhesion. In addition, Ncadherin-positive retinal axons can use R-cadherin as a substrate for axon elongation6. In at least some cells types, N-cadherin interacts in cis with the fibroblast growth factor receptor and activation of the receptor tyrosine kinase is a necessary component of ncurite outgrowth7-a,
Function N-c;ldhcrin tunctions t o promote ncuritc outgrowtll on ;istrocytcs, ITILISCIC cell.; a n d Scli~zr:~nn ccllh. It i q nlqo ;I necc.;s;lry component of cardi;ic cells comp;~rtmcnt;~liz;~tic,n clurin!: cnrlv h u r t i l c ~ ~ c l o p ~ n c nmvclhlast t", f~~sion"', skclct;~lrnu.;clc c l i t t c r c n t i a t i o ~ i ~;in11 ' ~ ~solnitc ~ forni;itionI~.
Distribution N-c;~ilhcrinis highlv csprcscccl in ;~ilultncur;~ltissue, c3rrliac ant1 skeletal muscle, lens . ~ n dcndot1icli;il cells. In t h e cmhryr), it is initially csprcsscd in mc,~odcrnimi,qr;~tili!: trom t h e primitive strc;ik ;In11 tlicn Inter in a n u ~ i l h c r oi c~nlirvonict ~ q s u c si~icluilings o ~ n i t c encur;~l , t u l ~ c;11id heart.
Disease association OMIM 1 13020 Thcrc is incrc;~sin,q~ ~ ' i t l c n ctor c ;I role of N-c;~ilhcrin in promotiux t h e migrfition, inv;~\ion;ind mct;~ctnsi.;ot cpitllclinl tunlour ccll.;l.l,Ji,
Knockout MGI:SS,Z5:', T111,C;VII~' i i 1 7 O ~ ' / < O i l iF(11.i \ / < ~ o l < "131 ~ ,0.3 N-c;~rllicrin mice die 1lv d;iy 10 ot scstntion dilc to i;liIure ot t h e lic;~rt tuhc t o c l c ~ ~ l onorm;~llv. p In ;idtlition, cpit1icli;ll org;~ni=nticl~l of t h e somitcs is dicruptctl, t h e mccoclcrrn;~l nil entlotlcrmnl layers oi t h c v ~ j l k sac scpnrntc, ;111it the IICLI~;II t ~ ~icl mnltormcdr'. ~ c
Amino acid sequence of human N-cadherin MCRIAGALRT LLPLLLALLQ AS-
-
--
-
&
-
-
-
--
-
A-
.
A
Tlic propcptitlc scclucnce r~ndcrlined:ind in it;~lic.; is c1c;lvcd t o torm t h e m;ltilrc protein.
Database accession EMI
References Yap, A.S. ct ;11. jlc)O7l Annu. Rev. Cell Dcv. Riol. 1,Z, 11')-146. Sacco, P.A. ct al. (199.il1. Riol. Chcm. 170, 30101-20306. Rnlsnnio, 1. ct ;I]. (199s)1. Cell Riol. 143, 52.3-532. Shapiro, L. ct al. (1995)N a t i ~ r c374, 317-,337. Tnmum, K. ct ; ~ l(199s) . Neuron 20, 115.3-1 16.3. Rcdies, C. and Takcichi, M. (191)21Glin S, 161-171. Willinms, E.T. et al. (19941 Neuron l,i, 3S.i-,594. Saftell, 1.L. ct ;]I. (19971 Neuron IS, 2.31-342. " Lin;isl<, K.K. et al. ( 1 9971 Dcv. Riol. 18.5, 148-1 64. Charlton, C.A. ct a\. (19971 1. Ccll Riol. I,iS, 3,i1-.3%36. " Gcorgc-Wcinstcin, M. ct al. (19071Dcv. Riol. 1S5, 14-34. Goichhcrg, P. ; ~ n dGeiger, R. ( 19981 Mol. Riol. Cell 9, 3 1 19-(3 1<3I . Linaslc, K.K. ct al. 119951 Dcv. Riol. 202, 8.5-102. I-' Nicman, M.T. ct al. (19991 I. Cell Riol. 147, 6.31-644. Ii H;iznn, R.R. ct ill. (10001 1. Ccll Iliol. 1 JS, 779-790. In Mak, T.W. (19981 T h e Gcnc Knockout F;lctsRook. Ac;ldcmic Press, London. 1' Rildicc, G.L. et nl. (19971 Ilcv. Riol. 181, 64-78.
Cadherin-3, placental cadherin
Family
Structure Molecular weights Amino acids Pnlypcptidc
829 91 427
SDS-PAGE rcduccd
115-1 10 kDa
Carbohydrate N-linked sitcs 0-linked sitcs
-1
Gene location
1hq22.1
Gene structmre
45
kh, 15 cxons Ilnouscl
"
I
"
Alternative forms Structure Like all classical typc I cadhcrins, P-cadhcrin is cxprcsscd initially as a precursor with an N-terminal pmpcptidc domain, which is cleaved off inside the cell during protein maturntion. The cxtraccllular domain contains five cadhcrin rcpcats of approximately 110 amino acids separated by inur calcium binding sitcs. Thc N-tcrminal domain contains the conservctl HAV motif requirerl for homophilic binding to P-cadhcrin cxprcsscd on noighhouring ccllsl,'. Thc structurc of the cadhcrins is discussed furthcr in Suction I.
Ligands P-cadhcrin mediates Ca: , -iicp~nduntho~notypicadhcsionl.
Function As dcmonstratcd by thc knockout micc (scc bclowl, tlic precocious mammary dcvelopmcnt in the nhscncc of P-cadhcrin sumcsts a rolc in maintaining the unditfcrcntiatcd statc of thc mvocpithleium.
Distribution P-cadhcrin is predominantly cxprcssed in thc placenta, epidcrlnis and mammary glantl.
Disease association OMIM 114011
Cadhcrin Family --
--
-
I
Knockout MGI:XXt3S6 The Gene Knockout FactsRonkJ, p104 P-cadhcrin -1- mlcc arc viahlc and fertile but with virgin fcmalcs exhih~tingprccocious diffcrcntation of the mammary gland and mammary hypcrplasla with agc5.
Amino acid sequence of human P-cadherin
Thc propcptidc scrlucncc underlined and in italics is cleaved to form thc mature protein.
Database accession EMRL/GcnRank SwissProt
X63629 PI2223
References Nosc, A. and Tnkcichi, M. (1986)J. Cell Riol. 103, 2649-2658. Yap, A.S. ct al. (1997)Annu. Rcv. Ccll Dcv. Riol. 13, 119-146. Takcichi, M. (1995)Curr. Opin. Cell Biol. 7, 619-627. Mak, T.W. [I9981 Thc Gcnc Knockout FactsBook. Academic Press, London. Radicc, G.L. ct al. (1997)J. Cell Riol. 139, 1025-10<32.
Family C ; ~ t l l i c r ~(tvpc n I ~ul~t;~m~lvI
Structure Molecular weights i \ ~ n ~ na oc ~ d \ Polvpcptlrlc
916
SDC-PACE rcrlucctl
120-1.30 kLh
100 136
Carbohydrate N-lin kcd sitcs 0 - l i n kctl fitcs
6
Gene location
?.Oq l .i..i
Gene structure Alternative forms Structure Like 211 C I ~ ~ S P I C ; I I type I c ; ~ J I i c r i n ~11-c;ldhcrin , is expressed initially
;IS
n
precursor with ;In N-terniin;il propcptidc domilin, which is clcavctl otf insitle t h e cell di1rin.q protein miiturntion. T h e cxtr;icclli~lnr doni;iin c o n t ; ~ i n sfive c;~dlicrinrepeats oi ;~pproxiniiitcl\,1 10 a m i n o acids scparatcrl hy lour calci~uii hincling sitc.;. T h e N-terminal domilin contiiins t h e conscrvctl HAV motit rccluircd tor liomophilic I>indin,q t o R-c;~rllicrin cxprcsscrl o n n c i ~ h l l o i ~ r i~nc~l l s l - ~T.h e structure of tlic carllicr~nr; is ilisc~~fsc,rl f ~ ~ r t l iin e r Section I.
Ligands R-c;~dhcrinnictli;ltc.; C ~ I. -tlcpcnclcnt ' liomotyl~icadhesion. In atldition, Ncatlhcrin-positive retinal axons cnn L I S ~R-c;~dhcrin;I.; 3 .;i~hstr;~tc ior a s o n clong;~tion'.".
Function It h ; ~ shccn proposctl that t h e ccll:ccll adhesion nicdi;itcd hy R-catllicrin may Ilc ilnl.rort;~nt in tlic torn1;ltion o t striatcti musclc ;ind cpitlicli;~l tissues', tlie scgreg;~tionof exocrine and endocrine cells lli~ringp;lncrcatic tlcvclopmcnt2, 3.; a sul~str;ltcior t h e outgro~vtliot N-c;~dlicrinretinal :lxonnA and in retinill n~orl~ho,qcnesis'.
Distribution In thc cmhryrr, 11-cnrllicr~nis csprcssetl in developing mu.;clc in t h e somitic mytome, c;~rlyskclcti~lmusclc and s m o o t h mucclc, l ~ not t c;~rdiacmuscle.
In a d d ~ t ~ noxprcsslon n, I S sccn In duvol.np~ngcpilthcl~nrn thc k~dncy,lung, thymus' and in thc c;~rlyoptic ncrvc glin6.
Disease association OMIM 603006
Knockout
Amino acid sequence of human R-cadherin MTAGAGVLLL LLSLSGALRA
'
(
1
-
- \.
1
.
L -
. . . . . . . . . . . . . . . . . . . . ,. ., . . . . . . . ... . . - - :.>!~.:.]?.>::,. : ., . - .-- , , , , . . .................................................... . > : . . . ... _,. . .. . ., .. . .. . -.. , . ,. . , , , , ... , . . . . . > . .... . . . . ,...., . . ','." ............. . , :Ii. .. ...:,-;......:.>:,:.,...,v<(i.':'.". . , ,. . ,. .". !,,:. . ; -.!,.:., . 1 c. . . . . .",,.' . . . .-.,,.. . . . . . .' .. . . .. . . - ..->^. . . r . . . . ... .. .. -.. ..... . . , , , . , . :.. ...... . i:, . . . . . . . . . . . . . . . . . ............ . . _ .;... . . . . . . . . , ; . , . . , . > , ; . ; . , . .,;. ,::-, . . . , . , , . . , .- . ...... , .(,,. . . .. .7;!.l:, . ,,. ..!, . .....- . . :..(.(..(,..::; . ,. - -.' .-- -- ,.-..-, :. j ..: :-:j ;'I: ;,;--. . - , : , ' - , .!(.. . ..(, . , - .- . ::::: :.;. .-.- .:.. -. . . . .. .,...> . .. ... .. . .. .) , , j , 7 . .;............ . -.. . ,. . .. . ,,.. ............ . . . . ,. . . . ".. . ...... \ , !. :. :.. ......: : ;',:'.':.::,::-., . .'.! :.: : : - .- , . . .. . . . ... . .. .. .. .. .. .. . . . : . ;" ...... ,.,,:.,l.,.:1 : . \ , . . .,... . .. ,. ...... . ..,,:.> . . . ......... . . . . . ;.. .. .. .. .. .,~,,;:.!.:,..: .. . .. .. .. ...,,. . . ,..:,;.. . . . . ............. ..... . . . . . . . . .. . ,,.. ,.,:.,:. ;. , :> -::- - -.Li : - I.,:? T . . . : .. ,,;; - ,. .,;, ; : ;,. - - - -.. .. . . . .. ..... .. .. ... .. ...: . . . ......,!:; ;,;,: . ,,>., ;.,;, .,.; ; ),. ... ;. 7,.......... ; ... , ;, ,., -. -. , -. - , .. J j < . . : . . , . . ,, . , . - . . .);(;.,! ,,:;.[: ;. . . . . . . . . ,. . ., . , ......... .... ;:. . -; :.... ;. ; ; , ., ........ , . , . , .....( ..) . . ,. , c: .. .-.., .......... , ,,, . .. . . . . ,,:,:, :: ' , .(
'
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,
'
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'
Thc propcptidc scqucncc unrlcrl~ncdand In ~ t a l ~ ciss c!c;lvcd t o form the rnaturc protein.
Database accession EMHL/Gcnhank SwissProt
L34059 PSSZK.1
References Inuzuka, H. ct al. (1991J Ncuron 7, 69-79, Hutton, J.C. ct al. (199,3)Mol. Endncrinol. 7, B 151-1 160. Taniharn, H. ct sl. (1994)CclI Adhcs. Commun. 2, 15-26. Yap, A.S. ut 31. (1997)Annu. Rov. Cull Dev. Rhol. 13, 119-146. mat sun am^, H. ct al. (109.7)J. Cell Sci. 10h, 401-409. C. nnd Tnkcichi, M. ( 1992) Glin 8, 161-1 7 1. "cdius, ' Roscnhcrg, P. ct al. (19971Dcv. Ric~l.187, 55-70.
*
Cadherin-5, vascular endothelial cadherin, CD144
Family Cndhcrin (typc I1 subfamily)
Structure Molecular weights A m ~ n oa c ~ d s Pnl\~poptldu
87 518
SDS-PAGE reduced
130 kDa
784
Carbohydrate N-linked sites 0-linked sitcs
7
Gene location
16q22.1
Gene structure
36 kh, 12 cxons (mouse1
Alternative forms Structure Likc thc clnssicnl typc I cadhcrins, VE-cadhcrin is expressed initially as a precursor with an N-terminal propcptidc domain, which is clcavcd off inside thc cull during protein maturation. The extracellular domain contains five cadhcrin repeats of approximately 110 amino acids separated by four cnlcil~m binding sitcs. In contnst to thc classical typc I cadhcrins, VE-cadlicrin has a shortcr . propcptidc sequence nnd a VIV rather than HAV motif in the . . homotypic hinding site in the N-terminal domaint2. Thc cytoplasmic d(llnain assr~ciatuswith catcnins thcrchy linking VE-cadhcrin to the actin cytoskeleton.?-'. The stnlcture of the cadherins is discusscrl further in Section I.
Ligands VE-cndhcrin mctiintcs C:I'.-dcpcndcnt homotypic adhesion.
Function The restriction of VE-cndhcrin to the cndothclial iunctions s u ~ c s t as rolc in promoting homotypic intcractions. Gcncration of VE-caiihcrin -1cmhryonic stem (ES) culls and antihody hlocking experiments in vitrt~wcrc uscd to dcrnnnstrate a rcquircmcnt for this carlhorin in vascular dcvolopmcntiJ>. In addition, VE-cadhcrin is necessary far maintaining cndothelial intcgrity as introduction of anti-VE-cadhcrin antihotiics in viva results in incrcascd vnsculnr pcrmcahility anci accelerated ncutrophil rucruitmcnt into the peritoneum'. Recent data from VE-cadhcrin dcficient cmhryos indicate that this cadhcrin is required in v i ~ r ofor undothclial ccll survival. Luss r)f VE-cadhcrin, or ciclction of the cytoplasmic Jomain, induccs cndnthclial apoptosis, This is duc to an inahilitv of the cclls to respond to vasc~llarcndothelial growth factor (VEGFI-A which in wild type cclls signals via the VEGF receptor-2 to activate PI.3-kinasc and A k t to incrcasc lcvcls of thc anti-apoptotic mcrliator RcllR.
- -
- -
-
--
-
---
Cndhcrin Family
Distribution VE-cadhcrin cxprcssion is restricted to all types of cndothclium. In thcsc cclls VE-cadhcrin is localized to the intcrccllular junctions whcrcas the other cndothclial cadhcrin, N-cadherin, is dispcrscd ovcr the plasma rncmhrane'.J.
Disease association OMIM 601 110 VE-cadhcrin cxprcssinn is reduced in human anginsarcomas
Knockout MGI: 105057 VE-cadhcrin -1- cnihryos retain the ability to assc~nhlccndothclial cclls into vessels hut die at E9.5 due to a failurc in rcmodclling and maturation of the vascular networkx.
Amino acid sequence of human VE-cadherin
The propcptidc sequence underlined and in italics is cleaved t o form the mature protein.
Database accession EMRLlGcnRank SwissProt
X7998 1 PA3 15 1
References Lampugnani, M.G. et a]. (1992)I. Cell Riol. 1 18, 151 1-1522. Yap, A.S. ct al. / 1997) Annu. Rev. Cell Dcv. Riol. 13, 1 19-146. Lampugnani, M.G. ct al. (1995)1. Cell Riol. 129, 203-21 7. Navarro, P. et al. (19981 1. Cell Riol. 140, 1475-1484. Vlttct, D. ct al. (1997)Proc. Natl Acad. Sci. USA 94, 6273-6278. "ach, T.L. et al. (1998)Exp. Cell Rcs. 2,38, ,124-3.34. Gotsch, U. ct al. (19971 1. Cell Sci. 110, 583-588. Carmelict, P. et a]. (1999)Cell 98, 147-157.
Cadherin-6, kidney cadherin -
.
Family Cadherin (type 11 subfamily)
Structure Molecular weights Amino acids Polypcptidc SDS-PAGE reduced
Carbohydrate N-linked sites 0-linked sites
Gene location
Gene structure Alternative forms Structure
6 (1 removed with propeptide)
F
Ill11 1 1 1 1 1 IIIII IIIII COOH
Likc thc classical typc I cadhcrins, K-cadhcrin is prcdictcd to hc expressed initially as a precursor with an N-terminal propeptide domain, which is cleaved off inside the cell during protein maturation. Thc cxtraccllular domain contains five cadhcrin repeats of approximately 110 amino acids separated by four calcium hinding sites. In contast to the classical type I cadherins, K-cadherin has a shorter propcptidc scclucncc and a QAI rather than HAV motif in the N-terminal domain, which does not appear to be involvcd in the adhcsivc f u n ~ t i o n ' . ~In. addition, hinding of CaL- does not protect K-cadhcrin from proteolysis". The cytoplasmic domain associates with catcnins thcrchy linking K-cadhcrin to thc actin cytoskclcton4. T h c structure of the cadherins is discussed further in Section I.
Ligands K-cadherin mediates Cal*-dependcnt homotypic adhesion. In addition, in mixed aggregation assays, K-cadherin partially interacts with cadherin-14l.
Function Prcdictcd t o function as a homotypic adhesion rcccptor in K-cadherinpositive tissues.
Distribution K-cadherin is highly exprcsscd in kidney, brain and ccrchcllum. Wcalccr expression is seen in lung, pancreas and gastric mucosa.
-
--
Cadherin Family -
- -
Disease association OMIM 603007 Expression is uprcgulatcd in some liver and kidney carcinomas~~J.
Knockout MGI: 107435
Amino acid sequence of human K-cadherin
Thc propcptidc sci~ucnccundcrlincd and in italics is clcavcd to form the mature protein.
Database accession EMRLtCenRank SwissProt
D.3 1784 P55285
References ?
Xinng, Y.Y. et a!. (1994)Canccr Rcs. 54, 3034-3041. Shimoynma, Y. ct al. (199.5)Canccr Rcs. 55,2206-221 1. Shimoynma, Y. ct al. (1999)J. Riol. Chcm. 274, 11987-1 1994. Paul, R. ct al. (1997)Canccr Rcs. 57, 2741-2748.
Family Cadherin (type I1 suhfamilyl
Structure Molecular weights Amino acids Polypeptide
793 87570
SDS-PAGE rcduccd
1.30 kDa
Carbohydrate N-linkcii sitcs 0-linked sitcs
6 (2 rcmovcd with propcpticlcl
Gene location
1hq21-1 hq22.1
Gene structure Alternative forms In rat and human, cDNAs c n c o d i n ~an altcrcd form of cadhcrin-d truncated in thc fifth cadhcrin rcpcat havc hccn isolntcd. A 95-kDa form r)f cadhcrin-8 has hccn dctcctctl in mt hminr.
Structure Likc the classical type I cadherins, cadherin-8 is predicted to he expressed initially as a precursor with a n N-terminal propcptidc domain cleavcd off insidc the cell during prt~tcin maturation. The cxtracellular domain contains five cadhcrin repcats of approximately 110 amino acids separated hy four calcium hinding sitcs. In contrast t o the classical type 1 cadhcrins, cadherin-X has a shorter propeptide sequence, a QAV rather than an HAV motif in thc N-terminal domain homotypic hinding site, and hind in^ of Ca?. does not protect cadherin-8 horn p r o t c o l v ~ i s ~ -The ~ . cytoplasmic domain associates with B-catcninl. The stmcturc of the cadhcrins is discussed further in Section I.
Ligands Cadhcrin-8 transfcctcd into L cclls ~ncdiateswcak homotypic adhesion'.
Function Thc d~strihutionof cadhcrin-X s u ~ c s t sa f u n c t ~ o nEn thc formation of particular ncural circuitsJ and/or rntcractions of thymocytcs wizh stromas.
Distribution In thc adult, cxprcsstnn is m a ~ n l ydctcctcd in thc Ix-ainstcm, ccrcbcIlum4 and CD4+ CD8+ thymocytesF. During development, cadherin-R is
expressed in rcstrictcd areas of the central nervous systcm and the thymus"'. In transfccted L cells, cadherin-8 was found localized to the cell periphery mainly at ccl1:ccll contact sites1.
Disease association OMIM 603008
Knockout MGI: 107434
Amino acid sequence of human cadherin-8
The propeptide sequence undcrlincd and in italics is cleaved to form the inaturc protein.
Database accession EMBL/GcnRank SwissProt
L,74060 P552X6
References
'
Kido, M. ct al. (1998)Gcnomics 28, 186-194. Taniharn, H. et al. (1994)Cell Adhes. Commun. 2, 15-26. .3 Yap, A.S. ct a]. (1997)Annu. Rcv. Ccll Dcv. Riol. 13, 119-146. Korematsu, K. et al. (1998)Neuroscience 87, ,3033 15. Munro, S.R. et a]. (1996)Cell. Immunol. 169,309312. Korcmatsu, K. and Rcdics, C. (19971Dcv. Dyn. 208, 178-189. ' Korematsu, K. and Redies, C. (1997)J. Comp. Neurol. 387,291-306.
Cadherin-11, osteohlast cadherin
Family
Structure Molecular weights A ~ n l n oacids Polvpept~dc
796 SX 049
SDS-PAGE rcduccd
1 15 kDa
Carbohydrate r"\'-linkc~lsites ()-linked sitcs
--I
Gene location
1 h q l l - l hq22.l
Gene structure Alternative forms An alternatively spliced truncntcd form of OR-cadhcrin with a different cytoplasmic tlomnin results from an insertion of 179 hp in an intronl.
Structure Like the classical type I cadhcrins, OR-cadhcrin is prcdictcd to he expressed initially a s a precursor with an N-tcrminsl propcptidc d o n ~ a i nclcavcd off inside the cell during protein mnturation. The cxtraccllular domain contains five cnrlhcrin rrpcats of ;lpproximatclv 110 amino acirls scparatcd hy four calcium hindin!: sitcs. In contrcist to the classical type I cntihcrins, OR-cadhcrin h;is ;I shorter propcpt~dcscqucncr and a QAV rathcr than HAV motif in the homntypic binding site in thc N-tcrminnl domain2-'. Thc nltcrn;itivcly splicrd torm of OR-cadhcrin is cxprcssccl on thc cell surfacc wit11 int;lct OIt-cndhcrinl. T h e cytoplasmic domain ot the intact form nssociatcs with p-catenin'. T h e structure of the cadherins is discussed further in Section I.
Ligands OIt-cadhcrin csprcssccl in L-cells n1cdi;itcs Ca? -dependent cell-cell ; ~ c l h c s i o n ~;. ~? ~n ~dthis interaction is strcngthcncd hy co-expression of thc truncated OR-cadhcrin isoformr.
Function T h e expression p;ittcrn ot OH-catlhcrin s u ~ c s t th:it s it m;iy hc involved in mcscnchymal diifcrcntintion', segmentation and c o ~ ~ ~ p a r t m c n t a l i z a t iofo n the developing hr:iinfi, mcdifiting trophohlnst-cndomctrium ~ntcractions' and honc forrn;ition2.
Cadherin Family -
-
-
Distribution OR-cadhcrin was initially idcntificd in ostcohlastic cell lincs, prccursor ostcohlasts and primary ostcohlastic cclls trom calvaria. Low lcvcl exprcswon is dctcctcd In vivo in a variety of tissues including honc2. During dcvclopmcnt OR-cadhcrin is n markcr of ~ncscnchymalcclls and restricted arcas of thc hrain5.",8.".
Disease association OMIM 600023
Knockout MGI:992 17
Amino acid sequence of human OB-cadherin LVCLGMLCHS HAf ;,i'(.':.',
-NYCLQm
.
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The propeptide sequcncc undcrlincd and in italics is cleaved to form thc maturc protein.
Data base accession EMRLlCcnRnnk SwissProt
W405h
P552X7
References Kawaguchi, J. ct al. (1999)1. Ronc Mincr. Rcs. 14, 764-775. Okazakr, M. ct al. (1984)J. Riol. Chcm. 268, 12082-12098. Tanihara, H. ct al. (1994)Ccll Adhes. Commun. 2, 15-16. Yap, A.S. ct nl. (1997)Annu. Rev. Cell Dev. Riol. 13, 1 19-146. Kimura, Y. ct al. { 19951 Dcv. Riol. 169, ,347358. K~murn,Y. ct al. (19961 Dcv. Dyn. 206, 455-463. ' MacCalman, C.D. ct 81. (1996)Dcv. Dvn. 206,201-21 1. S~monncau,L. ct al. [1995l Ccll Adhcs. Commun. 3, 1 15-130. S~monncau,L. and Thiery, J.P. ( 19981 Ccll Adhes. Commun. 6, 4.3 1-450.
-
-. -.
-
.
Cadherin-12, brain cadherin, N-cadherin 2
-
-- -
- --
.
- .-
Family Cadhcrin (type 11 subfamily)
Structure Molecular weights Amino acids Polypeptide
794 88 274
SDS-PAGE reduced
120-125 kDa
Carbohydrate N-linked sitcs 0-linked sites
4 unknown
Gene location
5p 14-5p 13
Gene structure Alternative forms Structure Like the classical type I cadherins, Rr-cadherin is predicted to he expressed initially as a precursor with an N-terminal propeptidc domain cleaved off inside the cell during protein maturation. Thc cxtracellular domain contains five cadherin repeats of approximately 110 amino acids separated by four calcium binding sites. In contrast to the classical type I cadherins, Brcadherin has a shorter propeptide sequence and a QAV rather than HAV motif in thc homotypic binding site in the N-terminal The structure of thc cadherins is discussed further in Section I.
Ligands Predicted to mcdiatc Ca2'-dependenthomotypic adhesion.
Function Thc cxprcssion pattern of Rr-cadhcrin is consistent with a role in neuronal development.
Distribution Br-Cadhcrin is expressed exclusivcly in neurons in thc central nervous system. During devclopmcnt, cxprcssion is dctectahlc with thc nnsct of synaptogenesis and dendrite outgrowth2.
Disease association OMIM 600562
Knockout MGI:1.09503
Amino acid sequence of human Br-cadherin MLTRNCLSLL L W P D G G L L TPLp,WPOOT L.alTRPPE,\TTTTiI HL FGURSHFO RI.'K.%k.57:iTN0 EFO'T"~:'CVLIIS DLDY:CECT\'KYTLiSDGGAG '?.:PTI DETTCU IF!,\IRSLDRE PF':LEEY:.:GS ETPFYTLRAO QVKATDADDP DMGCOLGGL!? NAEIFYNIVP SAGPFKDTAT FID121KSDGDS DLTEFPPEIS F.DFR?!NTAGI CNIJEAIFLFJ DDEGGGEEDT LQEPNDVDFTA MFGFEESYNP
AVDTETPXPL TYGMSA'WY GTTT?VITTLT GDGGNLFDrV VKIS3\!LDVDF. Y F T I KblFGT VFYETAVCEN ETRFNGYSPP GLSTGALIAI
EPESEPIIKV SILQGOPYFS DlrNDN?PRFP TDEDTOEGVI F'F:..?FSK?LLY I.L.T?!ELLDP.E AKPGQIIQIV QOELY FLPi;",.,' LLCI'JILLAI Ui?>l!;ALFtI PY',v7ZEF:::':? P?IPSLATYA Y EGSGSVAES DYVT
ODINDNEPKF LDGPYVATVP IDPKTCVIRT ALPNMDRFVI! KSIFHLVVPE S S P I G S A I G R KLKKPLDFET KKAYTFKVEA TNE'VY EDTFVG T I IG,'~LJTAQD STAQVNFSI I A S W S M P L L T SAADPDLSPA GQQFSFRLSP IEDSSY PVQS STNTMTIP.?T LPL?LYVALRRQ KKKHTLMTSK P P I Y P3C'LCL PRQF.PPMEDM L S S I DSLTTF ADQDYDYLTD
RMSPVGAYVL FOYOt'LIOAK I RAVDPDFGO SNLHLDHRFF LDVGSGA?.iP.Y SKvT.11L I P K L E.UIY.PE1FTV P.CDSDGTILS ED1 RDPXIHY TDIEDFIFQP b:GPRFYVLAD
The propeptide sequcncc undcrlincd and in italics is clcavcd to form the mature protein.
Database accession EMRLlGenRank SwissProt
L34057 P55289
References 3
Tanihara, H. et al. { 1994)Cell Adhes. Commun. 2, 15-26. Selig, S. et al. (1997)Proc. Natl Acad. Sci. USA 94, 2398-2403. Yap, A.S. et al. (19973Annu. Rev. Ccll Dcv. Biol. 13, 119-146.
-~
Cadherin-13, heart cadherin, T-cadherin, truncated cadherin
-
-
~
Family Cadherin (modified cadherin]
Structure Molecular weights Amino acids Polypeptide
SDS-PAGE reduced
Carbohydrate N-linked sites 0-linkcd sitcs
8 ( 2 in propeptide sequence) unknown
Gene location
Gene structure Alternative forms Structure Likc thc classical type I cadherins, H-cadherin is predicted t o be expressed initially as a precursor with an N-terminal propeptide domain cleaved oft inside the cell during protein maturation. The extraccllular domain contains five cadherin repeats of approximately 110 amino acids separated by four calcium binding sitcs. In contrast to the classical type I cadherins, H-cadherin has a EV/TT rather than HAV motif in the homotypic binding site in the N-terminal domain and is attached to the cell mcmbranc by a GPI anchor1.K In addition, 130 kDa forms of Hcadherin representing molcculcs retaining the propeptide can also he detected a t thc cell surfacc". Thc structure of the cadherins is discussed further in Section I.
Ligands Not known.
Function Thc ability of H-cadherin to reverse the invasive phenotype in H-cadherin negative brcast cancer cell lincs4S suggests a rolc in thc maintenance of the normal epithelial phenotype. Without a cytoplasmic domain it is prcdicted that H-cadherin may not function in mediating direct cell-cell interactions, rather it may initiate signalling pathways due to its localization with signalling complexes in caveoli6.
Cadherin Family
-
--
Distribution H-cadherin is highly expressed in heart and breast epithelium. In vascular smooth muscle cells, H-cadherin co-localizes with caveolin rather than to cell-cell or cell-matrix contact areas6.
Disease association OMIM 601364 H-cadherin expression is lost in many breast and lung cancers"'. Monitoring H-cadherin levels may have prognostic value as a marker for breast cancer development4.
Knockout MGI:9955 1
Amino acid sequence of human H-cadherin 1 MQPRTPLVLC VLLSQVLLLT SAFDLgCTPC JrCOFI'.r.W?!,:O FA11ESiED051 LNLTFSKI.:G ..,.:,- '.$'A.,,.,:L,c I . ,.. ;..;.....>,,. , r.... 7.-7-.-, ....,?.. . . ..: , ~:.~.::,,:-:'.:~.:.-!.z: ~;:.:,y,n?.-~:.'.;i' ::eci::~:~>as ,: .:,;.,; ,.j.,,.:,.,.. L~.i;;. ; .;-, .,~.: . , ,.*,, .-. . . . ... .,,.. . , . .- ., ,. , . : r -.. ... : ; i , E ; J . fiF'::J,.:,':c:', "., ,,, ,.-; . . ;.* . ...... :.- ."T PT:,>PE-.'I:+'.. .:'l?:,i;',.'ETTY$ pIGFT::iGPVP L~,!I\'I~Q>]D L
L
.
.
.
.
.
_
_
~
.
.
.
L ,l.
.
[;
-
, ,
D?<2DP.\TDE!A LIPYMIPQOT PPt(PSPb!k!:';'?' IEAQD?,!irGI.D !.'GLTCTIZTi\T IMIDDYFJLIHS PL:rTEL'!.:F'QA T','i.:T:GA'.'r3','1 PTTGA;;:P.:L~Y TIINGNPGOE; FEIHTNPOTN EG!dLS7,".'?'L D'iEIS2.FI'TL L I P ' : Y I E 7 3 '..?T,'F'iG?SS T.AT?JHITVI,D 1.T4EGPVFYPD iTDP?'LQ!iQ T1PYc;'l:'YDP AGWLMIMPIM GTJTPTTAVLP FK.T,"TPOFD:, S','C?'.'I,I,T"Tl PTSPF3,'I?!!S'.' ':'T.\LFL'rII?S GPlPP1,TGTCT LLTTLEDL7:D ?IAPFI?PTVA EVCDDAKTJLS >v.: -LC;.?,CCIF'D Lt!?P!TI??r?T CIH!'Q?<'.'FD!! \?!KISt:!P!Y!'r II:\L?.rSLI,ON NKANYMLPIM '.'TDSC? P?Y? !:IT7:,F'.'r?"'I LqCPP::';.'.'?CII ?:.YC;.P\,PFS:,F SIrLLLSLFSL ACL. !;? P i FPE'Y?';
Im;L" ?!EGC?T
GTT.?.!F!.!T?t.F
1DPEYGDII'T ..".'SI>.>I,C"E
TLFI:P;"CF.:,T '.'Pl>T':EDPDCI
.
Notes 1 Gh93 represents the site of lipid attachment. 2 The propeptide sequence underlined and in italics is cleaved to form the mature protein.
Database accession EMRLIGenRank SwissProt
W4058 P55290
References Tanihara, H. et al. (1994)Cell Adhes. Commun. 2, 15-26. Yap, A.S. et al. (1997)Annu. Rev. Cell Dev. Riol. 13, 119-146. Stambolsky, D.V. ct al. (1999)Riochem. Riophys. Acta 1416, 155-160. Lee, S.W. (1996)Nature Med. 2, 776-782. Lee, S.W. et al. (1998)Carinogenesis 19, 1157-1 159. Philippova, M.P. et al. (1998)FERS Lett. 429, 207-210. ' Sato, M. et al. (1998)Hum. Genet. 103, 96-101.
*
Family Cadherin family (type II suhfamilyl
Structure Molecular weights amino acids polypeptide SDS-PAGE reduced
Carbohydrate N-linked sites 0-linked sites
Gene location Gene structure Alternative forms
)
COOH
Structure Like the classical type I cadherins, cadherin-14 is predicted to he expressed initially as a precursor with an N-terminal propeptide domain cleaved off inside the ccll during protein maturation. The cxtracellular domain contains 5 cadherin repeats of approximately 110 amino acids separated hy four calcium binding sites. In contrast to the classical type I cadherins, cadherin-14 has a shorter propeptide sequence and a QAI rather than HAV motif in the N-terminal domain'-'. The cytoplasmic domain associates with catenin complexes". Thc structure of the cadherins is further discussed in Section 1.
Ligands Cadherin-14 mcdiatcs Ca!--depcndcnt homotypic adhcsion. In addition, in mixed aggregation assays, cadherin-14 partially interacts with cadherin-(,?.
Function The restricted expression of cadherin-14 to the central nervous system suggests a role in regulating ncural ~norphogencsis.
I
Distribution Cadherin-14 exhihits neural-specific expression and by Northern blot analysis is found broadly expressed in the adult central nervous system. In addition, cadhcrin-14 is detcctcd in small-cell lung carcinoma ccll lines which have a neuroectodermal phenotvpe'.
0 Disease association Knock out MGI:1344366
Amino acid sequence of human cadherin-14 1 2 1 KTHYJ,'LHAOA IDRPTF:KPLE PFSEFI IKVO 1R 1 ','TATDADUP? YGMSAPWYS ILQGQPYFS'J 2 1 1 MAGWGGLSG STT'JNITLTD VNDNPPRFPO 3 0 1 ?rDMTYSI I!IG DGteIGIFSIST DKETRrGILS 3 6 1 LGPFKDATIK K I IVGDXJDEP PLFSMPSYLM 4 2 1 1t:YFKFDDRF FNI 3AI.!TGTI RTTKVLDREE 4 R 1 '?IF.:DhlFPELAR EYDI IVCEMS KPGQVIHTIS 5 4 1 D?:EDP?TASIL TRRRRFSRTV ODVYYLPIMI 6 0 1 HAE4FLSSAG LSTGALIAIL LCVLILLAIV 6 6 1 EGGGEEDTEA FDIT!IL!?I.I?S AAEELKYZRD 7 7 1 AFADLDPSV" FYDSLOTYAY EGORSRAGSI 7R1 YGEIESEPTT
DINDFIAPKFT DPKTG'JIPTA KHYOLYVPES LKKPLNYEKK EVYENAKIGT TPWYrJITVTA ATDKDDFAFlC SDGGIPSLSS \?LCITLP,RSY IRPEIJKLTPF: SSLDSATTOS
DGP'iIVT%'?E LHI!MDPEAFE AO'.'GSA'JGKI KSYTL!!IFGA T."!GT\'LAODF SEI331FDLLS PFFPIFFLDER SICTLTIFVCA YREPLIISCED HOTSSTLESI DODYH7'LGD'.J
!4SDF!GTS7,'L0 PYS',".'IQ.\VD YAI.JDAi3TCSEI WTHLDFRFSH DSTE:SL'.'FYF F'JT'b'GI P'JLD LP'vT:PPlFTLK CERDGP'JFTC ~.'F!3F
The propeptide sequence underlined and in italics is cleaved to form the mature protein.
Data base accession EMRLIGenbank SwissProt
US9325 Q13634
References Shibata, T. et al. (1997)J. Riol. Chem. 272, 52365240. Yap, A.S. et al. (1997)Ann. Rev. Cell Dev. Riol. 13, 119-146. ~ h i m o y a m aY. , et al. ( 1999) J. Riol. Chem. 274, 11987-1 1994.
Cadherin-15, muscle cadherin --
--
Family Cadherin (type 11 subfamily)
Structure Molecular weights Amino acids Polypeptide
814
SDS-PAGE reduced
125 kDa
88915
Carbohydrate N-linkcd sitcs 0-linked sites
4 unknown
Gene location
16q24.3
Gene structure Alternative forms Structure Like thc classical type I cadherins, M-cadherin is predicted to be expressed initially as a precursor with an N-terminal propeptide domain cleaved off inside the cell during protein maturation. The extracellular domain contains five cadherin repeats of approximatcly 110 amino acids separated hy four calcium binding sites. In contrast to the classical type I cadherins, M-cadherin has a shorter propeptide sequence and lacks the HAV motif in the N-terminal domain. In addition, M-cadherin exhihits a higher sensitivity to proteolysis in the presence of Ca'-1.2. The cytoplasmic domain associates with catenin complexes thereby linking of M-cadherin with the actin cytoskeletonz. The structure of the cadherlns is discussed further in Section I.
Ligands M-cadhcrin mcdiatcs CaL--dependent homotypic adhesion'.
Function The expression of M-cadherin in myogenic cells during embryogenesis and in regcnerating adult musclc suggests that M-cadherin in involved in morphogenesis of skeletal muscle cells. In particular, hlocking studies have impllcatcd M-cadhcrin in thcir terminal diffcrcntiation3.
Distribution During development, M-cadherin is present at low levels in myohlasts and is uprcgulated in myotube forming cell^^.^. Shortly before birth, M-cadherin expression is downregulated but is re-expressed in regenerating skeletal muscle m y o b l a s t ~ , ~In ' . addition M-cadhcrin is expressed in spccializcd adherens junctions in the granulc ccIl layer of the ccrcbellar g l o m c n ~ l u s ~ .
Cadherin Family -
-
Disease association OMIM 114019
0 Knockout Amino acid sequence of human M-cadherin 1 MDAAPLLVLG LLAQSLCLSL G 1'PG!tTF.T.PTT L ?F!r'.VF,1 F.4 L pF(,:' ':-! ; ::!;'F t :..:>?? 6 1 'd .:,'>.:~;A:b:rj~ .. F?; ~ p ' ~ : : ; , : , { ~ y, ~ ~5, :{);(:; ~ 131 ~ , ~ F , : , L @ L G ~TcL : : ~ ~ P T D L F I:,?~::~y!pyp p .~,FLQ:,:,FTCW 1 8 1 DPETD?:AALP F S I L O O G S P E LFS IDTLTG? I?T'.'O','CLP? 1 4 1 T?iT,?iI;?iITTI. DDI?!3:!,i?FF 3 0 1 LECDFUGOFT I PTDFPT?TFG 3 6 1 Y'.'P!!U:!OU7:! EPF?'FOE:!PL 4 2 1 i:rLQ'.'3.:i.;.TGP ;QT@H".'L.SPA 4 8 1 Fk'LAP?PFGS LCSC;P![QGPG 5 1 1 I ? ~ i D L B ? P H @PEGLH?.T,SI,t, ~ 6 0 1 GLS[.GAL,'~!T7.' L:\ShLLLL,'L 6 6 1 E F E O D ? ~ ' ~ ~ I):,:::: ~::: : ',:-I::. '
TPDFFF!.!F.hI I'LS 1;'YALDY ?TSL.:iFG.:iPP SPFLYC-G1:.'\.'? LLLGATDEDL tJPUSG0??0Q ';'LL'.',JiLPAPF
EA?'SC:..'D;'GP FSCEH'FELE'.' GTL5.'ATFSAF AI\:[email protected]
PFLlGA?F!iF@ FCOPL!rlTIrC I'POSPGIIGLL I , L ~ : ! , : L P P D .?,p<jc:a;b!rOP GPCFi'AGTLS SIL?S@GD'D SPGALLPPt!? GPTA
S R IliR:1.I:7'J F F I S I 'SEt\r,YK.T :):y..'F:,::;s!:;, r)pF.y::lz :,
T , ' : , ~ ~ ~ ; v p ~v~?,\ET~,:,D :~y i7'.".'.A','YFILTL @',.'$E',lSGCT-L LE'.:E3D3LPG SP?TST,'A?.TI S',!Q!IE".PLO.\ XAL?AE?GQ?. DPD?FOLQ?i SYS:'D;'DFED OF??.:tT'_"?LS IEILB\?!DHA L F P P L F E L C P :!>!SLS07,.TT.'S P.CTrKDG:TLP G,Z;!ALL.IGGT 'I'L!!'~D"QCCC t!CPQ3PLPI?!: F P Y L P T C P L D IADF:?II~~;LF ODVDI'LPP!\'C P?C.APL.L.l?!.!Y
The propeptide sequence underlined and in italics is cleaved to form the mature protein.
Database accession EMBLlGcnBank SwissProt
D83542 P5529 1
References Yap, A.S. et al. (1997)Annu. Rcv. Ccll Dcv. Biol. 13, 119-146. Kuch, C. et al. ( 1997) Exp. Cell Res. 232, 33 1-338. -' Zeschnigk, M. ct al. [ 1995) J. Ccll Sci. 108, 2973-298 1. Donalies, M. et al. (1991 ) Proc. Natl Acad. Sci. USA 88, 8024-8028. Moore, R. and Walsh, F.S. ( 19931 Development 117, 1409-1420. " Irintchev, A. et al. (1994)Dcv. Dyn. 199, 326-337. ' Pouliot, Y. et al. 11994) Dev. Dyn. 2 0 0 , 3 0 5 3 12. q o s e , 0. et al. (1995)Pmc. Natl Acad. Sci. USA 92, 6022-6026.
Cadherin-16, kidney-specific cadherin - -
-
-
-A
Family Cadhcrin (modified cadherin)
Structure Molecular weights Amino acids Polypeptide
829 89 866
SDS-PAGE reduced
130 kDa
Carbohydrate N-linked sites 0-linked sites
4 unknown
Gene location
l6q21-16q22
Gene structure Alternative forms
COOH
Structure Unlike the classical type I cadherins', the extracellular domain of Kspcadherin contains sevcn rather than five cadherin repeats of approximately 1 10 amino acids, it lacks the HAV adhesion recognition sequence in the Nterminal domain, thcrc is no cvidcnce to support the existence of a propeptide scqucncc and thc cytoplasmic domain is relatively short2.". The s t n ~ c t u r cof the cadherins is discussed further in Section I.
Ligands Not known but hascd on homology t o LI-cadherin, Ksp-cadherin is predicted to mediate Ca2.-dependent homotypic adhesion.
Function Predicted to mediate cell-ccll adhesion in the kidney.
Distribution Ksp-cadhcrin expression is rcstrictcd to the krdney where it is found on the hasolateral mcmhrancs of the prnxlmal tubule, the thick and thin limbs of the loop of Henle, the distal convoluted tuhule and a suhpopulation of cells in the connecting tubule and collecting duct"*.
--
--
Cadherin Family
. ---
-. --
L
Disease association OMIM 603 1 18
Knockout MGI: 1Oh67 1
Amino acid sequence of human Ksp-cadherin
Database accession EMRLlGcnRank AFOl6272 TrEMBL
075309
References 2
Yap, A.S. et al. (14971Annu. Rev. Cell Dev. Rlol. 13, 119-146. Thornson, R.R. ct al. (1995)J. R~ol.Chcm. 270, 17594-1 7601. Thornson, R.R. et al. (199FIl Genomics 5 1,445-45 1 . Thornson, R.R. and Aronsm, P.S. ( 1949) Am. J. Physiol. 277, F 146-1 56
Cadherin-17, liverlintestine cadherin
-
. .. .. -
--
-
-
Family Cadherin (modified cadherin)
Structure Molecular weights Amino acids Polypeptide SDS-PAGE rcduccd Carbohydrate N-linked sites 0-linked sites
Gene location
Gene s t r u c t u r e Alternative f o r m s
COOH
Structure Unlike the classical type I cadherins', the extracellular domain of LIcadherin contains seven rather than five cadherin repeats of approximately 110 amino acids, it lacks the HAV adhesion r e c o ~ i t i o nsequence in the Nterminal domain, there is no evidence to support thc cxistcncc of a propeptide sequence and the cytoplasmic domain is relatively short*. The structure of the cadherins is discussed further in Section I.
Ligands LI-cadherin can mediate CaZ--dependent cel1:cell adhesion in transfected cells'. Unlike the classical cadherins, this adhesion is independent of the cytoplasmic domain as generation of a GPI-anchorcd LI-cadhcrin resulted in cell-cell adhesion in transfected cells equivalent to that mediated hy intact LI-cadherin,?.
Function Predicted to mcdiatc ccll-ccll adhcsion in livcr and intestine with an adhesive function complementary to that of the co-expressed classical cadherins3.
n Distribution
U
LI-cadherin has a restricted cxprcssion in livcr and intestine, where it is found on the hasolateral surfacc nf hepatocytcs and the latcral surfacc of intestinal epithelial ccllsz.
-
Cildherin Family
Disease association OMIM 60.3017
Knockout MGI: 1095314
Amino acid sequence of human LI-cadherin MILQAHLHSL CLLMLYLATG YG.'
.
.
*
, ,
. . ..
. . I.
* -
? .
'
. . ,
' - . -- - - -
-
.
-- .-
.-
.
Database accession EMRL/GcnRank SwissProt
U07Yh'l ( h l ~ m n n ) Psi28 I (r;ltI
References Yap, A.S. ct al. [I9971Annu. Rcv. Ccll Dcv. Riol. 1,Z, 119-146. Rcrndorff, D. ct al. ( 1 994) J. Cell Riol. 125, I;i5.3-l.<69. Krcft, R. ct al. (1997)1. Ccll Riol. 136, 1109-1 111.
-
. -
-7
7
-
Desmosomal glvcoprotein 213, DG2/DG3
Family
Structure Molecular weights Amino acids Polypeptide
891 100044
SDS-PAGE reduced
120 kDa
Carbohydrate N-linltcd sites 0-linked sites
7
Gene location
1 K ~closclylinkcd to dcsmocollin 21
I 11111
j
\Ill\ 11111
Gene structure Alternative forms Types IA (dcsmosnmal glycoprotcin 2) and IR (dcsmnsomal glycoprotcin 31 are produced hy alternate splicing Icading to different cytoplasmic tails.
Structure Dcsmacollin 1 1 - 7 is n type I mcmhranc glycoprotcin that shows overall homology to the classic cadhcrins, and similarly has a clcavcd N-terminal prnpcptidu and five cxtraccllular cadherin repeats of approximately 110 acids length. The mature form of the protein forms a homodimcr with adiaccnt molcculcs at thc ccll surfacc, utilizing conscrvcd mcmhranc proximal cystcine rcsidues. An adhesion recognition scilucncc that is involved in homopliilic interactions with cadhcrins on ncighhouring cclls is F/YAT/S, rather than HAV as sccn in the classical cadhcrins. A short cc~nscrvcdscqucncc (C domain1 in thc cytoplasmic tail of dcsmocollin 1 interacts with intcrmcdiatc filamcnts (keratin in skin and dcsmin in heart] via plakoglohin (y-catcnin) and other dcsmosomc-nssoci:~tcciproteins, such as dcsmoplakins ;ind plcctin (rcvic\vcd in refs 4-01.
Ligands Calcium-dependent Iiomophil~cadhesion occurs 1,ctwccn cadhcrin repeats of molcculcs in ndiaccnt cclls.
Function Dcsmocollin 1 is n component of thc intcrccllular dcsmosnmal junctionJ-", maintaining the strength and integrity of the cpithclium1@12. It mcdiatcs calcium-cicpcndcnt cell-cell nrihcsion and the interaction of mcmhrane plaque proteins with intrficcllular intcrmcdiatc filamcnts. It may also he
I
Cadherin Family --
involved in keratinization (epithelial maturation) and differcntial cellular adhesion via desmocollin variants interacting with different cytoplasmic component^^.'"^^.
Distribution There is strong expression in the epidermis but not in other, nonkeratinizing epithelia; there is lower expression in a restricted number of other tissucs such as lymph node.
Disease association OMIM 125643
Knockout MGI:109173
Amino acid sequence of human desmocollin 1 1 W S A A P G S IPCKQLLPSL LVLTLLCDAC OL':'!':.@:'.?S:! ( -;,;,.-7r:,r' -,.,.. 7 - , ,..: .. . .-. ..-: (.: : . : y .: r c. -.- .. ...
61
Ki<.sT"'?'>',r' F'F':::.?'I'
661 721 781
841
,vT:'L"" :,.,p t‘ 1p 8.
I F ' r D ? C r l . cC-RS:
YFFHQ.','TIF"T GVITTTTPF; TEIrEENP.ID?' PLPJY ?vr?J?O'.' ODCFPAGOEL. KTJFIOVP1T5',PJ PCF!GPPFOFF TxiP.','C!3C?TF' KKCFPEDIXQ EMVKGGYTLD KHCEDWCSY
..-. -
i>,~;r,!~~],CLi;~?
D?EV':'EQF,AL 'i7PCHC?SGTf: ',.'CK";TAr:'3;D D?E?:CPT":'OL IF!!?,'RD!.!GGO EII~?P~K'.'OT)O DI,P!!?PFr3r'?r ILO'.'C,'.'Tl!E?. OFFI:A?rC$OT LG'!'YhLDPEI FSCECLPYO? .Af,TW.','C,PSC? GT;'I"'.rIi'131?'x' I,D!!.SA.Sr"P'?l TEFKDGF'TAI SFCPFIY?Y ST R?'.'? F?I'P.'TLC: Q?lLI';SII?FG PGCE'.'TF.A?!I STJPGGGYQTI, CS',.'?G'.'GOGD EIYECYGSLAC: S','GCCSD?@E
.---
]:;,$?l7';>T&
;
.
:?73C?L!FC:1' ,?;=
c;F,..,,
;r,-;z8;:;y$;:''y:
[--{
YPY.A'T':'?~.D';'i .AFEYPLPLT I E?>TLHTP.LK YKILQQIPDH FFCLFbITGTI TISLEDENDM ','?'KILOGt!C!l C?IFI I S T 3 P N FT\1CTTTVT7~' K I IDSDEGPE LG3EDPKp!FEI NCI!ITGI)LRTL Pl@llAPOIDKE 'r'TICQFI?!EtlF LPOPOPILDYM Y Y S V P I O I K 3 PV.'AI LAl.%7SG S'VLLLCI LPT P;,P!,',;I::'I!TC ?T:?.ISVCT',,'G TGPi'hYTDXO SFTOPRLGSK EEGLEFLDHL EPRFRTLAKT
.\f:FFICLPS;S
.
. .; . , ~ c h , b . .. . ..2
~:;~~.?(:','[>~~~
KYFD3>:9>:A? PKHFSZHPI?T PPSFTETSYV TNEGVLCWK CIIPPVKVIQS MVLDRESKFV AVLKPVDPDG RHGLVATHML CPCVTAKPTV GOGIKTQOSF 'vfY:,CGOI)EEH CIKK
Notes 1 The propeptide sequence underlined and in italics is cleaved to form the mature protein. 2 In form 3h amino acids 830-840 are replaced by ESIRGHTLTKN, and 841 to 894 are deleted.
Database accession EMRL/GcnRank SwissProt
Z34522 Q08S54
References Troyanovsky, S.M. et al. (1993)Cell 72, 561-574. Theis, D.G. et al. (1993)Int. J. Dev. Riol. 37, 101-1 10. King, I.A. et 31. (1993)Genomics 18, 185-194. Ruxton, R.S. and Magee,A.I. (1992)Semin. Cell Biol. 3, 157-167. Koch, P.J. and Frankc, W.W. (1994)Curr. Opin. Cell Riol. 6, 682-687 Green, K.J. and Jones, J.C. (1996) FASER J.10, 87 1-88 1.
Cadherin Familv
Garrod, D. ct al. 119c)61 Curr. Opin. Ccll Riol. 8, 670-678 Troyanovsky, S.M. and Lcuhe, R.E. 119981 Suhccll. Riochcrn. 3 1 , 2hL3-2X9. " Kowalczyk, A.P. ct ;11. 119991 Int. Rev. Cytol. 185, 237-tZ02. I n King, I.A. ct ill. 11991 I FERS Lett. 286, 9-11. l 1 King, I.A. ct nl. j 19961 1. Invest. Dcrmatol. 107, 531-.5,3S. 'V3urdctt, I.D. 119981 Micron 19, 309-.32X. " Ruxton, R.S. ct nl. 1199,311. Ccll Rinl. 121, 481-4K.7. I J Schmidt, A. ct al. jlC1941 Eur. 1. Cell Rid. 65, 129-23.5.
Family Cadhcrin (dcsmosomal subfamily 1
Structure Molecular weights A n i ~ n oa c ~ d s Polypeptide
90 1
SDS-PAGE reduced
1 15 kDn
99961
Carbohydrate N-linked sites O-linked site5
5
Gene location
181112.3
Gene structure Alternative forms
S
O
H
Typcs 1 A (dcsmosom;~lglycoprotcin 2 ) and 2R (dcsmosomal glycoprotcin 31 arc produced hy alternate spllcing leading to diffcrcnt cytoplas~nictails'.
Structure Dcsmocollin 21--3is a typc !glycoprotcin of thc cadhcrin family composcd of five cadhcrin rcpcats wit11 3 clc;~vctl N-terminal propcptidc as in the clnssical cadhcrins [scc dcs~nocollin1 frlr gcncral structural details, w h i c l ~ arc well rcvicwottlJ-".
Ligands Calcium-dcpcnrlcnt hon1ophilic adhesion occur4 hctwccn cndhcrin rcpcnts nf molcculcs in ;~diaccntc c l l ~ .
Function Dcsmocollin 2 is n component c)f thc intcrccllular rlcsmosomal iunction+*, maintaining the strength and integrity of the cpithelillm and heart m i i s c l c ' ~ ~It~ . nlcdiatcs calciun~-dcpcndcnt ccll:ccll adhesion and the interaction of mcmhranc plaque proteins with intraccllular intcrmcdiate filaments. It may also he invr~lvcdin kcrntinization [epithelial ~naturation] and diffcrcntinl ccllulnr ndhcsion vin dcsmocnllin variants interacting with riiffcrcnt cytoplasmic components.
Distribution Strong expression in all cpithclin, lymph nodes and hcart occurs.
Disease association OMIIV 125643
Knockout MGI: 10,3271
Amino acid sequence of human desrnocnllin 2 MAAVGSMRSG SPAFGLGGHLL TLAILAL
'
Notes 1 Thc prt~pcpt~rlc sctllicncc ~mdcrlincdand 111 italics 1%clcavcrl to form the Tnaturc prc~tt.111. 2 In f o r m 2h atnino acirls X<37-KJ7arc rcplnccd hv ESTRGHTLTKN, and K4K t r j 901 are dclctcd.
Database accession EM1~LjC;unHank
S\vis.;Prot
X5hSO7 Q01.187
References I'arkcr, A.E. c t a1 ( I 99 1 1 1. Riol. Chcm. 266, 104.3K-10445. Ruxton, R.S. ct dl. ( 1994)Gcnoinic~i21, 510-5 16. Lorlmcr, I.E. ct ~ 1( 19941 . Mol. Mcmhranc RioI. 1 1 , 229-2.36. Ruxton, R.S.and M a ~ c cA.I. , 119921 Scmin. Ccll Riol. 3 , 1.57-1 67. Koch, P.J. and Frankc, W.W. 11994)C ~ l r rOpin. . Ccll Riol. 6 , 682-687. " Grccn, K.1. anti loncs, 1.C. I 19961 FASER 1. E 0, XJI-XXI. Garrorl, 13 c t ;)I 11 Y%I Curr. O p ~ nCcll . Riol. X, 670-678. T r o v n n o v ~ k v S.M. , :ind Lcuhc, R.E ( I WXI Suhcoll. Riochcm. 3 1 , 26<3-2XY. ' Korunlczyk, A.P. ct ;)I. 1199511 Int. Rcv. Cytol. 18.5, ?,37-.102. kin^, 1.A ct a1 ( 1991 1 FERS Lctt. 3 6 , 9-1 1. " kin^, I A. ct al. (109611. I u v c ~ tI3crmatol. . 107, 5,Zl-5,38. Ihrdctt, 1 I?. (19981M ~ c r o n29, ,409-.11X.
Formerly desmocollin 4
-
-.
-
..-. . .
Family Cadherin (desmosomal subfamily1
Structure Molecular weights Amino acids Polypeptide
896 99 968
SDS-PAGE reduced
1 15 kDa
Carbohydrate N-linked sites 0-linked sites
4
Gene location
18q12.1
Gene structure Alternative forms Types 3A and 3B are produced by alternate splicing leading t o different cytoplasmic tails.
Structure Desmocollin 31.2 is a type I glycoprotein of the cadherin family composed of five cadherin repeats with a cleaved N-terminal propeptide as in the classical cadherins (see desmocollin 1 for general structural details, which are well reviewed!-.
Calcium-dependent homophilic adhesion occurs between cadherin repeats of molecules in adjacent cells.
Function Its location in epithelial desmosomes and cadherin structure34 implies it has a role in epithelial cell-cell adhesion'lt.
Distribution Keratinocytcs and all other epithelia.
Disease association OMIM 600271
Knockout MGI:1194993
Cadherin Family
1
Amino acid sequence nf human desrnocnllin 3 MAAAGPRRSV RGAVCLHLLL TLVIFSR
-
--
--
-
&
Notes 1 T h e propcpt~ticscqucncc unrlurliucd 11nd In ~talicc1s clc,~vcdto torm thc mature protcln 1 In form ,317 ;iniint~;iclda S3?-X,39 arc rcpl.~ccdh~ ESIRGHTG, jnd H30 to S96 ilrc deleted.
Database accrssion ERIIiL C;cnHanlr S~v~wProt
Dl 7517 Q14i74
References
" "
''I
K:IM~;I~IILI~;~, K. c t ;I/. \ 1YL14\I. Riol. Cliciii. 269, ?6295-26<302. King, I.A. ct 31. j 19951 J. Invcst. llcriiifitol. 105, 3 14--32 1. lccll.Itioohcm. .ZI, 26-3-1S9. Kow;llczvk, A.P. ct ill. ( 19991 Fnt. Rev. Cytol. 1 H i , 1<37-.307. Kin,q, !.A. ct ill. I I99 I 1 FEI3S Lctt. X h , 9-1 2. King I.A. ct ;I]. I19Yhl I. Invest. Dcrn1;ltol. 107, 5,3I-S,3S. R~irdctt,1.1). 11 9981 Rlicroi~2'1, .309-,32X.
Family Cadherin (desmosnmal suhfamilyl
Structure Molecular weights Amino acids Polypeptide
1049 113 715
SDS-PAGE reduccd
16.5 kD;m
Carbohydrate N-Iinkcd sitcs 0-linkcil sitcs
3
Gene location
1Xq12.1-12.2
IIIII IIIII
i
IIIII 111l1
Gene structure Alternative forms
Structure Dcsmogllcn 1 IS a typc I mcmhranc glycoprotcin of the cadhcrin family. Thc cxtraccll~~lar N-tcrm~nusof dcsmoelcin 1 diffcrs from classical cadhcrins in \. having a short, 29 nmint~acid long propcptidc anrl only four cndhcrin repeat domains. Thc maturc fonn ot thc protcin fonns a homodimcr with adiaccnt molcculcs at thc ccll surhcc, utilizing conscrvcti mcinhranc prt~xi~nal cystcinc rcsiducs. The adhesion motif, RIYAL, utilizcd in homophilic adhesion with cadherins on adjacent cells also differs from that utiIized in classics1 cadherins [HAVJ.Thc intraccllular part of dcsmoglcin 1 divcrgcs substantially from other cadhcrins in containing fivc, 28-30 amino acid long, rcpeat scquenccs (desrnoglcin rcpcats). Whilst smaller, thcsc show some homology to cadhcrin rcpcats and arc prcdictcd to havc an antiparallel hcta-sheet structure. A short conserved sequence (C domain) in the cytoplasmic tail of desmoglein 1 intcracts with intcrmcdiatc filarncnts [kcratin in skin and desmin in heart) via plakoglohin (y-catenin\ and other desmosome-associated proteins, such as dcsinoplakins and plcctin [rcvicwctl In refs 4-91, f-l
Ligands Calcium-dependent homophilic adheslon occurs hetwccn cadhcrin repeats of mnlccules in adlaccnt cclls.
Function Dcsmoglein 1 is a component of intercellular desmosomal iunctionc9, maintaining the strength and integrity of the epithelium. It mediates calcium-dependent cell-cell adhesion and thc interaction of mcmhranc plaquc protcins with intraccllular intcrmcdiatc filamcntsrwr2.It may also bc involved in epithelial maturation and keratinization.
Distribution Suprabasal expression in keratinizing epidermis, including tongue, tonsil and oesophagus.
Disease association OMIM 125670 Desmoglern 1 l r the target antlgen for the development of autoantibodies in thc hlistcrrng skin discasc, pcmphlgus f o l i a ~ c u s ~ ~ ~ ~ .
Knockout MGI:949,70
Amino acid sequence of human desmoglein 1
The propcptidc sequcnct undcrlinod and in italics is cleaved to form the maturc prntcin.
Database accession EMRtlGenRank SwissPrrlt
X56h54 QOl413
References Nilles, L.A. ct al. (19911 J. Cell Scl. 99, 809-821. Whcclcr, G.N. ct al. (19911Proc. Nntl Acad. Scl. XX, 47964X00. Ruxtan, R.S.et al. (1994)Genomics 21, 510-516.
Cadherin Family
--
--
Ruxton, R.S.and Magee, A.I. (1992)Semin. Cell Riol. 3, 157-167. Koch, P. J. and Frankc, W.W. (1994)Curr. Opin. Ccll Bid. 6, 682487. Green, K.J. and Jones, J.C. ( 1996) FASER 1. 10, 871-88 1. ' Garrod, D. ct al. (19961Curr. Opin. Ccll Biol. 8, 670-678. Troyanovsky, S.M. and Lcube, R.E.(1998) Suhccll. Biochem. 31, 263-289. Kowalczyk, A.P. et al. (19991Int. Rev. Cytol. 185, 237302. lo King, I.A. ct al. (1991)FEBS Lett. 286, 9-12. l 1 King, I. A. et al. (199611. Invest. Dermatol. 107, 531-538. '2 Burdctt, I.D. (19981Micron 29, 309-328. Amagai, M. et al. (1991)Cell 67, 869-877. 14 Chidgcy, M.A. (1997)Histol. Histopathol. 12, 1159-1 168. l 5 Lin, M.S. et al. (19971Clin. Exp*Immunol. 107 (Suppl. 11, 9-12. 1" Moll, R. and Moll, I. (1998)Virchows Arch. 432, 487-504, 4
"
Family Cadherin (desmosomal subfamily)
Structure Molecular weights Amino acids Polypeptide
11 17
SDS-PAGE rcduccd
165 kDa
122,385
Carbohvdrate N-linked sites 0-linked sitcs
5
Gene location
18q12.1-12.2
IIIII IIIII
i
IIIII IIIII
dL
Gene structure Alternative forms
Structure
COOH
13csmoglein 2 is a type I membrane glycoprotcin of the cadhcrin family*v2. Like desmoglcin 1 (see entry for further details), it is has a short propeptidc (25 amino acids) and is composed of four cxtracellular cadherin repeats (Nterminal) and six intracellular cadherin-like (desmoglein) repeats (Cterminal) (reviewed in refs'-n\.
Ligands Hnmophilic adhesion occurs hctwccn cadhcrin rcpcats of molcculcs in adjacent cells.
Function It is a component of the intcrccllular desmosomal junctiomFR, maintaining the strength and integrity of the epithelium. It mediates calcium-dependent ccll-ccll adhesion and the interaction of mcmhrane plaque prntcins with intracellular intermediate filament^"^^. It may also he involved in epithelial maturation and kcratinization. It was originally found in colon cancer and designated 'human-desmo~lcin-colon'(hence, HDGC)12.
Distribution It is cxprcsscd in all simple and stratified epithelia.
Disease association OMIM 12.5671
Knockout MGI: 1 196466
Amino acid sequence of human desmoglein 2
The propeptide sequence underlined and in italics is cleaved to form the maturc protcin.
Database accession EMRLlGcnRank SwlssProt
Z26.317 QI4I16
References
' lo
l2
Koch, P.1. ct al. ll99l1 Eur. 1. Ccll Rlol. 55, 200-208. Schaefer, S. ct al. (19931 Exp. Ccll Rcs. 21 I, ,391-.399. Ruxton, R.S. ant! Magcc, A.I. (1992)Scmin. Ccll Rlol. 3, 157-167. Koch, P.1. and Frankc, W.W. (19941Curr. Opln. Ccll Rlol. 6, 681-687. Green, K.1. and ]ones, J.C. ( 1996) FASER J. In, 871-88 1. Garrod, D. ct nl. (1996)Curr. Opin. Cell Riol. 8, 670-678. Trovanovskv, S.M. and Leuhe, R.E. (19981 Suhccll. Rlochcm. .3l, 26.3-289. K~waIczyI<, A.P. ct nl. (1999)Int. Rcv. Cvtol. 185, 2,37-302. King, I.A. ct al. (I9911 FEES Lett. 286, 9-11. K~ng,I.A. ct a]. (I9961 I. Invest. Dermatol. 107, 5,11-538. Rurdett, I.D. 119981 Mlcron 19, 309-c328. Arncmnnn, 1 ct al ( I 9911 Gcnnmics I
Pemphigus vulgaris antigen, PVA
-
-
Family Cadhcrin [dcsmosomal subfamilyl
Structure Molecular weights Ammo acids Polypeptide
SDS-PAGE rcduccd
Carbohydrate N-llnkcd sites 0-linked sites
IIIII IIIII
Gene location Gene structure
W kb, 15 exons
Alternative forms Structure
7
I -.
IIIII IIIII
COOH
Dcs~noglcin3 is a typc I membrane glycoprotcin of thc cadhcrin family'42. Like desmoglein 1 (see entry for further details1 it is has a short propeptide (26 amino acids) and is composcd of four cxtraccllular cadherin rcpcnts (Ntcrminal) but only two intracellular cadherin-like (dcsmogleinl repeats [Cterminal) (reviewed in refs 4-9).
Ligands Calcium-dcpcndcnt homophilic adhesion occurs hctwcen cadherin repeats of molcculcs in adiaccnt cclls.
Function It is a component of thc intcrccllular dcsmosomal lunctionGv,maintaining
thc strength and ~ntcgritvof the epitheli~m'"'~. 1t mediates calciumdependent cell-cell adhesion and the interaction of membrane plaque prntcins with intraccllular intermediate filamcnts.
I
Distribution Epidermis, tongue, tonsil, oesophagus, carcinomas.
Disease association OMIM 169615 Autoantihodics to desmoglcin ,3 lead to the scverc blistering skin dlsease, pemphigus vulgar~s'*'?-~~, due to loss of epithel~alcell-cell adhesion, and to pcmphigus associated with lvmphold ncoplasms.
-
-
--
Cadherin Family --
-
Knockout MGT:99499 The Gene Knockout FnctsRook", p262 A mutation in mousc dcsmoglcin 3 rcsults in thc phcnotypc
Amino acid sequence of human desmoglein 3
The propeptide sequence underlined and in italics is cleaved to form the mature protein.
Database accession EMRLlGcnBank SwissProt
M76482 PA2926
References A m a ~ a i M. , ct al. [1991)Cell 67, 869-877. Silos, S.A. et al. (1996)J. R~ol.Chem. 271, 17504-1 751 1. Ruxton, R.S. and Magec, A.I. (1992)Semin. Cell Riol. 3, 157-167. 5- Koch, P.].and Frankc, W.W. (1994)Curr. Opin. Cell Riol. 6, hR2487. Green, K.J. and Jones, J.C. I19961 FASER J. 10, 871-881. ' Garrod, D. ct al. (19961 Curr. Opin. Cell Biol. 8, 670478. Troyanovsky, S.M. and Leube, R.E. (1998)Suhcell. Riochern. 3 1, 263-289. Knwalczyk, A.P. et al. (1999)Int. Rcv. Cytol. 185, 237-302. "'King, I.A. et al. (1991)FERS Lett. 286, 9-12. " King, I.A. ct al. (1996)J. Invcst. Dermatol. 107, 53 1-538. 12 Rurdett, I.D. (19981 Micron 29, ,709-328. l 3 Arna~si,M. ct al. (1998)J. CIm. Invcst. 102, 775-782. l4 Chidgcy, M.A. (1997)Histol. Histopathol. 12, 1 159-1 168. l 5 Lin, M.S. et al. (1997)Clin. Exp. Immunol. 107 (Suppl. l ) , 9-15. Moll, R, and Moll, I. (1998)Virchows Arch. 432, 487-504. I' Mak, T.W. (19981 The Gene Knockout FactsRook. Academic Press, London. l 8 Koch, P.J. et al. (1997)J. Cell R i d . 137, 1091-1 102.
Immunoglobulin Superf amily
This Page Intentionally Left Blank
-
-- --
- --
CDI66, BEN, DM-GRASP, neurolin, KG-CAM, SC1
I
Family lmmunoglohulin superfamily
Structure Molecular weights A ~ n ~ ac~ris no Polvpept~de
58.3 65 1\31
SDS-PAGE redilced
100-105 kDn
Carbohydrate N-llnkeci sitcs 0-linkcd sites
9
Gene location
3q 1~3.1-3~11,3.2
Gene structure
Alternative forms Structure
CO~H
ALCAM is a type I transmemhrane protein containing five Ig-like domains and a short 32 amino acid cytoplasmic domain. T h e CD6 binding domain ha4 hccn mappcd to the N-tcr~ninalIg domain'.*.
Ligands ALCAM is a counter-receptor for CD6, but has also been reported to act as a homophilic adhesion molecule in the nervous system" and hind to the chlcken L1 family memher, NgCAMJ.
Function The ALCAM-CD6 interaction mediates thymocytc-thymic epithelial cell adhesion anrl may play a role in T cell developmenti. In the nervous system, a role in axon guidancc has heen postulated",'.
Distribution ALCAM is found expressed on neurons, cpithclial cclls, fihrohlasts, activatcd T cells and activatcd m o n o c y t c ~ ~ - ~ " .
Disease association OMIM 601 662 It is speculated that an interaction hetween ALCAM and CDh+ T cells could hc involved in certain neurodegcncrative discasc pathologies. In addition, ALCAM expression correlates with the neoplastic progression of rn~lanomas~~.
..-
--.
-
..
Ig Family -
-
- - --
- - -
Knockout MGI: 131266
Amino acid sequence of human ALCAM : MESKGASSCR LLFCLLISAT VFRpG: !::.:'.'? ":::'.':'\::": : 7 !?,;F:,y ' r [I,] 1 '.'r r:;.:.:7r.rT.br .., -.--,,.. ,:: . ..,. . .- .,.- -,,.. . . ,. , . .", .' C:'"":<..'~p" !I' ':'C':'.' c..r-.. . -.."- .r ,, , :.., s .- qpcr.r. . I ,p,.. ',""",~;.,'-~",' ".>rrrv. 7r;,,:,:,;,!:.,.:::-) ; v y .. r.,<. . ..,.:..;,!,~...r.. r:.c)p":,~>l..,.~ . . , , . . . . . . : . .. . .....!Ji:. , . . 1'JI p:c:.>','.,'1 :rk.L: y . : ~ ~ ~ ' , !', !~~ :~' y ,~ '~: . y~-'y~ v:.-I.' ' r . A c y''y;';';T-8.yr-:$ y'~;)!.r~:~~;,.'~~ .- ,.. .. :,T':":'!'!':.-(7,~."' :'."'!,:,l':':!.\, C':..<:1,:: :.: : r,; : [:':,;':,':';:.'!' :.'!,!.",'l,rr;:,p:,: ,,., . .... ' .- .,. ;ill- . , y ' p n,.-:.~ - ~ - ~ ~...;.r.c[,I .: r ~ :,L'p- . ',q [ . ,. , . ~. -;': ? 'T 1,; ::: :."',,:r~ . . ~r:'.,:! r7;yr-?: 2;:;p ,. . ... . .... , , , 6. ...i . . . .. rl!': !i-':,"?Tr':'r:2 :;i,i!';'c;ll:C:'y ','i'7-:,:,(\",'"~,Vl.'UF:': T3,'Fr;Vr,:)T1.'!.' '
'
,
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"',7"
,
? 7 . L .
! :
-
,,L
.(-,. -,*-.!2'*' !
D""..
.I? : ~ y v - > ~ , , - c ; , r~ 7 : (7: [ ! " ~ , - ; y p;'?,:,:c:;.:~y~ .I? : "Tr,-f:T;~,r':[l :,rDT':!,?;;y,' ::,:,::T[\?-:jpT """nL'7'.r 1.. " . 1 " ,. :.i""'..',".' , ) ,, , : ,, , , $ , ,: :, ":!L';,l,(-:+]<,*l::.: P
.
...,
'T:
~ : ? < : y. ..,->. ; - ~ ~ ?T"~'::!CE':-' ,;,,nr::-?r.:2F yy,T!3[,:,v!,y',' .;:,v:,7F*::::!r T?,',, ~
T
zr:~~,-rr~'j
,:T.,",,:;,T,:,?,;~,
Database accession EMRLIGenRank W 8608 SwissPort
Q13740
References Rowen, M.A. et al. (19961 J. Riol. Chem. 271, 17390-1 7396. Skonicr, 1.E. ct sl. 11996) Biochemistry 35, 12287-12291. Corbel, C. et al. (1996)Proc. Natl Acad. Sci. USA 93, 2844-2849. DcRcmardo, A.P. ct al. ( 1996) J. Ccll Riol. 13.3, (157-666. 5 Osario, L.M. et al. (19981 Immunology 93,358-365. Burns, F.R.ct al. ( 1991) Ncuron 7,209-220. ' Kanki, J.P. et al. 119'14) J. Ncuroh~ol.25, 8,11-845. Bowen, M.A. et al. ( 19951 J. Exp. Mcd. 181,2213-2220. * Patel, D.D. ct al. (1995)J. Exp. Mcd. 181, 1563-1568. In Pourquie, 0. et al. (19921 Proc. Natl Acad. Sci. USA 89,5261-5265. van Kcmpcn, L.C. ct al. (20001 Am. J. Pathol. 156, 769-774. 2
J J
!
,
-
Siglec-2, BL-CAM, B lymphocyte cell adhesion molecule,
Family Immunoglobulin superfamily (siglec subfamily)
Structure Molecular weights Amino acids
a 647 amino acids
Polypeptide
a 73 202
p 847 amino acids p 95 347 SDS-PAGE reduced
a 130 kDa
f3 140 kDa
Carbohydrate N-linked sites
a 10
0-linked sites
Gene location
19q13.1
Gene structure
22 kb; 15 exons
Alternative forms
11m mP 7m PP?n
1 1
bbbbL bbbU ldbdJ JUbb COOH
COOH
Alternative splicing of the CD22 gene results in the CD22a isoform lacking Ig domains 3 and 4, and with a truncated cytoplasmic domain'.
Structure CD22 is a member of the siglec family of sialic acid binding lectins (sialoadhesin, CD33 and MAG) and, like other family members, is predicted to have an unusual disulphide bond between P strands B and E in domain 1, and a disulphide bond between domains 1 and 2'. The predominant form in humans is CD22P. The full cytoplasmic domain contains six tyrosine residues, four of which are in ITIM motifs. Tyrosine phosphorylation results in association with the tyrosine phosphatase SHP-1, the tyrosine kinase Sylz, and phospholipase C-y3z4. Other intracellular signalling molecules including Lck, PI3-kinase and Grb2 have also been reported to associate with the CD22 cytoplasmic domain. Some studies suggest that CD22 is a heterodimer of the a-and p-isoforms.
Ligands CD22 binds to the sialoglycoconjugate NeuAca2-6GalPl-4GlcNAc, which is widely present on N-linked carbohydrates5. Binding to sialoglycoconjugates requires that CD22 expressing cells do not themselves carry these ligands6. CD22 forms a loose complex with the B cell antigen receptor (BCR).
Function Engagement of the BCR results in an increased tyrosine phosphorylation of CD22, and the recruitment of SHP-1 and other signalling moleculesL8.This in turn results in the negative regulation of B cell signalling. In addition, CD22 functions as an adhesion receptor mediating the interaction of B cells with a2-6-linked sialic acid glycoconjugates. A role for CD22 as a B cell homing receptor mediating the interaction with bone marrow sinusoidal endothelium has also been proposed9.
Distribution CD22 is present in the cytoplasm of late pro-B cells and appears on the cell surface simultaneously with surface IgD, and is found on most mature peripheral B cells. Expression is lost with terminal B cell differentiationlo.
Disease association OMIM 107266 The presence of cytoplasmic CD22 is a marker for B cell precursor acute lymphocytic leukaemia.
Knockout MGI:88322 The Gene Knockout FactsBookll, p151 CD22 -1- B cells are hyper-responsive to receptor signalling, and display a reduced level of surface IgM, an enhanced Ca2+ flux and cell proliferation in response to Ig signalling and an increased rate of apoptosis. Mice have an augmented immune response, contain increased serum titres of autoantibody and an absence of recirculating B cells in the bone marrow. CD22 is not required for embryonic development, B cell development or isotype switching12-'6.
Amino acid sequence of human CD22a 1 61 121 181 241 301 361 421 481 541 601
MHLLGPWLLL NPEYNKNTSK MESKTEKWME VPMRQAAVTS PPKKVTTVIQ DNTTIACAAC EVQFFWEKNG VSMSPGDQVM WCQGTNSVGK QQGLQENSSG AESSEMQRPP
LVLEYLAFSD FDGTRLYEST RIHLNVSERP TSLTIKSVFT NPMPIREGDT NSWCSWASPV RLLGKESQLN EGKSATLTCE GRSPLSTLTV QSFFVRNKKV PDCDDTVTYS
SSKWVFEHPE KDGKVPSEQK FPPHIQLPPE RSELKFSPQW VTLSCNYNSS ALNVQYAPRD FDSISPEDAG SDANPPVSHY YYSPETIGRR RRAPLSEGPH ALHKRQVGTM
TLYAWEGACV RVQFLGDKNK IQESQEVTLT SHHGKIVTCQ NPSVTRYEWK VRVRKIKPLS SYSCWVNNSI TWFDWNNQSL VAVGLGSCLA SLGCYNPMME RTSFQIFQKM
WIPCTYRALD NCTLSIHPVH CLLNFSCYGY LQDADGKFLS PHGAWEEPSL EIHSGNSVSL GQTASKAWTL PYHSQKLRLE ILILAICGLK DGISYTTLRF RGFITQS
GDLESFILFH LNDSGQLGLR PIQLQWLLEG NDTVQLWKH GVLKIQNVGW QCDFSSSHPK EVLYAPRRLR PVKVQHSGAY LQRRWKRTQS PEMNIPRTGD
Amino acid sequence of human CD22p 1 61 121 181 241 301 361 421 481 541 601
MHLLGPWLLL NPEYNKNTSK MESKTEKWME VPMRQAAVTS TPKLEIKVTP KDQSGKYCCQ PTNYTWYHNG KVTTVIQNPM TIACARCNSW FFWEKNGRLL SPGDQVMEGK
LVLEYLAFSD FDGTRLYEST RIHLNVSERP TSLTIKSVFT SDAIVREGDS VSNDVGPGRS KEMQGRTEEK PIREGDTVTL CSWASPVALN GKESQLNFDS SATLTCESDA
SSKWFEHPE KDGKVPSEQK FPPHIQLPPE RSELKFSPQW VTMTCEVSSS EEVFLQVQYA VHIPKILPWH SCNYNSSNPS VQYAPRDVRV ISPEDAGSYS NPPVSSYTWF
TLYAWEGACV RVQFLGDKNK IQESQEVTLT SHHGKIVTCQ NPEYTTVSWL PEPSTVQILH AGTYSCVAEN VTRYEWKPHG RKIKPLSEIH CWNNSIGQT DWNNQSLPHH
WIPCTYRALD NCTLSIHPVH CLLNFSCYGY LQDADGKFLS KDGTSLKKQN SPAVEGSQVE ILGTGQRGPG AWEEPSLGVL SGNSVSLQCD ASKAWTLEVL SQKLRLEPVK
GDLESFILFH LNDSGQLGLR PIQLQWLLEG NDTVQLNVKH TFTLNLREVT FLCMSLANPL AELDVQYPPK KIQNVGWDNT FSSSHPKEVQ YAPRRLRVSM VQHSGAYWCQ
781 SEMQRPPRTC DDTVTYSALH KRQVGDYENV IPDFPEDEGI HYSELIQFGV GERPQAQENV 841 DYVILKH
Database accession EMBLIGenBank SwissProt
CD22a X52785 P20273
CD22P X59350 P20273
References Stamenkovic, I. and Seed, B. (1990)Nature 345, 74-77. Crocker, P.R. et al. (1996)Biochem. Soc. Trans. 24, 150-156. Doody, G.M. et al. (1995)Science, 269, 242-244. Law, C.L. et al. (1996)J. Exp. Med. 183, 547-560. Powell, L.D. and Varlzi, A. (1995)J. Biol. Chem. 270, 14243-14246. Razi, N. and Varki, A. (1998)Proc. Natl Acad. Sci. USA 95, 7469-7474. Doody, G.M. et al. (1996)Curr. Opin. Immunol. 8, 378-382. Cornall, R.J. et al. (1999)Curr. Top. Microbiol. Immunol. 244, 57-68. Nitschke, L. et al. (1999)J. Exp. Med. 189, 1513-1518. l o Law, C.L. et al. (1994)Immunol. Today 15, 442-449. Malz, T.W. (1998) The Gene Knockout FactsBook. Academic Press, London. IW'Keefe, T.L. et al. (1996)Science 274, 798-801. l3 Sato, S. et al. (1996)Immunity 6, 509-517. l 4 Otipoby, K.L. et al. (1996)Nature 384, 634-637. l5 Nitschke, L. et al. (1997)Curr. Biol. 7, 133-143. l6 O'Keefe, T.L. et al. (1999)J. Exp. Med. 189, 1307-1313.
Platelet endothelial cell adhesion molecule-1, PECAM-1
Family Immunoglobulin superfamily
Structure Molecular weights Amino acids Polypeptide
738 82 536
SDS-PAGE reduced
120-140 kDa
Carbohydrate N-linked sites 0-linked sites
9
Gene location
17q23
Gene structure
65 kb, 16 exons
i
PPPP PPPP bbbb bbbb coon
Alternative forms Alternative splicing in the transmembrane domain (exon 9) can result in soluble CD31 isoforms. In addition the cytoplasmic domain encoded for by exons 10-16 is subject to variable alternative splicing1. A Leu-Val polymorphism is found at amino acid 125'.
Structure CD31 is a type I transmembrane molecule with six C2 Ig domains. The first two Ig domains, with contributions from domains 3, 5 and 6, mediate the homophilic interaction3v4,whereas domain 2 is the main domain interacting with integrins5 and glycosaminoglycans6. Alternative splicing and tyrosine phosphorylation within the cytoplasmic domain modulates the configuration of the ligand binding domain, suggesting a mechanism for regulating ligand ~ p e c i f i c i t y ~ ~ ~ ~ 8 .
Ligands CD31 is a homophilic adhesion molecule3 but can also interact heterotypically with integrin ~ i , P , 5 2 ~ and glycosaminoglycans6. Recently malaria (Plasmodium fa1ciparum)-infectedred blood cells have been shown to adhere to CD3 1 on vascular endotheliumlO.
n
Ig Family
Function The majority of CD31 activities result from the homophilic CD31-CD31 interactions. These include leucocyte extravasation, bone marrow haematopoiesis and vascular development". There is increasing evidence that CD31 has signalling function via the ability of tyrosine phosphorylated CD31 to recruit the tyrosine phosphatase SHP-2" and other signalling components13. Activation of CD31 upregulates P, and P, integrins resulting in further adhesion interactions, and this receptor crosstalk is mediated by the small GTPase Raplz4.
0 0
Distribution CD31 is highly expressed by endothelial cells, where it localizes to cell-cell contact areas. In addition, expression is found on platelets, monocytes, granulocytes and other leucocytes.
Disease association
OMIM 173445 The polymorphism at residue 125 can result in acute graft-versus-host disease in mismatched bone marrow transplants.
I
Knockout MGI:97537 The Gene Knockout FactsBookz5,p166 CD31 -1- mice develop normally with no obvious vascular or platelet aggregation defects. Leucocytes are able to extravasate into inflammatory sites, although there are subtle defects in this process as evidenced by an increased number of arrested neutrophils between the vascular endothelium and basement membranez6.
Amino acid sequence of human CD31 1 61 121 181 241 301 361 421 481 541 601 661 721
MQPRWAQGAT VSTTSHVKPQ AEYQLLVEGV KNSRDQNFVI SPTGMIMEGA NYTCKVESSR KEDTIVSQTQ VIKGQTIEVR CHSHAKMLSE EGKPFYQMTS KGLIAWIIG SHYGHNDDVR PDAVESRYSR
MWLGVLLTLL HQMLFYKDDV PSPRVTLDKK LEFPVEEQDR QLHIKCTIQV ISKVSSIWN DFTKIASKSD CESISGTLPI VLRVKVIAPV NATQAFWTKC VIIALLIIAA NHAMKPINDN TEGSLDGT
LCSSLEGQEN LFYNISSMKS EA1QGGIVP.V VLSFRCQARI THLAQEFPEI ITELFSKPEL SGTYICTAGI SYQLLKTSKV DEVQISILSS KASKEQEGEY KCYFLRKAKA KEPLNSDVQY
Database accession EMBLIGenBank SwissProt
M377801 M28526 P16284
SFTINSVDMK TESYFIPEVR NCSVPEEKAP ISGIHMQTSE IIQKDKAIVA ESSFTHLDQG DKWKKSNTV LENSTKNSND KWESGEDIV YCTAFNRANH KQMPVEMSRP TEVQVSSAES
SLPDWTVQNG IYDSGTYKCT IHFTIEKLEL STKSELVTVT HNRHGNKAVY ERLNLSCSIP QIWCEMLSQ PAVFKDNPTE LQCAVNEGSG ASSVPRSKIL AVPLLNSNNE HKDLGKKDTE
KNLTLQCFAD VIVNNKEKTT NEKMVKLKRE ESFSTPKFHI SVMAMVEHSG GAPPANFTIQ PRISYDAQFE DVEYQCVADN PITYKFYREK TVRVILAPWK KMSDPNMEAN TVYSEVRKAV
Ig Family
References Yan, H.C. et al. (1995)J. Exp. Med. 184, 229-239. "ehar, E. et al. (1996)N. Engl. J. Med. 334, 286-291. Fawcett, J. et al. (1995)J. Cell Biol. 130, 451-460. 4 Newton, J.P. et al. (1997)J. Biol. Chem. 272, 20555-20563. 5 Buckley, C.D. et al. (1996)J. Cell Sci. 109, 437-445. 6 DeLisser, H.M. et al. (1993)J. Biol. Chem. 268, 16037-16046. 7 Baldwin, H.S. et al. (1994)Development 120, 2539-2553. Famiglietti, J. et al. (1997)J. Cell Biol. 138, 1425-1435. 9 Piali, L. et al. (1995)J. Cell Biol. 130, 451-460. lo Treutiger, C.J. et al. (1997)Nature Med. 3, 1405-1408. l1 Newman, P.J. (1997)J. Clin. Invest. 99, 3-8. a Sagawa, K. et al. (1997)J. Biol. Chem. 272, 31086-31091. 13 Pumphrey, N.J. et al. (1999)FEBS Lett. 450, 77-83. l4 Reedquist, K.A. et al. (2000)J. Cell Biol. 148, 1151-1 158. j5 Mak, T.W. (1998) The Gene Knoclzout FactsBook. Academic Press, London. '6 Duncan, G.S. et al. (1999)J. Immunol. 162,3022-3030.
Family Immunoglobulin superfamily (siglec subfamily)
Structure
I
Molecular weights Amino acids Polypeptide
364 39 726
SDS-PAGE reduced
67 kDa
Carbohydrate N-linked sites 0-linked sites
5 0
Gene location
19q13.3-q13.4
Gene structure
>35 lzb
5
COOH
Alternative forms There is evidence for alternative splicing in the mouse CD33 cytoplasmic domain1.
Structure CD33 is the smallest member of the siglec family (sialoadhesin, CD22 and MAG), and like other family members is predicted to have an unusual disulphide bond between P strands B and E in domain 1 and a disulphide bond between domains 1 and 2 ' . The cytoplasmic domain has two ITIM motifs which when tyrosine phosphorylated can bind SH2-containing phosphatases.
Ligands CD33 binds to the sialoglycoconjugates NeuAca2-3Galp1-3(4)GlcNAcand NeuAca2-3Galp13GalNAc on glycoproteins. CD33 ligand binding is down-modulated by N-linked glycosylation in the first Ig domain4.
Function CD33 mediates cell adhesion in vitro but an in vivo function in myeloid cells has yet to be determined. The demonstration that tyrosine phosphorylation in the cytoplasmic domain can result in the recruitment of the tyrosine phosphatases SHP-1 and SHP-2 suggests a method for regulation of ligand binding and/or a role as a signalling r e c e p t o F .
Distribution CD33 is absent from pluripotential stem cells, but then appears on myelomonocytic precursors and then the myeloid and monocyte lineages, although it is absent from granulocyte^^^^.
Ig Family
Disease association OMIM 159590 CD33 is expressed on some acute undifferentiated leukaemias and occasionally by acute lymphoblastic leukaemias.
Knockout Amino acid sequence of human CD33 1 61 121 181 241 301 361
MPLLLLLPLL WAGALAMDPN FWLQVQESVT VQEGLCVLVP CTFFHPIPYY DKNSPVHGYW
FREGAIISGD ERGSTKYSYK SAAPTSLGPR GIFPGDGSGK PTTGSASPKH VRTQ
SPVATNKLDQ SPQLSVHVTD TTHSSVLIIT QETRAGWHG QKKSKLHGPT
EVQEETQGRF LTHRPKILIP PRPQDHGTNL AIGGAGVTAL ETSSCSGAAP
RLLGDPSRNN GTLEPGHSKN TCQVKFAGAG LALCLCLIFF TVEMDEELHY
CSLSIVDARR LTCSVSWACE VTTERTIQLN IVKTHRRKAA ASLNFHGMNP
Database accession EMBLIGenBank SwissProt
M23 197 P20138
References
*
3 4
Simmons, D. and Seed, B. (1988)J. Immunol. 141,2797-2800. Tchilian, E.Z. et al. (1994)Blood 83, 3188-3198. Freeman, S.D. et al. (1995)Blood 85, 2005-2012. Sgroi, D. et al. (1996)J. Biol. Chem. 271, 18803-18809. Taylor, V.C. et al. (1999)J. Biol. Chem. 274, 11505-11512. Ulyanova, T. et al. (1999)Eur. J. Immunol. 29, 3440-3449. Andrews, R.G. et al. (1989)J. Exp. Med. 169, 1721-1731.
RDNGSYFFRM QGTPPIFSWL VTYVPQNPTT RTAVGRNDTH SKDTSTEYSE
T cell activation increased late expression/ TACTILE
Family Immunoglobulin superfamily
Structure Molecular weights Amino acids Polypeptide
569 63 887
SDS-PAGE reduced
160 lzDa (160, 180,240 lzDa unreduced)
yg-
Carbohydrate N-linked sites 0-linked sites
15
+++
Gene location Gene structure Alternative forms
\
Structure
COOH
CD96 is a type I transmembrane glycoprotein of the Ig superfamilyl and is composed N-terminally of two V-like and one C2-like Ig domains. The membrane-proximal part of CD96 is formed by a serine/threonine/prolinerich region, which is probably 0-glycosylated. It may consist of a disulphide bonded homodimerl.
Ligands Not known.
Function Probably involved in adhesive interactions of activated peripheral T cells and NK cells at late stages of immune response, such as following leucocyte emigration to sites of inflammation.
Distribution Low levels in peripheral T and NK, but not expressed in B cells; upregulated following T cell activation' and expressed by most T cell lines.
I Disease association 0 Knockout Amino acid sequence of human CD96 1 61 121 181 241 301 361 421 481 541
MEKKWKYCAV YYIIQIHFVK GVWEKTVNTE ENVYATLGSD VNLTCQTQTV GFFVQMQWSK
VTNKIDLIAV VLYPEGIQTK VEDNGTQETL LRSSTTVKVF IYITNEERKG LLGSEISSTD SMTTRGFNYP NGSTKTNHVH FKPPPPPIKY
YHPQYGFYCA IYNLLIQTHV ISQNHLISNS AKPEIPVIVE KDGFLELKSV PPLSVTESTL WTSSGTDTKK ITGIWKPK TCIQEPNESD
YGRPCESLVT TADEWNSNHT TLLKDRVKLG NNSTDVLVER LTRVHSNKPA DTQPSPASSV SVSRIPSETY DGMSWPVIVA LPYHEMETL
FTETPENGSK IEIEINQTLE TDYRLHLSPV RFTCLLKNVF QSDNLTIWCM SPARYPATSS SSSPSGAGST ALLFCCMILF
WTLHLRNMSC IPCFQNSSSK QIFDDGRKFS PKANITWFID ALSPVPGNKV VTLVDVSALR LHDNVFTSTA GLGVRKWCQY
Database accession EMBLIGenBank Swissprot
M88282 P40200
Reference Wang, P.L. et al. (1992)J. Immunol. 148, 2600-2608.
SVSGRYECML ISSEFTYAWS CHIRVGPNKI GSFLHDEKEG WNISSEKITF PNTTPQPSNS RAFSEVPTTA QKEIMERPPP
----- -- -
-
--
Ra~igin,EMMPRIN, OX-47[rat], etc
-
.
Family Immunoglobulin supcrf~mily
Structure Molecular weights Amino acids Polypeptide
269 29221
SDS-PAGE reduced
55-65 kDa (50-60, unreducedl
Carbohydrate N-linkcd sites 0-linked sites
3
Gene location
19~13.3
Gene structure
COOH
Alternative forms Snmc cvidcncc of altcrnatc RNA splicing in mouse yiclding different N-termini.
Structure Type 1 membrane glycoprotein of Ig superfamilyI.2 cnnta~ningone C2-like and one membrane-proximal V-like domain, that is in the opposite orrentation to most IR superfamily memhers. N-linked carbohydrates account for approximately 50% of the mass of CD147, varying betwctn t~ssucs. Hornologuc c ~ f the rat OX-47 antigcn7. Highly conscrvcd transmcmhrane reglon hctwucn s p c ~ i c s ' . ~ .
Recuntlv it has bcun shown that CD147 hinds interstitial callagenase (MMP-11 at the surface of tumour culls6.
Function Intcrcellular adhesion, such as of rctinal cellsn, is inhihitcd by antihodics to CD147, as is adhesion to matrix proteins (collagen IV, laminin, fibmnectin). Recnminant CD147 hinds to cells, though its receptor is not known. It was first described AS a tumour-cell-dcrived stimulator [EMMPRIN) of collagcnasc sccrction hv fihrohlasts', and is thought via this function to be involved in tumour invasion and metastasis. CD147 carries an oncodcvclopmental carhohydratc markcr cxprcsscd on tcratocarcinoma cells.
Distribution It is widely cxprcsscii in cmhrynnic and adult tissues, including the majority of circulating leucocytcs (weakly),epithelia and cndothelial cells, and is up-regulated upon lymphocyte activation3. There are some species differences in distrihu~innt.?~~.~.
Disease association OMIM 109480
Knockout MGI:88208 CD147 knockout mice show abnormal smell sensation and immunological changcslD.
Amino acid sequence of human CD147 ,
1 MAAALWLLG PALLGmGAS G:,>:7','3;_',' ..; ;.,, .- -,,,'.'. . ,.~.. r . . ." ,' , , . , .. . : 71,,..d..c'v r.:,;,: ..:, :. - , ,..;..:.. "' " ' . . : , ::1S;,':]l.';:. (:(,-..?(..T,.-.,. v(.,.-,r)-,-; --,--~,,'.,,. :.;,.-; *.. , , , . ... :.537:..f:;<;.,; ;y ;::;f:;>:-/!!:-J?(' !-P!- ->g?>':.T:-
..
]
A""
.
7
.
J . . ,
r?:,l:T:.:
:'F"'t ' .
:,:,':
_ . "", . . .i
.:-:,
:,:::".pTy""-'.'
,,;T,':?,';..
. ,,:: '
,:
'
?.....,. r ...
.',:':'i:".rc!,::
k!,-;r.y.,.:,,r.;,,..,.---:-.,.r .. ,..
::!r:.:!,i,':r, ' ;'TyE:!T:!Ef;F: -F:::,::'.!E:,?T' ;,?p).;,rT>...
Database accession EMRLIGenRank SwissProt
XA4364 R35h 1.3
References Fossum, S. ct al. ( 1991) Eur. 1. Immunol. 21, 671. Seulherger, H. et al. (1990)EMRO J. 9, 2151-2158. ,3
* lo
Kasinrcrk, W. ct al. (1992)J. Immunol. 149, 847-854. Miyauchi, T. ct al. (19911 J. Biochem. 1 10, 770-774. Gun, H. ct 31. (20001Cancer Rcs. 60,888-891. Fadool, J.M.and L~nser,P.J. (1993)Dev. Dynamics 196, 252-262. Riswas, C. et al. (1995)Cancer Res. 55, 434-430. Nehme, C.L. et al. (1995)Rlood 310, 693-698. Kanekura, T. ct al. (1991)Ccll Struct. Funct. 16, 23-30. Iagkura, et al. (19961 Riochem. Riophys. Rcs. Commun. 224, 33-36.
..?
Members CEA CEACAM 1
CEACAMS, CD66e CD66a, Cell-CAM 105, RGP, hiliary glycoprotein, NCA-160 CEACAM3 CD66d, CGMl CEACAM4 CGM7 CEACAM6 CD66c, NCA, NCA-90, CGM6 CEACAM 7 CGM2 CEACAMR CD66h, CGM6, CGMR, NCA-95 Notc: The carcinoembryonic antigen (CEA) family nomenclature has recently been red~fined'.~.
Family Immunoglobulin supcrfamilv
Structure
CEA
CEACAMI
A
Molecular weights Amino acids
Polypeptide
CEA CEACAMl CEACAM3 CEACAM6 CEACAM8 CEA CEACAM 1 CEACAM,? CEACAM6 CEACAMR
SDS-PAGE reduced CEA CEACAMl CEACAM,? CEACAMh CEACAMK
180-200 kDa 140-1 KO kDa 35 kDa 90-95 kDa 95-100 kDa
Carbohydrate N-linked sitcs
CEA CEACAMI CEACAM3 CEACAM6 CEACAMR
28
20 2 12 11
0-linked sites
Gene location
19qlS.1-19qlS.2
Gene structure
The CEA family comprises at lcast 28 separate genes.
Alternative forms CEACAMl, CEACAM3 and CEACAM7 are alternatively spliced. The largest isoforms are shown here.
Structure Thc human CEA family is part of a cluster of at lcast 28 genes divided into two functional groups. Ry genomic mapping, the CEACAM suhgroup contains seven mcmbcrs and the PSG (pregnancy-specific glycoprotc~nlsubgroup of secreted molecules contains 11 memhers. The remaining genes arc thought to he pseudogenesf. Within thc hcst charactcrizcd CEACAM members, CEACAMl and CEACAM3 cncodc type 1 transmembranc proteins while CEACAM8, CEACAMh and CEA arc GPI anchored in the membrane. All mcmhcrs possess an N-terminal V-type Ig d o m a ~ nfollowed by bctwcen 0 and h C2-type Ig doma~ns.Apart from CEACAM3, the extracellular domains are extensively N-glycosylatcd. CEACAMl and CEACAMd have putative tyrosine phosphorylation sites in their cytoplasmic domains, which could bind signalling components such as the tyrosine phosphatases SI-IP-1 and SHP-2; CEACAMl can associate with the cytoplasmic tyrosine kinases Src, Lyn and Hck7v4.Alternative splicing results in CEACAMI, 3 and 7 isoforms with varying numbers of Ig domains and/or shorter cytoplasmic domains'. Further structural and sequence information on other CEACAM family memhers and memhers of the PSG family can be found in refs 1 and 2.
Ligands The CEACAM family can mediate homophilic cell-cell adhesion and in certain combinations, hcterophilic interactions with other family memhers". Rinding is via the V-type domain6.'. In addition, CEACAMI and CEACAM6 have been reported to bind E-selectin, CEACAMl and CEACAM3 can act as a receptors for Neisserin ~ o n o r r h o e a eand Neisseria meningitidisR, murine CEACAMl and CEACAM2 arc receptors for murine coronaviruses9, and CEACAMh can bind galectins.
Tg Family
Function Rind~n,q;Issays indicatc a rolc for CEACAM family mcinhcrs in mctlinting ailhccion hctwccn granulocytes antilor hctwccn ~ r a n u l o c v t c sand epithelial cclls, ;lnd ;IS rnicrohi;ll rcccptors. In addition, signalling via CEACAMI 2nd CEACAM3 cytoplasmic dc~inains-Irnny rcgulatc the adhcsivc ;ictivity of the p, intcgrinsln and the cytolytic tunction of intracpithclial l y i ~ ~ p l ~ o c y t e ~ ' ~ . Diffcrcnt splice v;~ri:~ntsof CEACAMI : ~ n d.i display different hactcrial trrlpism anrl invrlsionJ. I~ilportnntlv,mcmhcrs of thc CEACAM family arc strongly rlown-rc~~ilatcrl In ~nalisnancics,implicating thcsc receptors rls p ~ i t ; ~ t i v tuniour c suppressors4. It should he noted that Cell-CAM 105 originally identifier1 in mts nnd tlcscrihcd ns n honiophilic adhesion molcculc involved in the fortnation and rnaintcnancc of hcpatocytc prllariz;ltion nnd cxhihi ting ecto-ATPnsc activity12J7, is CEACAM 1.
Distribution CEACAMI and CEACAM6 Arc abundant on granulocytes r~ntlcpithclinl cclls, CEACAMK 2nd CEACAM.3 arc restricted to ~ranulocvtcs,s n ~ CEA l is mostly found on cpithclinl cclls.
Disease association O M I M CF.A,I I 4890; CF.ACAM I , I 09770; C F . A C A M ~ ,I cl.wxn. CEACAMl ;mil CEA arc strongly down-regulated in colon ; ~ n dother carcinomas. Ev~dcncc that CEACAM proteins can ; ~ c t 3s tiunour suppressors comes from studies in which transfcction of CEACAMl in carcinoma cclls rcsultcd in a n inhihitinn c ~ ftumour tlcvclopmcnt in nude tnicc ;lntl conversely down-regulation in h c n i ~ ncclls rcsultcd in increased tlllno~irigcnicity~.CEA levels in serum arc used roiutincly 3s clinical markcrs in t h c diagnosis and scrial monitoring of cancer patients for rccurrcnt tliscasc o r rcsponsc to therapy.
Knocknut MT.1:1.317143 (CEACAM I I
Amino acid sequence of human CEA MESPSAPPHR WCIPWQRLLL TASLLTFWNP PTTA.
In CEA thv C-tcrininus is protcolyticnlly clcnvcrl and n GPl anchor attechcd. H~IVCVCT, t l ~ site c of clc;~vagchas not hccn unarnhigouslv cictcrm~ncd.
Amino acid sequence of human CEACAMl 1 HGHLSAPLHR VRWWQGLLL TASLLTF!:Tl? FTTI'OLTTFS (J A ~ , - r ~ : ' , ~ ~ ~ -k;:;.-- ; ; ~ ,. ,-t "- -l. -~ .-, V ;I!.' C:.Y;>IC'T"O.PI PGFAI:SCRET 12 1 'T'IV!I KSDLi' :!!i!i;:'[-r'L)!-'ll?.' YI'ELPT?:;I5 Cr!?I5F:P:~E3K 181 EIF!OSLjP'VSPP LOLSb!r3P!PTL TL,LS::T?!!3_ C-P'r.ECEIOM? ? , I 1 TISPSDTY'r'P PCC!l[,S[,?C!' ?..?LSE:?P?..O?~ r:'LT?lGTFOQS 3 0 1 fiE!E?ST'?GCt!P ?T7.?<TII:.'TT !ASr'.'~~.'.A??Q YA.SLTT?'T';D 3 6 1 FPElOSLPSSE FI4Y LSO[;?!T? LS II:Y,.'VPFD .~.G?Y'I'.I'C~~!T?I 4 7 1 Q!7E!r31dSPGAI .~.G7'~.'II~'~."~.~AL ',...\LIX,V.;tL>.C FLIIFGKTGF?. 6 8 1 S!~:~p?!!y'.'~ll: ....., ...:':,-: y,:!!::';., [I,.;,;": 1.1; : :,,.?. ?::[,T,:iyrI Iy 51
f.cF'FIIT'AEG'F: ?'LLL\'H!,II,PQ I Y?llASLL TI) P!;'TOIJDTCC? Dh?'AFTCI:?I: TQ@T~'I'L~,':II ~~S~AlIP.S!lF!:"TL!!:.'TYG?'lT? '?Q?LFTPlIl.T !.:I!1I.SG.SY?CH KE??%':!T.?CC7 N3TCT.S TF:'!F PT ?K:!V?T)?: b~l.?T~:'PIYN,~i? ? E O F D I r T ~ l < K?.5',.'.5?lYTQr)!l sp.;KF()
Amino acid sequence of human CEACAM3 1 MGPPSASPHR ECIPWQGLLL TASLLNFWNP PTTAY L T I E S !.1PLS',.'AE(;VF. [ [ . -i,: ;...,..;... ,.,. . t-c; ET','-v"- ..' , T..' I:':.. -I(::!',y :': PC;,:L,:..'?'S{;?ET TIYTI!;SLLTQ
6l
A t
171 T : A p . p IF-S DL'.' 7 :E t-?,'['L;VF! IT ';QFE!!,, 1R 1 P T S JOpD:>KE QO?Q-:.IL;!?CP 2 4 1 'iCF!.?DHV,:F.:' AS
PC; ,1 F'.'
Ci'7YT.??,F5!.:
'\'LiL\'HF:LP.O I:~..'TgImI~F;' G;.VAG I T!TC?.' ],VG\'I'IL,:Jil.:iI, YCF! ,IA:,AYTC: .C.?IS.C.:~.'.,!~:, I'::.'!. : :%: ; : ' : : ? "..;:,?U?T!JI
Amino acid sequence of human CEACAMG 1 HGPPSAPPCR LHVPWKEVLL TASLLTPWNP 6 1 ::'i ;r:"7:.:'.')'1-; F>'.'3! .':!?:,l'.: r:'/.'TC'' Zy;, : 1 ? 1 TLVII KSDL.:! P::'CCATCK,HS; YFEI,P'.";S r s 1H 1 EIGOSLFVSPP, 505S?:C?i!.'TL TCLS!.;?DFID!l, 7.4 1 T:SPSKAF:'r'P. PGET!LE!LSCI! i,,:\SETPP.\QY S 3 n l AtIMS.\TCl ,t!P '?T',?-t.! I ':':;.SC: S?li'?7,:;:li'.IT
PTTAVl. l' 1 1,:s TFI:FI',.'~L~XV~:.'>.':dLLi>.-.~ GS':'ECEIO!!P ?,,SiF1PS3P3,r'T LI.!\'LYG?DG? I.:r: :,lGTFcQS 7 O E L F I P?Il? VF!NSC;SV'.?CO :'C>iTIC-':S,III
i??LI
The sequences sequences underlined and in italics are cleaved off to form maturc CEACAMh and a GPI anchor is added.
Amino acid sequence of human CEACAM8 1 MGPISAPSCR WIlIPWQGLLL TASLFTFWNP 5 1 I>.'UG'. ::';.' .'?T; 1. !-:.':);:..-':' : I (;'-. : s:!lJC] : :' 1 2 1 TLO'.'T ZLF
I;.C'..l!Lt:>5Cti ~T.'P!.lI-',:S3
PTTAOLTI E?, ':'?SNI:.:ICGKE T'I;:'.\'<S:\I?ET :)'p:!r\,SLLJ
T'L',LT'Ht:!,PO FT:.'TUFIDTGS? TO!IT':"~'L:.,~..-.: I.!?"!,YG?D,7? TK:l5CS?ACtI
The sequences sequences underlined and in italics are cleaved off to form maturc CEACAM8 and a GPI anchor is added.
Database accession CEA CEACAMl CEACAM3 CEACAM6 CEACAMR
EMRLIGenRank M 17303 X 16354 LO0692 M29541 X52378
SwissProt PO673 1 PI3688 P40198 P40199 P31997
References Reauchemin, N. et al. I19991 Exp. Cell Res. 252,243-249. 2
"
http://www.uni-frcihurg.de/cea Skuhitz, K.M. et al. (1995)J. Immunol. 155, 5382-5390.
Ig Family
ohrink, R. ct al. (19971Curr. Opin. Ccll Riol. 9, 616-626. Rcnchimol, S. ct al. 119891 Ccll 5 7 , 327-334. Tcixcirn, A.M. ct al. (19941Blood 84, 21 1-219. ' Yamanaka, T. et nl. (19961 Biochcm. Riopliys. Rcs. Commun. 219, 812-847.
In
I?
Virii, M. ct al. jl996l Mol. Microhiol. 22, 929-9\19. Dvekslcr, G.S. ct nl. 11991I 1. Virol. 65, 6881-6891. Skuhitz, K.M. ct al. 119961 I. Lcukocytc Riol. 60, 106-1 17. Mornles, V.N. ct a]. 119991 I. Immunol. 163, 136,3-1370. Lin, S. H. (198911. Riol. Chcm. 264, 14408-14414. Sippcl, C.1. ct nl. 119961 1. Riol. Chcm. 271, ~3LZ095-.Z3104.
-
Human gp13.5 (chick F11, mouse F3) -
-
>
-
-
I
Family Immunoglobulin superfamily
Structure Molecular weights Amino acids Polypeptide SDS-PAGE reduced
Carbohydrate N-linkcd sitcs 0-linked sites Othcr
Gene location Gene structure
Alternative forms Two isoforms in adult human brain with differing N-termini are formed hy RNA splicing.
Structure Contactin-1 is a member of the IgSF and contains six N-terminal C2-type Jg domains and four membrane proximal fibroncctin type 111 (Fn31 repeats1. It is predicted that contactin-1 is GPI-linked2 in a similar manner to the F,3 hears the CD57 murine orthologue F3 and the chicken orthologue FB (HNK-1J carbohydrate epitope.
Contactin hinds tenascin5. It mediates cell-cell adhesion in vitro, possibly via the 190-kDa associated transmembrane glyocoprotcin, CASPR (p190, 'contactin-associated protein', ncurcxin 4; OMIM 6023461, which contains multiple protein-protein interaction sequences. In addition, contactin-1 can form cis complexes with members of the L1 familyh.
Function Selcctivc ccllular ;~nrlcompartmental distril~ution during dc\,clopmcnt s u x ~ c s t s;I r(1Ic in ;ixonal p;~ttcrniiig'. 171 r-itro experiments sugxcst ;III involvciiiciit In intcrccllul;~raggrc~r;itiona n d ncuritc oiit,~ro\vtlix~" possibly hy intcr~lctinq 111 c.ir: with L I i:~mily ~ n c n i l ~ c rand s moilul:iting their :~rllicsivc :~ctivities'". Evidence th;lt cont:~ctin-l c;in nioJul:ltc sign:~llin!: prlthxvnvs has ctnnc irc111i t h e demonstration thrit it c ; ~ n torrn stnhlc ~ n t c r ; ~ c t i o nins c i s with prtjtcin tyrosinc phosphat;ise-;~lyh;~ 1PTPtvl which can tlcphosphoryI:~tc;ind ;~ctivritcnon-rcccptor tvrosinc k i n n ~ c s ~ ~ .
Distribution Restricted rlixtrihution t o ncuron;il axonal suhpopulations in developing m i ~ r i n cc c r c h c l l ~ ~ r maxiiii:~ll!l n ~ ~ ~ ~ , csprcsscd in ;~ilultbrain.
Disease association CIMIM 600016
Knockout MGI: I O i 9 S O Cont;icti11 -/- :11li111;11> 1lisp1;1y ;I severe ilt;isic plic~iotypc;111cl ilic I1ctorc postnat;il d:ly 1 X ot ccrcl~cllutn ricfect~. An;ilgsis of the riiut;lnt mice dcnionstratcs :I role tor cont:lctin in controlling the intcr;~ctions of ccrcl~t.llnrintcrncuronhs".
Amino acid sequence far human contactin-1 MRMWLLVSHL VIISITTCLA
--
Tlic scqucnccs ~~ncicrlirictl ;i111l in italic.; :Ire clc;ivccl ~ ) i to t form m;lturc ct>ntnctin 1 ;inJ ;I C;I'I ;lnchor is a d ~ l c d .
Database accession EMl
UO7SIO Ql2S60
--
---
-
Ig Family -
References Reid, R.A. and Hemperly, J.J. (1994)Brain Res. Mol. Brain Res. 21, 1-8. Berglund, E.O. and Ranscht, R. (1994)Genomics 21, 571-582. Brurnmendorf, T, et al. (1989)Neuron 2, 1351-1361. Wolff, J.M. et al. (1989)Biochcm. Biophys. Rcs. Commun. 161, 931-938. Zisch, A.H. et al. (1992)J. Cell Biol. 119, 203-213. Sakurai, T. et al. (1997)J Cell Biol. 136, 907-918. ' Ranscht, B. and Dours, M.T. (1988)1. Cell Biol. 107, 1561-1573. Gennarini, G. et al. (1991)Neuron 6, 595-606. Durhec, P. ct al. (19921J. Cell Biol. 117, 877-889. 1f)Brummendorf, T. et al. (1998)Curr. Opin. Neurobiol. 8, 87-97. Zeng, L. et al. (1999)1. Cell Riol. 147, 707-714. l2 Faivre-Sarrailh, C. et al. (19921J. Neurosci. 12, 257-267. l3 Berglund, E.O. et al. (1999)Neuron 24, 739-750. 2
-
Tntercellular adhesion molecule-1, CD54
Family
Structure
Molecular weights Amino acids: Polvpcpt~dc:
i.32 57 X2h
SDS-PAGE reduced
90-1 15 kD;1
Carbohydrate iV-linked site5 0-linked sitcs
S
Gene location
l~pl.3.~3-plL~.2
Gene structure
12 kh, 7 cxons
COOH
Alternative forms A numhcr ot altcrn;ltivcly exprcsscd forms lilcking combinations of the second, third nntl folirth Ig rlomnin hnvc hccn dctccterl in the niousc'. Soluhlc form5 have hccn dctcctcd En scra'.
Structure ICAM-1 is a type I transincinhranc int~leculcwith five C 1 Ig domains. T h c intcgrin cl,p, hinding sitc is within Ig domain 1 and the top of Ig domain l'.J. T h c intcgrin R,,& hinding sitc is within 1~-Jnrnnin*3$. Rhinoviruscs hind a n ovcrl;lpping sitc with lntcgrin cu,P? (In domain 1 [and possihly 11"*' and I'l(lc~nodiurni(~lci~?rrrrlrr~ hinds a distinct sitc in Ig domain Crystal structure frnnl the first twrllg dnniains has hccn ohtnincd'.".
Ligands ICAM-I hinds to thc lcucncytc intcgrins n, P,, cr,,P, nnd t ~ , [ 3 , ~ ~ ' In ~ ~ addition ". it is the receptor for :I group of rhinoviruscsrl ;lnJ I'la,v!7lodiun7 i ( ~ l c i p ( i n ~ r n infected erythrocytes2.
Function ICAM-I pl;lys an important rnlc in mcriiating iminunc i ~ n dintlnmmatory responses. It mctiiatcs the adhesion of monocytcs, lynphocytcs and neutrophilsto activated cndothclium, and contrihutcs to the cxtrnvnsntion ot Iciicoc\~tcs from I7lood vcsscls into infliiminatorv sitcs. ICAM-1 on anti,ccn prcscnting cells has ;I key mlc in antigen-specific T cell ;~ctivation".".
Ig Family
- -
-
--
Distribution ICAM-I is basally cxprcssed in significant amounts on a wide range of both haematopoietic and non-haematopoietic cellsJJ. Expression on leucocytes and cndothcliiim can hc up-regulated hy activation or inflammatory mediators such as IFNy, IL-la, TNFty and LPSlr'5.
Disease association OMIM 147840 Expression of ICAM-1 has hcen implicated in tumour metastasislh. A highfrcqucncy African polymorphism in thc N-tcrminal domain of ICAM-1 is associated with increased susceptibility to cerebral malaria1'.
Knockout MGI:96392 The Gene Knockout FactsRookiR,p5,35 ICAM-I knockout micc show no gross abnormalities in dcvclopment or lnicc have elevatcd numbers of fertility. Howcvcr, ICAM-1 -1ncutrophils and lymphoeytcs, and exhihit ahnormal inflammatory responses including decreased allogeneic T cell responses, contact hypcrscnsitivitv to 2,4-dinitrofluorohcnzcnc and a rcduccd ncutrophil emigration in rcsponsc to thioglycollatc-induced peritonitis and endotoxin challenge. Mutant cells providc no stimulation in a mixed lymphocyte rca~tion~"~~.
Amino acid sequence of human ICAM-1
Database accession EMRLIGcnRank SwissProt
X06990 PO5362
References King, P.D. ct al. (1995)J. Immunol. 154, 60804093. Bcrcndt, A.R. ct al. (19911 Cell 68, 71-87. Rosenstcin, Y. et al. (199 1 ] Nature 354, 233-235. Staunton, D.E. ct al. (19881 Ccll52,925-933. Diamond, M.S. et al. { 199 1 ) Cell 65, 961-97 1. "taunton, D.E. ct al. (19901 Ccll 61, 243-254. ' Bella 1. et al. (1998)Proc. Natl Acad. Sci. USA 95,4140-4145.
Ockcnho~lsc,C.F. et ;I]. 11 992) Ccll 6 X , 6.7-69. C;is;lsnov;is, J.M. ct ;i1. (199X1 Proc. Natl Ac;id. Sci. USA 95, 41.33-4139. dc Foi~gcrolles,A.R. c t al. Il99.51 Eur. J. Imniunal. 25, 1005-1012. fl Grcvc, I.M. ct ;iI. (IYX'II Ccll 56, 8.4'1-547. I' Springer, T.A. ct ;I]. ( 1 9901 N;iturc ,146, 42.5-JLU. X~i,H.ctal.11Y94)1.Exp.Mcd. IXO,95-l09. I J S~iiitli, M.E.F. and Thomas, J.A. 119901 1. Clin. Pnthol. 43, 89.3-900. l5Dustin, M.L. and Springer, T.A. 119911 Annu. Rcv. I~nmimol. 9, 17-66. Iohnson, I.P. ct al. (19891 Proc. Natl Acad. Sci. USA $6, 641-644. I' Fcrnandcz-Reycs, D. ct al. 119971 Hum.Mnlcc. Gcnct. 6, l.Z,i7-1360. In M;ik, T.W. ( 199K) Thc Gcnc Knnckout FactsBook. Acadclnic Prcss, London I" Sligh 1.E. Ir. e t ill. 11 9'1.31 Prt~c.Natl Ac;id. Sci. USA 90, X519-X.i.3.3. "
-~
Intercellular adhesion molecule-2, CD102 . -
i I
> - -
Family Immunoglobulin superfamily
Structure Molecular weights Amino acids Polypeptide:
275 30 653
SDS-PAGE reduced
55-65 kDa
Carbohydrate N-linkcd sitcs
Gene location
17q23q25
Gene structure
4 cxons
2
COOH
Alternative forms Structure ICAM-2 is a type I transmcmhrane molcculc with two C 2 Ig domains. X-ray crystallography reveals a distinctive integrin recognition domain'. Thc cytoplasmic domain of ICAM-2 can bind the ERM (ezrin, radixin, moesin) membrane-cytoskeleton linker m o l e ~ u l c sand ~ ~ ?a-actinin4.
Ligands ICAM-2 is a counter-receptor for the leucocyte integrins nLP2and ah,P25.6.
Function ICAM-2-mediated adhcsion can provide a co-stimulatory signal for T cell activation and may therefore be important where antigen-presenting cells exprcss little or no ICAM-1'. Antibody blocking experiments and using ICAM-1 -1- endothclium s u a e s t that ICAM-2 plays a role in leucocytc transendothelial m i ~ r a t i o n ; ~ .howcver ~, ICAM-2 -1mice show no differences in lymphocyte recirculation.
Distribution TCAM-2 is exprcsscd by a subpopulation of lymphocytcs, monocytes, splenic sinusoids, dendritic cells, platelets, stromal cells and at high levels on vascular endotheliumf0. In endothelial cells, ICAM-2 is down-regulated by pro-inflammatory mediatorsrr.
Disease association OMIM 146630 Increased endothelial ICAM-2 expression has been detected in lymphoid malignanciesr2.
Ig Family
Knockout MC,I:96,393 T17iz G c ~ ~Kl7oi.ko1it c F i ~ c\ROO~C", t p.5,37 n in the ICAM-1 - / - mice show an imp;~ircdn c c ~ ~ n i i ~ l n t iofc ~cosinophils f in t h e cntiothclia. No lung in response to allergens due to lack c ~ ICAM-2 diftcrcnccs in Ivmphoc\~tc rccircul;~tion to thc lvrnph nodes or in NK responses ~ v c r cohscrvcd.
Amino acid sequence of human ICAM-2 MSSFGYRTLT VALPTLICCP G
'
... .
. .
7 . ,
Database accewion EMRL, C.cnR;lnl< Sw~\sProt
X 15606 P1.3594
References Casasnovas, 1.M. ct al. (1997)Naturc 387, ,312-,3 1.5. Heisk;~,L. ct ;I]. 11 9941 I. Riol. Chem. 27.3, 21 K9,3-21'100. Yonemurn, S. ct al. (1119S)I. Cell Riol. 140, XKS-895. Hciskn, L. ct 31. 119961 I. Riol. Chcm. 171, 26214-16219. Staunton, D.E. ct al. I19891 Naturc 3.39, 61-64. " Xie, 1. ct al. (l99.5l 1. Immunol. 1.55, k3619-h36?H. Dnnilc, N.K. ct nl. 119921 J. Immunol. 144, 665-671. Rciss, Y. ct al. (19941 Eur. 1. Immunol. 28, 3086-,309'1. " I ~ s c k u t zA.C. , ct ;11. (199911. Lcitkocvtc Ricil. 6 5 , 1 17-126. I n dc Fougcrollcs, A.R. ct al. (1991l J. Exp. Mcd. 173, 2L3-267. J I McLaughlin, F. ct al. 119981 Cell Adhcs. C o n i ~ n u n 6, . 381-400. Rcnkoncn, R. ct al. (1991)Am. I. Pathol. 130, 7h,3-767. l 7 Mak, T.W. 119081 T h e Gcnc Knockout FactsRook. Academic Press, London.
Family Immunoglobulin superfamily
Structure Molecular weights Amino acids Polypeptide:
547 59 383
SDS-PAGE reduced
110-135 kDa
Carbohydrate N-linked sites 0-linked sites
15
Gene location
19~13.3-p13.2
Gene structure Alternative forms Structure
7
PIP PPP did dbb GOOH
I C A M 3 is a heavily glycosylated type I transmembrane molcculc with five C 2 Ig domains. The cytoplasmic domain is phosphorylated on tyrosine residues following cell activation1. Binding to intcgrin aLP1is mediated hy ICAM-3 Ig domain 1 2 and, unlike ICAM-1, this hinding utilizes both faces of the domain1.
Ligands ICAM-3 displays calcium-dcpendcnt binding to intcgrin and unPZ6. Unlike ICAM-1 and ICAM-2, ICAM-3 does not bind integrins ah,PIor a,Pz7. Rcccntly, 3 novel ICAM-3 countcr-receptor, DC-SIGN, has heen identified on dendritic cellsR.
Function I C A M 3 mediates interccllular adhesion hetween leucocytes. It is constitutively expressed on resting antigen-presenting cclls, including dendritic cells, and appears to be important in the initial interactions hetween T cells and dendritic cells leading to T cell activationP. Optimal integrin a,P? hinding requires activation of the integrin expressing cellsrR but binding of integrin is constitutive. Antibody cross-linking of ICAM-3 on T cells can stimulate T cell adhesion and proliferationlf.lz, mob~lizeintracellular Ca" If, and activate tyrosine phosphorylation and the association of ICAM-3 with the tyrosine kinases Fyn and Lck. ICAM-3 can regulate ICAM-llintcgrin a#,-mediated adhesion'?. Interaction of 1CAM-3 on resting T cells with dendritic DC-SIGN enables engagement of the T ccll receptor hy stabilization of the dendritic-T cell contact zoneR.
Distribution Constitutively high on Icucocytcs: cpiclcrmal Langcrhnns cells. TCAM-.Z is torms arc rlctcctcd in scralJJ5. not cxprcsscd o n cntlothclin. Snl~il>lc
Disease association OMIM 1466,11
Knockout MGI: 10 1 792
Amino acid sequence of human ICAM-3 -.
MATMVPSW,W PRACWTLLVC CLLTPGVQG2 (
-
"
I I.
i
,
. ...
Database accession EMlZLi'GcnRank S~vi~~Prot
S500 1ijXh97 1 1 P.32042
References Skuhitz, K.M. ct al. (1995)1. Immunol. 154, 2888-2895. Van Koovk, Y. ct al. (1'1961J. Exp. Med. 183, 1247-1252. Rcll, E.D. ct al. (19981 J. Immunol. 161, 1,363-1370. Fawcctt, 1. ct al. 11992) Nnturc XiO, 48 1-484. Vazeux, R. ct al. 11992)Nnturc .ZciO, 485-488. "an dcr Vicrcn, M., ct al. (19'1.51lmmunitv ,Z, 6K.3-690. de Foligcrollcs, A.R. ct 81. (19951 Eur. 1. Itnmunol. 25, 1008-1012. T c i i t c n h c c k , T.R. ct al. (2000'1Ccll 100, 575-585. " Starling, G.C. ct nl. (1995)Eur. 1. Immunol. 25, 2528-25,32. lQdc Fougcrollcs, A.R. c t al. (19941 J. Exp. Mcd. 17'1, 6 19-629. Tuan, M. et al. (19941J. Exp. Mcd. 179, 1747-1 7.56. l2 Hernandez-Cascllcs, T. ct nl. (199,31 Eur. J. Immunol. 23, 3799-2806. Cnnipancro, M.R. ct al. (199,31 J. Ccll Riol. 123, 1007-1016. lJ Dcl Pozo, M.A. et 31. 11994) Eur. J. Immunnl. 24, 2.586-2594. Ii Pino-Otin, M.R. ct al. 11 995) 1. Immunol. 24, 2586-2594.
Intercellular adhesion molecule-4, CD242, Landsteiner-Wiener blood group-antigen,-LW - -
Family Immuno~lohulinsuperfamily
Structure Molecular weights Amino acids Polypcptidc:
27 1 29 265
SDS-PAGE reduced
42-43 kDa
Carbohydrate N-linked sites 0-linked sites
4
Gene location
19~13.3
Gene structure
2.65 kh, 3 exons'
COOH
Alternative forms A cDNA encoding an alternatively spliced form, which lacks the transmemhrane and cytoplasmic domains, has been isolated2.
Structure ICAM-4 is a typc I transmcmhranc molcculc, which, like ICAM-2, contains two C2 Ig domains with partial conservation of critical residues involved
in integrin hlnding'. The molecular hasis for the Landsteiner-Wiener (LWl(al/LW(hJpolymorphism is a single bascpair mutation changing Gln to Arg at amino acid 100'.
Ligands ICAM-4 hinds to the leucocyte integrins a$,,
aMPzand a,P2J
Function ICAM-4 is predicted to function as an intercellular adhesion molecule in haematopoietic cells.
Distribution ICAM-4 is found on erythrocytes and subsets of both R and T cells".
Disease association OMIM 11 1250 ICAM-4 may he depressed during pregnancy and in some diseases, e.g. Hodgkin's disease, lymphoma, leukaemia and sarcoma.
0 Knockout
--
Ig Family
Amino acid sequence of human ICAM-4 MGSLFPLSLL FFLAAAYPGV GS
--
-
ZJ
I .
-
-
. - --
Database accession EMRL/C;cnRank SwissPrat
L27671 Q1477,3
References ?
(
Wurmand, P. ct 31. (Irl961Rlood K7, 2962-2967. Railly, P. ct al. (1994)Proc. NatE Acad. Sci. USA 91, 5.306-i310. Hcrmnnd, 1'. e t AI. (19951Rlnod Kh, 1590-1594. Railly, TI. ut 31. (1995) Eur. J.Fmmunol. 25, 331h-L3320. Oliveira, O.L. et al. 1 1 9841 J.lmmunogcnct. 1 1, 297-do,?.
,
I
Intercellular adhesion moleculed, telencephalin --
Family Imrnunofilobulin superfamily
Structure Molecular weights Amino acids Polypeptide:
924 97 184
SDS-PAGE rcduccd
130 kDa
Carbohydrate N-linked sites 0-linkcd sitcs
13
Gene location
19p13.211
Gene structure Alternative forms
Structure ICAM-5 is a type I transmembrane protein with nine Ig-likc cxtracellular
domains, and is most closely related to ICAM-I and ICAM-3z3.
Ligands ICAM-5 hinds intcgrin cr,P,. Unusually this hinding is divalcnt cationindependent and not activated by protcin kinase C7.J.
Function ICAM-5 functions in signalling specific subsets of telencephalic neurons to make correct synaptic connections with growing axons5 and to mcdiatc lcukocyte hinding to neurons in the central nervous systemd.
Ig Family
Distribution ICAM-5 is a brain-specific adhesion molecule expressed on the somadendritic membrane of subsets of telencephalic neurons. Expression is first detected at birth parallel with dendritic development and synapse formation in the telencephalon'.5.
Disease association OMIM 601852 Increased serum concentrations of ICAM-5 are indicative of damage in the mesiotemporal or hippocampal areas of the brain, and may provide a differential diagnosis of seizures7.
Knockout MGI: 109430
Amino acid sequence of human ICAM-5 1 61 121 181 241 301 361 421 481 541 601 661 721 781 841 901
MPGPSPGLRR RPERGGLETS DRVELMPLPP LTATVLARRE VGSERPVSCT ICNVTLGGEN VPGQPAQLQL WPEGPEQTLR KDVTLTVEYA RVAREHAGTY KPQPSVKCVG SAESPPEMDE GTYHCVATNA WRAPPGALNI GGAAGGAALL PEAAGGAAES
ALLGLWAALG LRRNGTQRGL WQPVGENFTL DHGANFSCRA LDGLFPASEA RETRENVTIY NATENDDRRS CEARGNPEPS PALDSVGCPE RCEATNPRGS SGGATEGVLL STCPSHQTWL HGTDSRTVTV GLSSNNSTLS AAGAGLAFYV PAEGEVFAIQ
LGLFGLSAVS RWLARQLVDI SCRVPGAGPR ELDLRPHGLG RVYLALGDQN SFPAPLLTLS FFCDATLDVD VHCARSDGGA RITWLEGTEA AAKNVAVTVE PLAPPDPSPR EGAEASALAC GVEYRPWAE VAGAMGSHGG QSTACKKGEY LTSA
QEPFWADLQP REPETQPVCF ASLTLTLLRG LFENSSAPRE LSPDVTLEGD EPSVSEGQMV GCTLIKNRSA VLALGLLGPV SLSCVAHGVP YGPRFEEPSC APRIPRVLAP AARGRPSPGV LAASPPGGVR EYECARTNAH NVQEAESSGE
RVAFVERGGS FRCARRTLQA AQELIRRSFA LRTFSLSPDA AFVATATATA TVTCAAGTQA ELRVLYAPRL TRALSGTYRC PPDVICVRSG PSNWTWEGS GIYVCNATNR RCSREGIPWP PGGNFTLTCR GRHARRITVR AVCLNGAGGG
Database accession EMBLIGenBank TrEMBL
U72671 Q9Y6F3
References
3
Kilgannon, P. et al. (1998)Genomics 54,328-330. Yoshihara, Y. et al. (1994)Neuron 12, 541-553. Mizuno, T. et al. (1997)J. Biol. Chem. 272, 1156-1 163. Tian, L. et al. (1997)J. Immunol. 158, 928-936. Yoshihara, Y. and Mori, K. (1994)Neurosci. Res. 21, 119-124. Tian, L. (2000)Eur. J. Immunol. 30, 810-818. Rieckmann, P. et al. (1998)Lancet 352,370-371.
LWLNCSTNCP RGLIRTFQRP GEPPRARGAV PRLAAPRLLE SAEQEGARQL LVTLEGVPAA DDSDCPRSWT KAANDQGEAV ELGAVIEGLL GRLFSCEVDG HGSVAKTVW EQQRVSREDA AEAWPPAQIS VAGPWLWVAV AGGAAGAEGG
Junctionaladhesion molecule ~p
p p p
- -
~
-
..
..
Family Immunoglobulin superfamily
Structure Molecular weights Amino acids Polypeptide
299 35216
SDS-PAGE reduced
36-41 kDa
Carbohydrate N-linked sitcs 0-linked sites
2 0
<
COOH
Gene location Gene structure Alternative forms Structure JAM is a type I transmembrane protein with two extracellular V-type Ig domains'.*.
Ligands Prcsumcd to be homotypic.
Function In vitro experiments s u g ~ c s that t JAM promotes ccllLccll adhesion, possibly by participating in the assembly of tight junctions. Anti-]AM antibodies are effective in blocking leucocyte transmigatinn in vivo and in vitrcP and are able to attenuate cytokine-induced meningitis in mice4.
Distribution JAM is found in vivo and in vitro on endothelial and epithelial cells, where it localizes to sitcs of ccll-ccll contact in particular to tight junctions. In addition expression is detected on mesothelial cells and megakaryocytes and, suprisingly, constitutivc ]AM cxprcssion is found on human but not murine peripheral blood leucocytes. Treatment of endothelial cells with TNFa and IFNy results in a redistribution of JAM from the junctions to the non-iunctional areas of the cell membrane'-3.
0 Disease association
Knockout MGI: 1.371.39S
Amino acid sequence of human JAM MGTKAQVERK LLCLFILAIL LCSLALG
Database accession EMliLIGcnRank Sw~ssProt
AFI 1 1 -
References O x k i , H. et ;I]. (I9991 1. Immiinol. 16.3, 353-,557. Mrilliarns, L.A. 11 9901 Mol. Imtnunol. .ZA, 1 175-1 I SS. Mllrtin-P;ld~ir;l,I. ct ;11. 119081 I. Cell Riol. 147, 117-177. del Milschio, A. ct ill. (19991 1. Exp. Mcd. 190, l.Z31-I,Z56
Family Immunoglobulin superfamily
Structure Molecular weights Amino acids Polypeptide
1257 140002
SDS-PAGE reduced
200 kDa
Carbohydrate N-linked sitcs 0-linked sites
20
Gene location
Xq28
Gene structure
-16
kh, 2R exons
7 PPPPP '779 bbddb bbd
Alternative forms
' C M ) H
Altcrnativc splicing can rcsult in a four amino acid insertion in the cytoplasmic domain and fivc amino acid insertion in the N-terminus of neural hut not non-neural L1 (see amino acid sequence].
Structure L1 is a type I transmcmhranc protein comprising six C2 type Ig domains followed hy five fihronectin type 111 (F3) domains. Proteolytic processing can result in cleavage after ArgR64 within the third fihronectin type I11 domain, resulting in a extracellular fragment non-covalently associated with a mcmhrane-hound fragment. Thc cytoplasmic domain associates with the cytoslceleton via its ahility to hind ankyrinJ.
Ligands L1 can mediate homoph~lichinding. This binding is enhanced by L1 interacting in cis with other adhesion moleculcs such as TAG-llaxonin and NCAM, and with signalling receptors such as fibroblast growth factor receptorfJ. Ll also hinds integrin a,@,and ( Y ~ P , ~ ~ .
Function L1 mediates neuron-neuron and ncurnn-glia interactions. It is implicated in ncuronal cell tnigration, f;lsciculation : ~ n d o~~tgrowth'.". In hac~zlatopoictic cclls, L I homotypic intcrnctinns can uictii;~tc tllc aggrcgatinn c ~ factivated R cclls1V1nrt thc interaction of L1 with intcgrins may provide nn nltcrnntivc mcchanisni for the hind in^ of CD.31-vc lymphocytes to cndc~tliclialccllsr.
Distribution L1 is wirlcly cxpressctl in thu adult and cmlryonic ncrvous systcm. On pnst-mitotic, prcmigratory ncurons, L1 is localized to t h e cell bodies. O n post-migratory neurons, L1 is Iocalizurl predominantly to tlic axons. L1 is a l s t ~prcsunt on Schwann cclls and a suhpopulatinn of cpithclial cells9. In the hncmatnpoictic svstcm, L1 is prcscnt on 10-20"O of pcriphcrnl hlnod ly cxprcssion to that of CD31 5 . lymphocytcs with R ~ n u t ~ l a l cxcluslvc
Disease association OMIM .ZOXX40 Mutations in LI are ;~ssociatctlwith a nuniher of X-linked neurological deficits including X-lined hydrocephalus, MASA syndrome (;iJiluctetl thumbs) and spastic p i ~ r ; ~ p l c g i ; ~ t l - ~ ~ .
Knockout MG1:86721 L 1 - / - mice act 21s an anim;ll mt>tlcl of the L1 mutation X-linked nc~irologicaldeficits. T h e size of the corticospinal tract is reduced ;lnJ nonmyclinating Schwann cclls show i~npaircd association with axons. T h e mice arc smaller thnn wild typc, lcss sensitive t o touch and pain, and havc
wcnkcncd, ~~ncoordinaterl hind l c ~ s ~ ~ , ~ ~ .
Additional information Thcrc is some controversy as to t h e relationship of L l with rclntcd mtllcculcs ~ r o mother spccics, p;~rticularlychickcn NgCAM and chickcn NrCAM. All thrcc receptors h3vc ;I similar structure in that they contain six C2 type I!: domains and five iihroncctin typc 111 domains, ;lnrl ;I conserved cytoplasmic dtlmain which can interact with nnkyrin. They arc capahlc of hoint~typic;~rlhcsion,can intcract with TAG-l/;ixonin, ;~ntl and function to mcrliatc ncuronal adhesinn anrl o ~ ~ t g r o w t h ' ~NsCAM '. NrCAM arc not given separate cntrics here, hut thcir tl;~tal>ascacccssion numhcrs arc givcn hcltjw. In gcncrnl, chickcn NgCAM is regarded as ;In L1 orthologuc, whcrcas NrCAM, together with murinc CHL-I 2nd nci~rotascin, are rcg;~rtlcd a s vcrtchratc L1 t;~niily mclnhcrs. T h e rcltltionship ot L1 with Drosophilrr ncuroslinn ant1 Iccch trnctin h ; ~ syet to he cstal>lishctl.
-
Ig Family
Amino acid sequence of human L1
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The two scqucnccs undcrlinctl ant! in italics arc cncodcd for hv cxons 2 and 27 and arc spliced o u t in non-neural cells.
Database accession L1 NgCAM (chicken\ NrCAM (chickcnl
EMNLl~~cnI~r~nk XSYK47 X56969 X584X2
Suri~sl'rot P.32004 Q0,3696 P.353,Z 1
References Rrummcndorf, T. et al. ( 1 9981 Curr. Opin. Ncurohiol. 8, 87-07. Kadmon, G. ct 31. (1900)J. Cell R~ol.1.32, 475-485. Walsh, F.S. and Dnhcrty, P. (1997)Annu. Rev. Ccll Dev. Riol. 13, 425456. .' Malhotra, J.D. ct al. { 19981 J. R~ol.Chcm. 27.3, 3,3354-3.3<359. Ehcling, 0.ct al. (19961 Eur. J. Imrnunol. 26, 2508-2516. Montgomery, A.M.P ct al. (19961 1. Ccll Riol. 132, 475-485. Ruppcrt, M. ct al. (1995)J. Ccll R~ol.1.31, 1881-1891. Rlness, S. ct al. (1998)J. Ncurochcm. 71, 2615-2625. Schachncr, M. ( 1990) Cihn Found. Svmp. 145, 156-1 72. l-owitz, A. ct al. 1199.71 Clrn. Exp. Metastasis 11, 419-429. l1 Roscnthal, A. ct al. (19921 Naturc Gcn. 2, 107-1 12. louct, M. et al. (1994)Naturc Gcn, 7, 402-407. l 3 Kcnwrick, S. and Dohcrtv, P. (1998)Riocssays 20, 668-675. Dahmc, M. ct al. (1997)Naturc Gcn. 17,346-.Z49. l 5 Cohcn, N.K. ct nl. (19981 Curr. Rio!. 8, 26-,3,?.
Mucosal addressin cell adhesion molecule 1
I
Family
Structure Molecular weights Amino acids Polvpoptidc:
406 32 664
Carbohydrate N-linkud s ~ t o s 0-linkcd sitcs
1.
Gene location
l 9q lL3.\3I
Gene structure
5 cxons
Alternative forms
+++
Octamer repeats
COOH
Altcrnativcly spliccd transcripts hnvc hccn dctoctcd in human llrain2.
Structure T h c two C2-tvpc Ig at tho N-tcrminus arc rclatcd to cquivalcnt domains in thc othcr i n t c ~ r i nbinding proteins: VCAM-1, JCAM-I, ICAM-2 and ICAM-
MAdCAM-1 hlnds intcgrin ru,fi- via its Ig domains nnd L-sclcctin via thc sialogIycoconii~g;~tcs in tlic ~ilucin-likestalkF-'.
Function Encitlthclial MAdCAM- 1 hintls to ~ t ~ t c g r ru i n,p. and L-sclcctin on lcucncvtcs thcrchy contrihutiny: t o thc rccircu1;ltlr~nnf naivc lymphocvtcs to Pcycr's pntchcs ; ~ n dtncscntcric lymph nodcs, and thc homing of n suhpopl~l:~tion of
activated or memory lymphocytes to the gut lamina proprian. Ry hinding to both intcgrins and sclcctins, MAdCAM-I has a prnposcd role in mediating 170th the rolling and the firm adhesion of IymphocytcsR.
Distribution MAdCAM-I is cxprcssed at high lcvcls of the high cndothclial vcnulcs of Peyer's patches and mcscnteric lymph nodes and on flat-walled venules within thc gut lamina propria. It is also cxprcsscd on vascular cndothclium in mammary glands, pancrcas and the splccn marginal sinus and on hlood vcsscls in areas of chronic i n f l a m r n a t i ~ n ~In . ~vitro, . MAdCAM-I expression is inducible by TNFa and IL-1.
Disease association OMTM 102670
Knockout MGI: 103579
Amino acid sequence of human MAdCAM-1 1 MDpGLALLLA GLLGLLLGr;):: :,(J','v Y'j v.'r7 7 r 7 ...:-?[): . . . . . . . .. . , , . . . .: .. .. i r :
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Database accession EMRL/CenRank TrEMRL
U43628 Q 13477
References Leung, E. ct al. (1997)Immunogcnctics 46, 11 1-1 19. Leung, E. et al. ( 1996)Immun. Cell Riol. 74, 490-496. Tan, K. ct n l . (1998)Stn~cturc6, 79,3-H01. Shyian, A.M. ct al. ( 1996) J. Immunol. 156, 2851-2857. Berg, E.L. ct al. ( 1993) Naturc 366, 695-698. q c r l ~ nC. , ct al. (1993)Ccll 74, 185-195. Rriskin, M.1. ct al. (1996)J. Immunol. 156, 719-726. Rutchcr, E.C. and Picker, L.J. (1996)Scicncc 272, 60-66.
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Family I r n m i ~ n o ~ l c ~ lsupcri,lliiiIy ~~~lin (siglcc s i ~ l ~ f ~ l i i i I ~ \
Structure Molecular weights A m ~ n oa c ~ d s Polvpcptldc.
hlh 69 0hS
Carbohydrate 121-linltcrl sites C)-linltcd sitcs
S
Gene location
19~112-I9rl l<3.2
Gene structure
I h kl,, I .< cxons
COOH
Alternative forms
A l t c r n ~ t i v c L I W c ~ tcxons 12 ant1 1.3 results in long {LI- and short lS1cvtop1;lsmic tlc~mainMAC; isrdornls.
Structure MAC; is ;I mcmhcr ot t h e siglcc family of sialic acid hindin!: lcctins ICD.3.3, C D l l llnri sinlo;~Jhcsinl.Structur;~llyMAC, contnins onc V t!'pc nnd four C1 type Ig-lilrc d o ~ n a ~ n sA' . rc1;ltctI protvin Scwann cell mvclin protein (SMP; .;iglco-4hI h ; ~ shccn idcnt~ficdin qi1;tlI (Gcnl3.1nk accession numhcr SX,771 11.
Ligands M A T . hintls to thc si;~l(~glycc~conii~g;~tc NvuAccu2-~3Gnlpl-.ZG;1INAc on rZr:ind 0-linlicil c~ligos;~cch:~riJcs ;lnrl g;lng1iosirlcs2,'. In ;I sitnilnr ni;lnncr t o CL)77 ;lnil CLI.I,I, MAC; l i ~ ; ~ n hintling tl c:ln he niodul:ltcil hy its o w n s i ~ l \ , l ; ~ t i oIn n ~adilition, . MAG has lwcn rcportcd t o hind t o c o l l n ~ c n sI-V15.
Function lri \ . l ! r o MAG-csprcssing cclls hintl specifically t o ncuronal glycoconii1g;1tc.5' anil hlockin,q experiments originally implic;~tcd;I rolc for MAC, in n c n r C myc1in;ition. An;ilysis of MAG - / - mice [see hclowl si~ggcstsMAC. tunctioti in t h e integrity ;~nrlIon,q-term m ; ~ i n t c n a n c rof hoth myclin ~lntl;lsons r;lthcr th;m t h e process ot niyclinntion itself.
Distrihtltinn .MAC; is cxprc.;scJ !,I
oligodciidrocvtvs ;~nrlSchwnnn cclls.
-
-.
-
Ig Family
Disease association OMIM 159460 Mapping of the mouse gene led to the suggestion that mutations in MAG undcrlic the neurological 'quivering' (clv)disorder.
Knockout MG1:96912
In MAG -1- mice there is no gross ahnormality in the dcgrcc of myclinntion or its compaction. Mutant animals appear normal in motor coordination and spatial learning, hut show a suhtlc intention trcmor. Howcvcr, the organization of the pcriaxonal rcgion is partially impaircd and u1tr;lstructural studics show that thcrc is a dccrcasc in the proportion of myclinatcd axons in the optic ncrvc and a variation in the amount of rnyclin laid downLY.Moreover, after 8 months of ngc mice show both axon and myclin dcgcncration.
Amino acid sequenc of human MAG
Database accession EMRL/GcnRank SwissProt
M29273 P209 16
References S~ato,S . ct al. (19891Riochom. R~opliys.Ros. Comniun. 16,3, 1473-1480 Kclrn, S. et al. (19941Curr. Riol. 4, 965-972. Collins, R.E. ct 91. (1997)J. Biol. Chcrn. 272, 1248-1255. Tropak, M.R. and Rodcr, J.C. 11997) 1. Neurochcm. 68, 175.3-1 763. "ahrig, T, ct a]. (1987)EMRO J. 6, 2875-2883. "1, C. ct al. (1994)Nature ,369, 747-750. ' Montag D. ct al. 119941 Neuron 13, 229-,746. F r ~ ~ t t i gM. c r ct a]. (1995)Eur. 1. Ncurosci. 7, 51 1-515. Li, C. ct al. ( 1998) J. Ncurosci. Rcs. 5 1, 2 10-2 17. 2
CD146, MCAM, Mel-CAM
Family
Structure Molecular weights A i n ~ n oacids Polypcptirlc
641, 71 70.1
SDS-PAGE rctluccd
1 15-1 30 kDa
Carbohydrates iV-linl
S
Gene location
1 l qZL3.,3
Gene structure
14 kh, I6 c x t ~ n s
Alternative forms
Structure M U C l S is a hixhly N-xlycosylntcd typo I trnnsrncmhrnnc protoin with five I , q domains followed hy n smnll illclnhranc proximal stalk r c ~ i o nand n hd ;)mini)acid cytopl;~smicJolnainl.?.
None idcntificii.
Function Owing to its Ii(lnio\ogy to other 1,cSF mcmhcrs, MUC E X is proposctl to act 3.; an ntlhcsion receptor. At lcnst in part, this putative ndhesivc function m;iy hc incrliatcrl hv ;I MUCIX signalling function a s MUCIX engagement rcsiilts in tyrosinc phosphorylation of focal adhesion kinase, possihly hy the M U C l S rccruitmcnt of thc tvrosinc kinasc Fyn?.
Distribution MUCIX w:ls origin;llly idcntificd as an cndothclial ;~ntigcn whcrc it loc;~lizcsto ccll-cell contact nrcas. Is is also cxprcsscd on smooth muscle, intcrmctli;itc trophohlast and a s u h p o p ~ ~ l a t i oofn activated T cclls. Much intcrcst in MUClK is that it is n merkcr nssocintcti with tumnur progrcssir)n and rnctastatic Jcvclop~ncntof malign;lnt mclanomas4.
L32
Neural cell adhesion molecule, CD56, fascilin I1 (Dmsophila),spCAM (Aplr~sio)
Family Immunoglohulin superfamily
Structure Molecular weights Amino acids
Polypeptide
SDS-PAGE rcducod
NCAM-120 NCAM- 140 NCAM-180 NCAM- 120 NCAM- 140 N C A M - I80 NCAM- 120 NCAM-140 NCAM-180
Carbohydrates N-linked sitcc 0-linked sites
Gene location Gene structure
> 100 kh, >
20 cxons (mouscl coon
Alternative forms NCAM is suhicct to oxtensivc altcrnativc splicing resulting in 20-.Z0 different isoforms. The three mnior isofurms arc NCAM- 180, - 140 and - 110. NCAM-180 differs from NCAM-140 hv thc inclusion of cxon 18, producing a longer cytnplas~nicdo~nain.NCAM-120 arises from the inclusion ot cxon 1.5, which produces a GPI-anchorcd istlform. In addition, there is variahlc insertion of the ten aminn acid VASE cxon, which converts the fourth Ig domain from :I C2 to ;i V typc, and of the MSDl cxons hetween the two fihroncctin tvpc I11 (F.11rcpcatsr.?.
Structure NCAM is a tvpc I transmcmhranc protein containins fivc C2 Is domains followed by two fihroncctin typc It1 (MIdomains. In addition to different isoforms gcncrated Ily alternatively splicing, N C A M is suhiect to posttranslational motiification hy the addition of varying length of a?-8-linked sialic acid (polvsialic acid), which accounts for up to cZO"o of the molecular weight in thc NCAM-180 isoform2. The solution structure of the first two Ig domains has hecn reported3.
Ligands NCAM mediates hemophilic hinding, which involvcs all fivc Ig domains pair~ng in an antiparallel alignment" In neurons, N C A M can hind to
1g Family
chondroitln sulpliatc protco,qlvcans in the cclls matrix5. In nddition NCAM can interact in c2.y w ~ t hother ccll adhcsion ~ ~ ~ o l c c u lsuch c s , 21s L l , ; ~ n dwith signalling rcccptors, slicll as the fihrohl;lst growth lactor r ~ c c p t o r ~ . ~ .
Function NCAM has hccn sli(~wnto he involved in a divcrsc range of contactmcdiatcd interactions, h u t most notably hctwcen ncurons, ncurons and astrocytcs, ncurons ;mil oIi,qodcndrocytcs, and ncuron;~l processes nnrl myotuhcs. Thcsc cvcnts have implicated 3 role for NCAM in axnnal outgrowth, fascic~~lation, ccll migr;~tic~n, learning anil memory'.
Distribution NCAM is cxprcssctl in ;itfult nci~raltissue ant! ~ n u s c l con , human NK cclls, a suhpop~ilnt~on of T cells ant1 in n niunhcr of cinhryclnic t i s s ~ ~ c s ~ .
Disease association OMIM 1 l hY,3O NCAM cxprcssion is up-rc~ulatcd in a niunhcr of tunlour ccll types including ncurohlastoti~i~s,sm;111 ccll lung cc;~rcinonin, invcloinas nntl Wiltn's tumoursH.
MGI:Y72X 1 TIjr GczjrJl i r ~ o i . k o r ~Frrr.tslJc~oli", r 1.17x.3 NCAM -1- ~ n i c carc vi;ll,lc ;~ntlfcrtilc I ~ u with t s 10";, rctli~ctionin overilll hr;~in~ r c i g h t ,a 3(i'T:, reduction in olf;~ctoryhulk size Ic;~tlingt o tlcfccts in the migration of olfactory ncurons, ant1 dcficits in spatiill IcarninglT 1Ry clirninilting only NCAM-180, ;)n ccli~iv;~lcnt tlcfcct is c1hscrvcdJ1, indicating that NCAM dcficicncics result from loss of the highly polysialylatcd NCAM form. Intcrcstingly, hctcrozygous mice with a secreted form of NCAM tlied in utrro at EX.5-E9.5".
Amino acid sequence of human NCAM-120 . -. MLQTKDLIWT LFPLOTAVS' t.
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Ig Family
Amino acid sequence of human NCAM-140 MLQTKDLIWT LFFLGTAVS
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T h e NCAM 180 isoforin rcs~iltsfroni insertion c ~ cxon f IS at EX09 l s h n ~ l n in hold\
Amino acid sequence of mouse NCAM-180 (transmembrane and cytoplasmic domain
Database accession NCAM 120 NCAM 140 NCAM 180
EMIIL/C;r.nRrlrtk XlhXJI S71X23 X 1.5052 (~nouwl
SrwcvProt Pld592 PlcZ.591
-
References IValsh, F.S. ;inti Dohcrty, P. (1991l Scmin. Ncurosci. .3, 271-283. UTalsh,F.S. and Dohcrty, P. (1907)Annu. Rcv. Ccll Dcv. Riol. I,>, 4 1 5 4 5 6 . lensen, P.H. ct al. (1999)N;lturc Struct. Riol. 6, 4 8 6 4 9 3 . Ranhcim, T.S. ct ;)I. 1l99hl Proc. Natl Acnd. Sci. USA 9,Z, 4071-4075. Fricdlander, D.R. ct ;iI. 1 19941 J. Ccll Ric~l.125, 669-6RO. Saifcll, 1.L. ct al. (19971 Ncuron l X , 2,31-212. Goodman, C.S. i19LlhlAnn. Rev. Ncurnsci. 19, .131-<377. Goridis, C. and Rrunct, J.F. 119911 Scrnin. Ccll Riol. 3, 189-197. ' Mak, T.W. (199Xl Thc Gcnc Knock(~ut FactsRoclk. Acadcmic Press, London. I n Cremer, H. ct al. (19041 Nilturc .W7, 455-459. Tomasicwicz, H. ct ;I]. ( 199.3)N c l ~ r o n1 1, 1 lh,Z-1 174. l 2 R:lllinowitz, I.E. c t ;I[. [19L)61 Proc. Natl Acad. Sci. USA 9.3, 6421-6423.
~
~
p -
-
Myelin protein zero, MPZ, P-zero .-
.
Family Immunoglobulin superfamily
Structure Molecular weights Amino acids Polypeptide
258 27 555
SDS-PAGE reduced
28 kDa
Carbohydrate N-linked sites 0-linked sites Other
Complex, sulphated
Gene location
1q22
Gene structure
7 kb, 6 exons
Alternative forms Structure P(0) is a type I integral membrane protein, containing one V-type Ig dornain'ez. The cytoplasmic tail contains potential phosphorylation sites. The crystal structurc of the Ig domain has been determined3. One of the two modes of molecular interaction found providcs a model for the role of P(0) in homophilic interactions. Individual monomers on the ccll memhrane are predicted to associate in an antiparallel orientation with monomers on the opposing cell memhrane. This would fit a role for P(0l holding adjacent memhranes together in the individual wraps of the myclin sheet. Some mutations in Charcot-Marie-Tooth Disease (see helowl would disrupt predicted structure.
Ligands P(0)homophilic interactionJ
Function Guiding, linking and compaction of adjacent lamcllac of myelin sheath.
Distribution P(O1 is the major structural protein of peripheral nerve myelin shcaths, produced hy Schwann cells. It is ahsent from the central nervous system.
Ig Family
Disease association O M l M 159440 Mutations in the MPZ gcnc arc associated with the autosomal dominant for111 of Charcot-Maric-Tooth discasc (Typc lhl, which is duc to ncuronal dcmyclination lcading to various forms of pcriphcral ncuropathy and distal muscular atrophy, and somc othcr inherited periphcral neurological svndrornc~~.~.
Knockout MGI: 103177 A knockout n ~ o u s c~ n t ~ d cfor l P(0) function has bccn rcpnrtcd to show
peripheral nerve mvclin degeneration similar to that seen in human mutations'.
Amino acid sequence of human P(0) : . .. ...-, .. .. ., .. .' . ,
&&RAPAPAPA
mPGAPSSS[' 5 : ' : :,.':.;L,;i,
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p,,9[,,,...,,.r,,.
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Database accession EMRL/C.cnRank D 105.37 SwissProt
P25 1 89
References Havasaka, K. et al. (1991)Riochcm. Riophys. Rcs. Commun. 180, 515-518. Havasaka, R. ct a!. (1993)Gcnomicq 17, 755-758. Shap~ro,L. et al. (1Y96l Neuron 17, 435-449. Filh~n,M.T. ct al. (1990)Naturc 644, 871-872. Havasaka, R. ct al. (1993)Naturc Gcnct. 5, 266-268. Havasaka, K. ct 81. (1993)Nnturc Gcnct. 5, 31-34, Mart~ni,R. ct a]. (19951 Natuac Gcnct. 11, 281-286.
Family Immunoglobulin supcrfnmily [siglec subfamily1
Structure Molecular weights Amino acids I'olypcptidc
I 693 182 973
SDS-PAGE rcduccd
185 kDa
Carbohydrate N-linked s ~ t c s 0-linked sitcs
15
Gene location
2Op 13'
Gene structure
5 COOH
Alternative forms Two
Structure Sialoadhcsin is a member of thc siglcc family of sialic acid binding lcctins (CD,3.3, CD22 and MAC.]. Structurally sialoadhcsin contains 17 Ig domains of which domains 4-17 are made up of sevcn homologous tandcm rcpcats consisting of a short and long Ig do~nain?.Likc othcr members of the family, sialoadhcsin is prcdictcd to have an unusual disulphidc hond hctween p strands R and E in domain 1, and a disulphidc hond hetwecn domains 1 and 2". Thc sialic acid binding site has hccn localized to the Nterminal Ig domainJ and thc crystal structure of this domain in complcx with sialyllactosc has hccn ohtaincd5.6.
Ligands Sialoadhcsin hinds to thc sialo~lycoconiugatcsN c ~ A c t r 2 ~ 3 G al73(4IGlcNAc lp and NcuAcn2--3Galp 1 -3GalNAc on glvcoprotcins and glycolipids'. Likc othcr siglccs, sialylation of sialoatihcsin ncgativcly regulates ligand binding-?.
Ig Family
Function Sinlo:iclhcsin functions as n mncrophngc-rcstrictcd adhesion receptor mediating prctcrcntinl recognition of cells of the granulocyte l i n ~ a g c ~ . ~ .
Distribution Sialoadhcsin is cxprcsscd on suhscts of macrophnges in honc marrow and secondary lymphoid organs2. Expression in resitlcnt peritoneal mncrophnges is down-rcgulntcd hy IL-4'".
Disease association OMIM 600751
Knockout MGI:9966H
Amino acid sequence of mouse sialoadhesin ..
MCVLFSLLLL ASVFSLGQT'
.
..-
--
.
.
.. . .
. -
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,..
-
. . -- .
-
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-
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--
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Database accession EMHLC;cnRank TrEMRL
Z.3629<3(iiioi~sc\
Qh22,iO
.--
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-
.
-, ,
References 2
"
''I
Mucklow, S. ct nl. (1995)Gtnomics 28, ,343-316. Crockur, P.R. c t al. (1994)EMRO 1. 13,4490450,3. Crockcr, P.R.ct nl. (19961Riochcm. Soc. Tmns. 21, 150-1 56. Vinwn, M. et a]. I19961 1- Riol. Chcm. 171, 9167-9171. May, A.P. ct al. (1998)Mol. Ctll 1, 719-778. Crockur, P.R.ct al. 11999)Rlochcm. J. 341, 3.55-,361. Kclm, S, ct al. (19931Curr. Riol. 4, 965-971. Barnes, Y.C. t t al. (19991Rlood 93, 1245-1252. van dun Rurg, T.K. ut 81. (199211. Exp. Mcd. 176, 647-655. McWllllam, A.S. ct a]. (1992)Proc. Natl Acad. Sci. USA 89, 10522-10526.
Family Immunoglohulln suycrfamily
Structure Molecular weights Amino acids Pol~,pcptidc
1040 1 13 .30.3
SDS-PAGE rcduccd
135 kDa
Carbohydrate N-linked sites 0-linked sitcs
10
Gene location
1q32.1
Gene structure
40 kh, 23 exons
Alternative forms
Snluhlc TAG-I is released from culturcd ncurons.
Structure Type I memhrane glyoprotcin of the C2 subset of 1g superfamily with six C2 type Ig domains and four mcmhrano-proximal fihroncctin typc 111 rcpcatsl-3. TAG-1 has n o transmemhrane scquence and is GPI-anchored.
Ligands TAG-I hinds to L1 family mcml~crs. Rccent data suggest that this interaction occurs in cis in the plane of the membrane rather than rcprcsenting a hctcrophilic intcraction hctwccn ncighhouring ccllsJ,5.
Function TAG-I is involvcd in nouritu o u t ~ r t ~ w tinh r ~ i t r oant! pathfinder axonal cxtcnstion in cmhryogcncsis"'. Neurons1 migration and TAG-1 cxprcssion arc up-rcgulatcd hv nctrin-1, 2 Ionz-range diffusible factorx. Ruccnt studies indic:itc that tho main function of T A G - I is to intcract in cis with L1 family memhcrs and therehy rcgulate L1 -mediated adhesive intcracti~ns~.~.
-
Ig Family -
- -
-
--
-
Distribution Rcstrictcd to neural tissue in a suhsct of central and peripheral neurons in the developing embryo, with ret.ention in adult hrain and spinal cord*".Tqll.
Disease association OMIM 190197
Knockout MGI: 104518
Amino acid sequence from human TAG-1
The scqucnccs undcrlincd and in italics arc clcavcd off to form mature TAG- 1 and a GPI anchor is added.
Database accession EMRLICcnRank SwissProt
Xh8274 Q02246
References Haslcr, T.H. ct al. (1993)Eur. 1. Riochem. 21 1,529-339. Tsiotra, C.P. ct al. (199,7)Gcnomics 18, 562-567. Kozlov, S.V. ct al. (1995)Gcnomics 30, 141-148. Walsh, F.S. and Dohcrty, P. (1997) Annu. Rev. Ccll Dcv. Riol. 13, 425456. Rrummendorf, T. et al. (1998)Curr. O p ~ nNeurohinl. . 8, 87-97. "urlcy, A.1 ct al. (1990)Ccll 61, 157-1 70. Kuhn, T.R. ct al. (1992)J. Ccll Riol. 115, 11 13-1 126. 127, 1359-1372. Alcantara, S. ct al. (20001 Dcvclop~l~cnt ' Dodd, J. ct al. (1988)Neuron 1, 105-1 16. lo Stocckli, E.T. et al. [ 199 1 ] J. Ccll Riol. 112, 449-455. l1 Karagogcos, D. ct a!. (1991)Dcvclopmcnt 1 12, 5 1-67,
-
Vascular cell adhesion molecule 1; CDlO6
Family
Structure
Molecular weights Amino acids Polypeptide SDS-PAGE reduced
Carbohydrate I\r-linked sites 0-linked sitcs
Gene location
I p32- 1p
Gene structure
-25 kb, 9 cxons
Alternative forms A variant lacking the fourth Ig domain is produced hv alternative splicing1. In the mouse, there is a GPI-anchored form of VCAM-I containing the N terminal three Ig dom;lins-?'.
Structure VCAM-I is a type I trnnsmcnihranc protein with scvcn C?-type Ig domains. Ig domains 1 and 2, and domains 4 and 5 show homology t o domains 1 and 3 of the other intcgrin-binding IgSF molcculcs: MAdCAM, ICAM-1 (CD541, ICAM-2 (CDIO2I and ICAM-<3ICD~OI-'.~. T h e intcgrin hinding domain of VCAM- I has hccn c r ~ s t a l l i z e d ~ ~ ~ .
Ligands VCAM-I hinds intcgrins C Y , ~ ,and c u , P - ' with 3 preference for n a$,. Binding tlomains for tu,P, have hccn mapped to domains 1 and 5.'. More recently, intcgrin C Y , , ~ , on cosinophils has hccn shown to 3ct as a VCAM-I ligandR.
Function VCAM-I mediates the adhcsicln of lymphocytcs, monocytcs and cosinophils to intlammcd cndnthclium hy promoting hoth the initial tethering and rolling of lymphocytcs, and the suhscqucnt firm adhesion. In
Ig Family
-
.
-
--
-- -
non-vascular cells VCAM-1 has been implicated in the interaction of haematopoietic progenitors with bone marrow stromal cells, R cell adhesion to dendritic cells, co-stimulation of T cells, embryonic development and metastatic spread of tumour cell^"^*^.'^.
Distribution VCAM-I is present predominantly on activated endothelial cells hut is also expressed by tissue macrophages, dendritic cells, bone marrow fibroblasts, myohlasts and m y o t u h e ~ ~ " ~ . l l .
Disease association OMIM 192225 There are studies indicating that deficiencies in VCAM-1 can result in epicardial dissolution and subsequent myocardial thinning". The ability of VCAM-1 to mediate adhesion of melanoma cells to the endothelium may play an important role in mcstatic disscminationI3.
Knockout MGI:98926 The Gene Knockout FflctsR~ok'~, p 1065 The maiority of VCAM-1 -1- mice die at 9.5-1 1.5 days of gestation due t o failure of the allantois to fuse t o the chorion. Mice that survive the placental defect subsequently display scvere heart abnormalitics. Howcver, a few mice develop to become healthy fertile adults, indicating that VCAM1 is not essential for normal organ d e ~ e l o p m e n t ' ~ ' ~ .
Amino acid sequence of human VCAM-1 1 MPGKMVVILG 6 1 ' l i j l Ll.;PL:;CI 1 2 1 IHL,SCPI,E.P\C 1 R 1 TFTF",'IEDIC: 2 4 1 S7,,'T!4TCSSEG 301 FKE'..ELIVQE 3 6 1 SFGTNSTLTL 4 2 1 'I'T~'SCYVP:V 4 R 1 L'.'COAKLHID 5 1 1 APYILWSPQL 6 0 1 PDIKLTAFPS 661 YnAG'm.'?ECES 7 2 I PvAr:brrrGsYs
ASNILWIMFA ASQRFKICT? PES3i'LAOIG \ ' : :I t:G r I C": L 'r;':P7JSFGNWS?LCTATCF.
K?TT',.'KC.Sq,J,h 'J:'L:'CRAKLH LPhPE1FT:'SR KPFT'vfE1SPG SF\TSFEPIEHS Y?L.IlRLETFL
D.;?PFDSLEI IDEMDSVPW Y,LDNGNLO!IL PPIAAQIGDS YLCTVTCGHK LKGFTILENI
DLLKGDHLPU 'QAi'KF,SO"!Y
SCNATLTLIA 'VVLTCS'JMGC KLEKGIQVEL EFLEDTDMVS D!.?EFF,FKORO STOTLYi'NJA PPDTTVV,T? PNGCLQPLSE lJATLTLISTR MI?DSGTZVLCE ESVKEGDTVI ISCTCGYVPE TWI I LKKKAE KNKI!GSQLFS LTL3'r'QGREN NKDYFSPFLL
3S7,'SLTCSTT GC7SFFFS:JF SPILEKGTV.' EIV.SF?KDFE SQZFLEDADR KSLETKSLE.! I S P ? l l K 7 T S J . ' PIPSTXLOFGG MF,~!EDSCI'I'~I Cl?G;TILIG!:?I ESPSF,CG!PTO ID.S?LSG"'.'P. Y S ? P P ? P E I F MSGGL'rT.lGSS LE?!?SLEI,1TF IPTIEDTGKA 551LEFGSS',' TJb!TCLSQT,FP GII.!OAGFSF?: F.'ELIIO1.'TP TG3T'.'LKSID GA'IT1FF:AOL ' I L Y F A S S L I I PAIGMIIYFA
T,I'EAOPSW
Database accession EMRLIGenRank SwissProt
M73255 P19320
References Cyhulsky, M.I. e t al. (1991)Proc. Natl Acad. Sci. USA 88, 7859-7863. Revilacqua, M.P. (19931 Ann. Rev. Immunol. 1 1, 767-804. Vonderheide, R.H.et al. ( 1994) J. Cell Riol. 125, 2 15-222.
In
f2 1" lJ
Jones, E.Y. ct a]. (19951Nature ,37,3, 539-544. Shvian, A.M. c t al. (1996)1. Immunol. 156, 2851-2857. Wang, J.H.ct al. (19951Proc. Natl Acad. Sci. USA 92, 57145718. Rcrlin, C. et al. (199,1)Cell 74, 185-195. Grnyson, M.H. ct al. (1998)J. Exp. Mcd. 188, 2187-2191. Carlos, T.M. and Harlan, 1.M. ( 1994) Blood 84, 2068-21 01. Rutcher, E.C. and Picker, L.1. (1996)Science 272, 60-66. Masinovskv, R. et al. (1990)J. Immunol. 145, 2886-2895. Olson, E. and Srivastava, D. (1996)Scicncc, 272, 671-676. Taichman, D.R. et a]. (1991)Cell Regul. 23, 47-55. Mak, T.W. (1998) The Gcnc Knockout FactsRook. Acndcmic Prcss, London. Gunter, G.C. et al. (1995)Gcncs Dev. 9, 1 4 . Kwcc, L. ct al. (19951Development 121,489-503.
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Integrins
This Page Intentionally Left Blank
--
CD1 l a , LFA-1 --
Family Intcgrin (LFA/CD11 subfamily)
Structure Molecular weights Ammo a c ~ d s Polvpeptlde SDS-PAGE reduced
1170 128 819
180 kDa (170 kDa unrcduccdl
Carbohydrate N-l~nkedsites 0-llnkcd sites
12
Gene location
16p11.2 ( m a cluster with the other C D l 1 genes1
Gene structure
>.32 kb, >6 cxons (introncxon arrangcmcnt is s ~ r n ~ lfor a r all of the CDl l a chains].
+
7 -
..a
*. * \
q
Y
C D l l dCD18
Alternative forms Structure Intcgrin a , is a type I mernbranc glycaprotein integrin a chain' that dimerizes with P, to form aLP?;the p, chain is shared with thc other integrin a chains of the C D l l family (see entries). a, contains seven repetitive domains, approximately 50 amino acid long, in its cxtraccllular part; these rcpcat regions have hccn modcllcd to a beta-propcllcr fold as found in the P suhunits of trimeric G proteins2. The membrane-proximal three (V-V111 contain calmodulin EF hand-like sequences and arc involved in hinding divalent cations. The a, chain is phosphorylated,'. The a , chain helongs to thc suhfamily lwith the other lcucocytc functional antigen (LFA)iCDll group of Icuco-intcgrin CY chains] of integrin a chains with an inserted or 'I' domain and lacks past-translational proteolytic cleavage'. Thc I domain of cr, [CDl la1 shows scqucnce homology with von Willehrand factor; it has hccn crystallized and a structural modcl is available that ~. shows s t n ~ c t u r a homology l with an rr-p dinucleotidc binding f ~ l d ~It. also contains an imperfect 'metal ion-dependent adhesion sitc' (MIDAS1 with onc uncoordinated sitc that is thought t o he introduced from the intcgrin ligand, for examplc, from Glu,?4 of ICAM-lA. T h e amino acid sequence VGFFKR at the mcmhranc proxilnal part of the cytoplasmic tail of a , is involveri in receptnr dimerization.
Integrin Family -
- --.
I --
-
Ligands 'Counter-receptors': ICAM-1 (CD541, -2 (CD1021, -3 (CD501, which contain immunoglobulin supcrfamily (IgSF) domains (see individual entries for ICAMS)',~. Interactions occur through the I domainq. Bacterial lipopolysaccharides (LPSPa.
Function Involved in a variety of immune functions. Cell-cell interactions during lymphocyte transit through cndothclium to sites of inflammation and during recirculation through lymph nodes7."11. Co-stimulatory function in T lymphocytc activation, and effector functions during inflammation and immune responses to T cell antigens. Leucocyte intercelluar adhesion/aggregation. Adhesion of cytotoxic T cells to targets cells. Interaction with ICAM ligand is energy dependent, requires an intact actin cytoskeleton and is divalcnt cation-dependent (stimulated by magnesium, inhibited by calcium)12. Constitutively cxprcsscd but 'activation' of the receptor is required for it to bind ligand; this occurs via intracellular signalling and under the influcncc of cations.
Distribution Lymphocytes, monocyte lineage cclls and othcr lcucocytes. Transiently upregulated during T cell activation11.13. Absent from non-haemopoeitic tissues and platclcts.
Disease association OMIM 153370 Deficiency of cr, Pz leads to lifelong recurrent hacterial infections and is due t o mutations in its common pz chain (see 'lcucocyte adhesion dcficicncy', LAD-1, under entry for integrin pz; OMIM 116920). Polymorphic determinants exist on the n , chain'd. Antibodies t o P, family of integrins (to a or p chains and ICAM ligand] block lcucocytc immune functions, and arc being evaluated clinically for use in a variety of inflammatory diseases and transplant rejection.
Knockout MGI:96606 The Gene Knockout FactsBookf6, pp. 140-142. No ohvious phenotype at birth. Mice show defective T lymphocyte proliferative rcsponscs to T cell mitogens and viruses. Normal thymic development and peripheral blood T ccll suhscts indicate that a, is not required for T ccll devclopmentfs.
Amino acid sequence of human integrin or,
I domnin pnsition 170-~349.
Database accession EMI3LiCcnRank Sw~ssProt
YO0796 P2070 1
RefErencEs Larson, R.S. ct al. (19x91I. Cell Biol. 108, 703-712. Springcr, T.A. (1997)Proc. Nntl Acad. Sci. USA 94, 65-72. Hihhs, M.L. ct al. (1991)7. Exp. Mud. 174, 1227-1238. Qu, A. and Lcahy, D.I. (1995)Proc. Natl Acad. Sci. USA 92, 10277-10281. QLI,A. and Lcahy, D.1. (19961Structurc 4, 93-942. Luu, 1.0. ct 31. llOY.5) Structurc 3, 1.33.3-1.340. Springcr, T . A . (1990)Nature ,346, 425-4,3.3. Springcr, T.A. 11994) Cell 76, 301-314. Landis, R.C. ct nl. ( I 994) 1. Ccll. Riol. 126, 529-537. lo Wright, S.D. nnd long, M.T.C. (19861 J. Exp. Med. 164, 1876-1888. fl Patarroyo, M. ut al. 11990) Imnlunol. Rcv. 114, 67-108. l2 Dransficld, 1. ct al. ( 1 9921 J. Ccll Riol. 1 16, 219-226. Larson, R.S. and Springer, T.A. [I9901Immunol. Rev. 114, 181-217. lJ Pischcl, K.D. ct nl. (10X71J. Clin. Invest. 79, 1607-1687. l5 Schmits, R. ct al. 11996) J. Exp. Mcd. 183, 1415-1426. Mak, T.W. jl99KI The Genc Knockout FactsRook. Academic Press, London.
- -
-
C D l l b , Mac-1, CR3 --
-
-
Family Intcgrin (LFAICDI 1 suhfamilyl
Structure Molecular weights Amino acids Polypcptidc
1 153 127 178
SDS-PAGE reduced
1 70 kDa ( I65 kDa unrcduccdl
Carbohydrate N-linked sites 0-linked sitcs
19
Gene location
lhp11.2
Gene structure C D l l blCDl8
Alternative forms An extra codon is fnund at hp 1580 hctwccn cxons 13 and 14 in somc a,, cDNAs (thcrc are no functional effects due to insertion).
Structure lntcgrin a,, is a type I mcmhrane glycoproteinl-I forming non-covalent dimcr with the p, integrin chain, forming a,,p2. Thc a,, chain contains an N-terminal inserted 'I' domain and is not proteolytically cleaved. T w o crystal structures of thc 'I' domain have hccn ohtaincd, possibly rcprcscnting different 'activation' states-; most ligands (for example, ICAMs, iC>3h,fihrinogcn) hind via thc I domain". a,, contains seven repeat rcgions, the memhrane proximal three heing involved in divalent cation binding and rcccptor activationTR.
Ligands Complement fragment iC3h (possibly via its RGD sequencc), ICAM-1 (CD54) via its third Ig domaing, ICAM-2 (CD102) and ICAM-4, fihrinogcn, clotting factor X, CD23, hookworm 'neutrophil inhibitory factor' and heparin. p-Glucan and bacterial LPS and other microbial products, denatured proteins such as a l h ~ i m c n 1 ~The 2 ~ " .I domain plays a major role in ligand r e ~ o g n i t i o n ~ . ~ ~ ~ " .
Function Intcgrin a,, has scvcral roles in inflammation. It mcdiatcs adhesion to, and transmigration2Z2' through vascular cndothelium of monocytcs and granulocytes. It also participates in lcucocyte aggregation, and is involved in chcmotaxis, apoptosis and othcr phagocytic a c t i v i t i e ~ ~ (uptake " ~ ~ . ~of~ ~ ~
Integrin Family
cornplcmcnt-coated particles, hcncc its original description as 'complement rcccptor .?';CR.?I and suhscrlucnt cixidative respiratory hurst. It interacts with thc FcyR receptor in immune complex-stimulated ncutrnphil function. Several associated memhranc proteins involved with a,,@ in i m ~ n u n cfuncticms havc hccn idcntifictl: CD14,CD87, Fcy receptor4 CD16 nnrl CD,Z2, and UPAR~",~'.
Distribution Lcucocytcs, such as ncutrophils, monocytcs, eosinophils and hasophils, NK cell^^^^^*. Uprcgulated in mveloid cells during inflammation (via rapid mohilizaticm from intraccllular granules upon cxposure to chcmoattractants, such as fMLP, complement components and leukotricncs) and clifferentiation, but rcduccd in tissuc macrophages (scc intcgrin a, cntryl.
Disease association OMIM 120980 See entry for ~ n t e g r ~p, n for detail5 of 'leucocyte adhcs~on deficiency' svntiromc (LAD-1,OMIM 1 169201.
Knockout MGI:Y6607 The C;ene Knockout Fctct~Rook'",pp. 14,Z-144 Outwardlv normal a t birth, thc mutant micc arc not scvcrely immunocomprcimised. Thc micc have normal lcucocytc counts, hut these arc funct~onallv ahnormal and respond poorly t o somc inflammatory stimuli (rcsponsc to chcmoattrnctants and rcduccd phngocvtosis hut normal peritoneal ~ccumulationwith thinglycollatel".
Amino acid sequence of human integrin a,
I domain position 164-,349.
-.
Integrin Family
-
-
Database accession EMRLICenRank SwissProt
- -. ---
-
103925 PI 121
References Corbl, A.L. et al. (1988)J. Biol. Chem. 263, 12403-1241 1. Amaout, M.A. et al. (19881J. Cell Riol. 106, 2153-2158. Hickstein, D.D. et al. (1989)Proc. Natl Acad. Sci. USA 86, 257-261. Lee, J.O. et al. (1995a)Cell 80, 631438. Lee, J.0. et al. (199517)Structure 3, 1333-1340. Raldwin, E.T. et al. (1998)Structure 6, 923-935. Zhang, L. and Plow, E.F. (1999)Biochemistry 38, 8064-8071. Oxvig, C. et al. (1999)Proc. Natl Acad. Sci. USA 96, 2215-2220. Michlshita, M. et al. (1993)Cell 72, 857-867. Sanchez-Madrid, F. and Corhi, A.L. (1993)Semin. Cell Biol. 3, 199-210. l o Reller, D.I. et al. (1982)Exp. Med. 156, 1000-1009. Wnght, S.D. et al. (1983)Proc. Natl Acad. Sci. USA 80, 5699-5703. l 2 Zhang, L. and Plow, E.F. (1996)1. Riol. Chem. 271, 18211-18216. l 3 Lecoanet-Henchoz, S. et al. (19951Immunity 3, 119-125. l4 D~amond,M.S. et al. (1995)J. Cell Riol. 130, 1473-1482. l 5 Thomton, B.P. et al. (1996)Immunol. 156, 1235-1246. l6 Wright, S.D. and Jong, M.T.C. (19861J. Exp. Med. 164, 1876-1888. Davis, G.E. (1992)Exp. Cell Res. 200, 242-252. l R Dlamond, M.S. et al. (1991)Cell 65, 961-971. l9 Alteri, D.C. et al. (1988)Proc. Natl Acad. Sci. USA 85, 7462-7466. Wright, S.D. et al. (1988)Proc. Natl Acad. Sci. USA 85, 7734-7738. a Dlamond, M.S. et al. (1993)J. Cell Blol. 120, 1031-1043. 22 Springer, T.A. (1994)Ccll 76,301314. 21 Amaout, M.A. ct al. (1988)J. Cell Physiol. 137, 305409. 24 Gresham, H.D. et al. (1991)J. Clin. Invest. 88, 588-596. 25 Carlos, T.M. and Harlan, J.M. (19901Immunol. Rev. 114, 1-24. z6 Petty, H.R. and Todd, R.F. 111. (19961Immunol. Today 17, 209-212. 2' Anncndov, A. ct al. (1996)Eur. J. Immunol. 26, 207-212. 2R Larson, R.S. and Springer, T.A. (1990)Immunol. Rev. 114, 181-21 7. z9 Patarroyo, M. et al. (1990)Immunol. Rev. 114, 67-108. lo Mak, T.W. (1998) The Gene Knockout FactsBook. Academic Press, London. 31 Coxon, A. et al. (1996)Immunity 5, 653466.
Family Integrin (LFAICDI 1 subfamily)
Structure Molecular weights Amino acids Polypeptide
1163 127 885
SDS-PAGE reduced
150 kDa ( 145 kDa unrcduced)
Carbohydrate N-linked sites 0-linked sitcs
8
Gene location
16~11.2
Gene structure
25 kh. ?, 1 exons
Alternative forms
CDllelCD1B
Structure lntegrin a, is a type I rnemhrane glycoproteinl forming a non-covalent dimer with the pl intcgrin chain, a&. The a, chain contains an Ntcrminal insertcd I domain and is not proteolytically cleaved. It contains seven N-terminal repeat regions, the membranc proximal three being involved in divalent cation binding.
a, has similar ligands to a, hut they are less well characterized: complement fragment iC3b, fihrinogcn, ICAM-1 (CD.541, CD23 and bacterial LPS"'.
Function It has a similar function to a,,PI (CDl lh], including cytotoxic T cell killing, and monocytc and granulocyte adhesion to cndothclium"? Maior pz receptor of tissuc macrophages.
Distribution Tissue macrophages and monocytcs (high levels, inverse distribution to a,P, during monocyte-macrophage r n a t ~ r a t i o n ) ~and " less on other leucoc~tes~~~~.
--
-
Integrin Family -
-- -
Disease association OMIM 151510 See cntry for intcgrin 9, for dctnils of 'Icucocytc adhcsion deficiency' syndromc (LAD-1, CIMIM 1169201.
0 Knockout Amino acid sequence of human integrin a,
I domain position 165-35 1.
Database accession EMllL/GcnRank SwissProt
M8 1 1695 P20702
References Corhi, A.L. ct al. (1987)EMBO J. 6, 4023-4028. Myoncs, R.L. ct al. (1988)J. Clin. Invest. 82, 640451. ? tlc Fougcrollcs, A.R. ct al. (19951Eur. J. Immunol. 24, 1008-1012. J.D. et al. (1991)Proc. Natl Acad. Sci. USA 88, 1044-1048. "ooike, Postigo, A.A. ct al. (1991)J. Exp. Mcd. 174, 1313-1322. Wright, S.D. and Tong, M.T.C. 11986)J. Exp. Med. 164, 1876-1 888. ' Ingn!ls, R.R. and Golcnbock, D.T. (1995)J. Exp. Mcd. 181, 1473-1479. V e i z e r , G.D. et al. (I9871 J. Immunol. 138, 313017136. Stackcr, S.A. and Springcr, T.A. (1991)J. Immunol. 146, 648-655. Larson, R.S. and Springer, T.A. (19901Immunol. Rcv. 114, 181-21 7. fl Patarroyo, M. ct al. (1990)Immunol. Rev. 114, 67-108.
Family Intcgrin (LFAICDI 1 suhfnmilyl
Structure Molecular weights A m ~ n on c ~ d s Polypcptitic
1162 126liXh
SDS-PAGE r c d ~ ~ c c t l150 kDa
Carbohydrate N-l~nkcdsites 0 - l ~ n k c dsitcs Othrr
10
Gene location
lhpl1.2 (CDI 1 family gene clustcr on chromosome 1hll
Gene structure Alternative forms Structure Intcgrin a,,fnrms a typical intcgrin hctcrndi~ncrwith intcgrin (CDlXI tn form C X , , ~ , . It contains nn N-tcrminal I domain as with other 6, ( C D l 11 suhfa~nily1ncmhursJ.2.
Ligands It hinds ICAM-3' (CDSII), hut nrjt ICAM-1 (CDSSI. cr,, Interacts w ~ t h VCAM-1 (CDIOhlTon uc~s~nophlls.
Function Currcntly undcfincd though likcly to hc s ~ r n ~ l atnr other p? intcgrlns, including a rolc in phagocytosis hv macmphages.
Distribution Moderate levels nn peripheral leucncvtcs~,and higher expression on tissuc ~iiacrophagessiich as in spleen'.
Disease association OMlM 602453
-
-
-
Integrin Family -
I
-
-
-
--
Knockout
I Amino acid sequence of human a, mPG-LLS :-' , .... > ..:,, ;.-;
i--, . '
7 '
VLASYHG:'::: -~,:..,.,l: -i,,"
i~::;? 7.b.T
yf:,?l-:>:,:
.(
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..#..'.'!... ;:!.,:)I.;
1
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8-'
1 .!.I..-.",;..
:,,'8-;t.#.
PjiJ
. . . ......... . . . f::;:,,.,;.,:-::l ; -I>: ~.....~..~.rj?[. : ? ~ . r . ~ ~ ~ ~ ~ ! . ~ ~ ~ p : ; .;,:,..,. . .,.......... , . ,. ,-; ;I,)::.::, :,,'::>I 1, ~:>-, :.< . ........ ,.~-lrtlil.,!y <.F..';);..';.:Gp[:
-.
.
,.:.
7,f
. .... . . . ;,.(. :..,,.... . . ......i.!. . . ,:,,:.,-.,. ,,,., r .::: TPYI?:'?T,~?,- 0'?,*:"3r :'."_ :.:'I:!,TTT:..T: T:,T""'T'-. .I lI>!::: . .:... . . ;..:.L.:,:. Fl,.,p7 I.T7?~~ . . . . . . - : . . ...... r,t:,,..-... ; .:,..-7 - . . , - z , r..7.....-..- . -[l;,:!..;F(:.:,q ---7 -. J,.,T' . ...".......... ... ' ........... . . . . .. ,<,.,,;E,,,.r,::-,x . . s - :,......cr,-?-:-,., ..-. ... ;.. . , ; .......... t ; > '.::r?L':,: F';.. . . . ,. ;,... . . . :.,;:.->,<[,: . , . . ,..,-I. ;..... .~ : . , - r , x , ; , .. r,.;. T,;:,,yr:r[,J.:r. f....... . .. . , -...,.'.... ' r . -. . -. . >.- .: - . :.. ..,.;:-,7. . . '-:#?.' . . '. i,'.':[; . . 'l,',.:,:,l; . ,;Q!,[,-L,,c:>.: .;.; .(: .. ;. (~. .: . ..... ,,,'.. . . - .. .. .. .. .. .. .. . . . . .....,,.. ............ . .. -. ... .>. .. . '-...!,!:...c >.',.:",:-,-::Qy ,,, . ;... . ..... . . - .c.... . c , < : s,::,[,f;lL(~::\:[, !-.-"-'.'-. . .- .L. .- .'"*r. - l:L,::::,... -. . 1 7.7,. r-,. ..:.,I, ..:,",'o: - -r>:::!. .:r.'-:..:'.' ..77 !,I,.:,"L..7,r? . . . . . . . . . . :;..,-.. . . . . . . cl:'7:>'-F.-f:3:(; -. ..,...., . . . -: . ,-:. ,,,. . ... .7,F.. ......... ........ ,~.r ......... .;I ;.,::,,-l::>K.. ' - , ; , ~ , , ~ ; ' ~ , r ' : l ~ , ~ . .. .'.l,, . . ",,'"(.. . ........," . .-", . . :.. .,: . c;,; ....!, ;,I .,,rl>':";, .., '..'..,. , .. , , .,. - LI ...:,: .:;:: r,. ..... . . . . .-. F :,",".'i':, . : , ; ' I "K.". .:.F...? 7 .i,: r,.rrr:.c~c;.;. -,- ..,. s... -....... , cr, . .~ .......-..-...>.. , ..,. . ' . . . . . .. . .. . . .., -. .-. -. ,-r,.rvr.',' v7,.~.r >.,. . ....,. ....... ,-,,?:n 7 r. . , .., . . . ..n... . . .......... . . . . ..^ . .-,. . ,!-..;. -,- ; - ~ , r t,",-rc;'~ . . . . . . '.- z .q r '.* . .- ,:>r.: ., . .,.7,.,,,rr,,-.7,.. . . . v .. ,,, , . . . . . ,. * -. >-q--;-,-):,P . . . .......... . . . : . . . _ . r,-r,-..,;,r.-.,7,! ...... >.. ......',. r:>l'. , , u ; r,l',.."' ;,.,n,.: .....: . :,:; : ,:.,l_l.- < ...L - ,.. .. ,............... ...... . . . . . . ..,. ,....:,:, . , , ............. . i i .
. . 7
L,
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.I.
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nr.,r
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.,
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;
,
,L,
-
:
I domain position 164349.
Database accession EMRL/GenRank SwissProt
U,Z7028 Q 1,3349
References
4
Tf--
-7..-
p . 7- d - .
_
- 7 .
2
1
1
Wong, D.A. ct 81. (1996)Gcnc 171, 291-294. Van Dcr Vieren, M. et a]. (19951Immunity 3, 683-690. Grayson, M.H. ct al. (199811. Exp. McJ. 188, 2187-2191. Danilenko, D.M. et al. (1995)J. Immunol. 155, 35-44.
-TI-
-
Family Intcgrin
Structure Molecular weights A m ~ n oacids Polvpcpt~rlc
llil 117 837
CDC-PAGE reduced
110 kDa 1200 kDa unrcrluccdl
Carbohydrate ?\r-l~nkcti ~tcq 0-linked s ~ t c c
26
Gene location
C h r o ~ n o w m c5
Gene structure Alternative forms Structure
CM9&D29
Thc type I membrane glvcoprotcin intcgrin a, chain nssociatcs with p, to form the non-covalently linked n , P , hctcrodimcrl. The a , chain falls into the suhclass of intcgrin rr chains with an N-terminal inserted 206 amino i~cidscqucncc, the 1 domain, and i s nnt pnst-translatinnally protcnlytically cleaved. It is heavily N-glycosyIated comparctl with other intcgrin cu chains.
Ligands Laminin [ E l ir~~grncntl and crlllagcn2.'.
Function Cell lines for example, mclano~nalhave hccn shown to hind laminin and collagen via rr,p,"', hut adhcsion of stimulated T cclls to collagen iiocs not utilize n,P,J A rolc in c~nhryonic nervous system dcvclopmcnt and placentation is suggested hv its carly expression, hut this is not supported hy mouse knt~ckoutdata - scc hcl(~w.The finding of n , P , on T cclls in certain immune diseases indicates a functional rolc in inflammationi.
Distribution Widespread distribution, including in cmhqogencsis (placenta, nervous systcml. Kcy collagen receptor in smooth muscle and liver+'. Expresser1 by some hacmopoictic cclls including mrmocvtcs and Ivmphocytesx. Resting T lvmphocytcs express low lcvcls of cr,P,, nnrl this is increased suhstantinlly ~ ~in, ~soinc inflammatory conditions, upon prolonged stimulation ~ I rI ~ i t nand such as in rhcutnatoi~larthritis snri inflammatory howcl disease. This feature led to its initial namc, 'vcry late T cell nntigcn' (or VLAI.
--
Integrin Family
Disease association OMIM 1929hR
Knockout MGI:96599 T11cGEIIC K n o c k o ~ ~F t( z ~ ~ f s R op.~619. k~, Live, fertile c~ffspringhave no ohv~ousphenotype. Fibroblasts from a, -1mice show dcfcctlvc acihcsion and rnigratlon nn collagcn type IV and laminin, though adhcs~onto collagcn type I 1s normalrn.
Amino acid sequence of human integrin a,
I domain position 147-,360.
Database accession EMI%L/GcnRank SwissProt
X6H742 PSh199
References I3ricscwitz, R. ct al. (199,31J. Rid. Chcm. 26X, 2989-2996. Hall, D.E. ct al. ( 19901 J. Ccll Rml. 1 10, 2 175-2 184. Kramer, R.H. and Marks, N. 119891J. Rid. Chem. 264,4684-4688. Goldman, R. ct al. [1992l Eur. J. Immunol. 22, 1109-1 114. MacDonald, T.T. et a]. (1990)J. Clin. Pathol. 43,313-.315. Ignatius, M. and Rcichardt, L,F. (19881 Neuron 1, 713-725. ' Rclkin, V.M. et 81. (1990)J. Cull Riol. 1 1 1, 2159-2170. Hcmlcr, M.E. (19901 Annu. Rev. Immunol. 1 14,365-400. Hcmlcr, M.E. ct al. (1984)J. Immunol. 132, 301 1-3018. lo Gardner, H. ct al. (1996)Dcv. Riol. 175, 301-312. l1 Mak, T.W. (1998) Thc Gcnc Knockout FnctsRook. Academic Press, London. 2
Family Integrin
Structure Molecular weights Ammo acids Polypeptide
1181 136<37X
SDS-PAGE reduced
16.5 kDa ( 160 kDa unrcducedl
-e
Carbohydrate N-l~nkcds ~ t c s 0-linked sites
10
Gene location
5~12.3-~3 1
*---a
*C,
Gene structure CD49blCD29
Alternative forms Structure lntcgrin cu? is a type I memhranc glyoprotein intcgrin a chain forming a . a? chain falls into the suhclass of hctcrodimcr with P Ito form a 2 P I 1The intcgrin tu chains with an N-tcrminal inserted or I domain (hctwccn the second and third of the seven cr chain repeat domains), and is not posttr;lnslntion;~lly protcolytically clcavcd. Thcrc arc thrcc cation-binding domains in the a? chain. The 1 domnin from cr2 has heen crystallized and its structure solvcd2.
Ligands Collagen types I-IV and laminin.'. Echovirus-1 receptorJ.
Function Magncsium-dependent platelet adhesion to collagens is mediated hy alpI; this hns been suggested to occur via the amino acid sequence DGEA in collagen" and involve the integrin I domain'. Other cells also use n,P, to interact with c o l l a ~ c n ~ -The ' ~ . interaction hctwcen cu!p, and laminin is only found in certain tissues; thus, cell lines, hut not platelets utilize n, to hind Iaminin. Fihrohlnsts may utilize n?p,in tissue collngen remodelling during wound repair",". The level of cu@, is mndificd in neoplastic tissues and may hc involved in tumour progrcssionl?-14.
Integrin Family --
Distribution Originally identified as one of the 'very late antigens' (VLA)of stimulated T cells", a#, was subsequently identified in scvcral other tissues-fibroblasts, endothelium, peripheral nerves-and several blood cell types including platclets"J5Jb.
Disease association OMIM 19274 Inherited deficiency of platclct a l p , has hccn dcscrihcd in japanese populations and leads to a mild bleeding diathesisl'. A point mutation at amino acid position 534 (Lys to Glu transformation) leads to the platelet antigen Zav/Hc/Rr(a), and is involved in neonatal and transfusion alloimmunc thromhocytopcnialR.
Knockout MGI 96600
Amino acid sequence of human integrin cx, 1 MGPERTGMP LPLLLVLALS WILNCCLA':'
:!'.'C:,Ft-i*.YIF SGliSSFOFCP' G::?i-;'<,7 ' ' . : . A . T ~ ~ ~ ]]?".i.r:;:,:'?:..?! ~S~ '{T~~J:','],'T'T',' . l Q l AI!PG?Q:CC':' FGS'..L.CS'.'D'. DI.'DTT?Il'.'I,> '.'r3,2?:~Tt'!~!SI?L P'.?E?C?',"f~F 5 ~ : 1 O F I , ? C ? > f I r C !:'"pF~:.T?.,T:\,?., :,.SnT!!bllDf:~l! D"T'.'C.S?',FP! @~I.CC:.,'.''?':':'I! 6 CI 1 .5OVTl.C?T)I~?., F?SLlr.@'!'FC? ?l,D~~:'~'GDl,!lGD.?T??'.'.STC.l: F(:O'.",'C)18!." :!?!C.'.'II'."i'::I TLL7r)C:FS.c? 6 6 1 ?? ?E?:ITL.'I.I I:!l.?.OI I LI'LC ?S'..?F??T?O 7 11 !:FPC;,O?I!'.:I.' '.rl!p:*,Q-CC171?i! I I'I-I UFI'SD'.. -.'IIS:~=IL?'I-CI SLE!:FCllSI3?~ 1 FSIPFH"D83G F3r:I,C:CD!8',' :,T)".'PO: PA.:tO FO?~I'.'SPI@II F'?[,?"S'~,"?:.81: R-:l T'.Y'13F.S"tI:.C F?t.SF.S:,P'!EC TE'.'TCD'.'?r.?
61 [:.::,:',''>S!!;:,: 12 1 r-!:h!CTGGI;',T
I domain position 188378.
Database accession EMRL/GenRank SwissProt
XI 7033 PI7301
References "
5
Takada, Y. and Hemler, M.E. (1989)1. Cell Riol. 109, 397-407. Emsley, J. et al. (19971J. Riol. Chem. 272, 285 12-295 17. Hemler, M.E. (1990)Annu. Rev. Immunol. 114,365-400. Rergelson, J.M. et al. (1992)Science 255, 1718-1 720. Staatz, W.D. et al. (19891J. Cell Riol. 108, 1917-1924.
At'OOFIt!PKG TI!?.!SLGLILT SL:F.".-,:.'CD TPEEI,:Y',':iTS !.!I,:;;~:DO~:I L8EL::';G'?;GF0
t.:T.CPGFr',:CP !JE!:G!::T',r:O TIL:?GTLCoH C:{OCT:PT;:'1. ?T-'t?'.'i.,T EAS IrT.5?GLFI'E:1 LE,:I-~'SET,~I?'.' YIYPESA'Y'?:TG FTTIIFDF?:TI.O TSST)GIT'?s? TI?~AC;DISC:I '
--
--
Integrin Family
"taatz, W.D. ct al. (1991)J. Rlol. Chem. 266, 7363-7,367. Kamata, T. ct al. (19941J. Rlol. Chcm. 269, 9659-9663. Goldman, R. ct al. (1992)Eur. 1. Immunol. 22, 1109-1 1 14. Ehces, M.1. and Hcmler, M.E (19891 Proc. Natl Acad. SCI. USA 86, 9906-99 10. "'Wavncr, E.A. and Carter, W.G. (1987)J. Cell Rlol. 105, 1873-1884. Schlro, J.A. et al. ( 19911 Cell 67, 40.3-410. l2 Kleln, C.E. ct al. (19911J. Cell R~ol.115 1477-1436. Chen,F.A. etal. 119911J.Exp. Med. 173, 1111-1119. l4 Chan, R.M.C. ct al. (19911 Sc~encc 25 1, 1600-1602. l 5 Hcmler, M.E. ct al. (19841J. Immunol. 1\32,301 1-<3018. 1" Pcrcz-V~llar, J.]. et al. (19961Eur. ]. Immunol. 26, 2023-2029. I' Nlcuwcnhu~s,H.K. ct al. (19851Nature 318, 470-472. lR Santoso, S. ct al. (199,3)J. Clln. Invest. 92, 2427-24\32.
-
1
CD49c, VLA3, galactoprotein P3 -
Family
Structure Molecular weights Amino acids Polypcptidc
105 1
SDS-PAGE reduced
130, 25 kDa (150 kDa unrcduced)
116612
Carbohydrate N-linked sitcs 0-linked sites
14
Gene location
17q
Gene structure
26 exnns
Alternative forms An a, form with a variant cvtaplasmic tail has heen detected in brain and heart, and arises by alternate splicing.
Structure chain associates with P, to Thc typc I memhranc glycoprotein integrin form the non-covalently linkcd a,P, heterodimerl-I. The n, chain falls into thc subclass of intcgrin a chains without an inserted I domain and is posttranslationally proteolytically cleaved into a heavy and a light chain, which are disulphide hondcd. The a, chain contains seven homologous repeat domains, the three most membrane proximal having divalcnt cation hinding sequences.
Ligands will hind fihronectin in an RGD-dcpendcnt manner but only if thc a$, fihrnnectin receptor is not expressedJ. A second site is involved in interaction with collagen and laminin 5 [E3 fragment]*s and binding is not sensitive to inhibition hy RGD peptides. a$, in epithelium also hinds the epithelial basement membrane protein, epiligrin6.'. The bacterial coat protein, invasin, is an additional ligandH. Fibroncctin binding is inhibited hy calcium, but not collagen and larninin adhesion.
a$, has complex ligand binding s p e c i f i ~ i t y ~ Thus, .~. a$,
Integrin Family
Function Epithelial-hascmcnt mcmhranc interaction and structural intcgrity in, for example, the epidermal-dermal iunctir~n.Expression in trnnsfornicd cells (as 'galactoprotcin p(3') suggcsts a pnssihlc rnlc in nncogcncsis. It is onc of thu intcgrin dimcrs cxpressctl on T lymphocytes after prolonged stimulation ('very late antigcn', VLAI. cr,P, is also found at situs of cell-cell contact and thus may also hc involvcd in interccllular as \veil as cell-matrix adhesionY.
Distribution Low levels on monocvtcs, R and T cclls, kidney, thyroidl%nd nlost nonlvlnphoid adllcrent cell lincsll. Exprcssinn levels in lymp11oc)ltcs arc increased upnn culture in vitrt~.
0 Disease association Knockout MGI:Y6602
Tlic Grnr Knockout FrlctsNoc~k~~, p. 620. Mutant mice die ; ~ llirth t with abnormalities in kidney and lung, ; ~ n dskin blistering duc to dcfcctivc cell-basement i n t c r a ~ t i o n l ' . ~ ~ .
Amino acid sequence of human integrin a , --
MGPGPSRAPR APRLMLCALA LMVAAGGCW SA,,
1
. .
..
. ..
I
. .
..
.
. .,
.. . .
8
/
.
. . . ,..
..
.
..
. . .
.*.,
-
I
-
Proteolytic clcavngc site at posit~nn871.
Database accession EMI%L/Ccnllank M.59911 SwissProt PI6006
. .
I
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.
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Integrin Family
. -
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-
--
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.
-
-
--
.
--
References Takada, Y. et al. (1991)1. Ccll Biol. 115, 257-266. T S U ~T. I , et al. (1991)J. Riochcm. 109, 659-665. Takada, Y. et al. (1987)Proc. Natl Acad. Sci. USA 84,32393243. Elices, M.J. et al. (1991)J. Cell Riol. 112, 169-181. Gehlscn, K.R. ct al. (1989)J. Riol. Chem. 264, 19034-190<38. "arter, W.G. et al. (1991)Cell 65, 599-610. ' Wcitzman, J.R. ct al. (1993)J. Biol. Chcm. 268, 8651-8657. Isberg, R.R. and Leong, J.M. (1990)Cell 60, 861-871. Kaufmann, R. ct al. (1989) J. Ccll Riol. 109, 1807-1815. i R Hemler, M.E. (1990)Annu. Rev. Immunol. 114, 365-400. * I Rettig, W.J. and Old, L.J. (19921Annu. Rev. Immunol. 7, 481-51 1. l2 Kreidherg, J.A. ct al. (19961Development 122, 3537-3547. DiPcrsio, C.M. ct al. (1997)1. Cell Riol. 137, 729-742. ld Mak, T.W. (1998) The Gene Knockout FactsRook. Academic Press, London. 2
Family Intcgrin
Structure Molecular weights Amino acids Polypeptide
1038 1 1 1 22X
SDS-PAGE reduced
150 kDa [ 1XO, 150 kDa unrcducedl
Carbohydrate
-
I
p
-4
N-linked sites 0-linked sites
11
Gene location
2q3 1-q32
*- _. *- * a.
Gene structure Alternative Eorms
CDlQdtCD29
An additional 180 kDa form is also found (n, 11801 in non-reducing SDSPAGE and may he the main functional form of a,'.'.
Structure Intcgrin a, is a type I membrane g l ~ c o p r o t c i n Jthat ~ ~ forms non-covalently linked dimers with two intepin P chains, P, and P-, to form a,P, and a&. The a, chain does not hclong to the two main groups of intcgrin a chains.'. It neither contains an I domain nor is it proteolytically cleaved in a standard a chain manncr; instead thcrc is variahlc cleavage in some cell types of the 145 kDa protein into two, similarly sized, non-disulphide linked fragments of 80 and 70 kDa (at Arg5971J.5.n.Thc largcr 180 kDa form is functionally acti~e'.~. The extracell~~lar portion of a, contains three EF-hand loop-like domains that hind divalent cations and are involved in modifying adhesion.
Ligands
U I
VCAM-I (CDlOhl in activated cndothcliump and altcmatclv spliced forms of fihroncctin in matrix [via ElLDV sequence in the CS-1 region of fihron~ctin)J"'~ bind to both integrin a, dimcrs, a,P, and n,P-. MAdCAM-1 is an additional counter-receptor for a,p-i2~f4tsand thrombospondin for a&. a, is a further integrin cellular receptor for the bacterial coat protein, invasin.
Function a , integrins are key molecules maintaining the structural integrity of the placenta and heart during cmhryogcncsis (see helow). In the adult a, integrins arc involved in lymphocyte homing to Peyer's patch high venular
cndothclium via intcmction hctwccn ru$- anti MAdCAM-1 (see cntry for P-lJ1h).Initial adhcsion and rolling, nnd suhscqucnt tight adhcsion of T cclls on vascular cndothcliuln after cndnthclial activation is mediated hy n , intcgrinsl: and is indcpcndcnt of scloctins (CD6?I (scc cntryl. Mcdiatcs homotypic cull-ccll awrcgstion of a,-positivc lymphocytes. Fihrnncctin h T binding hy a l p , intlliccs T ccll activation and proliferation t h r o ~ ~ gthe ccll rcccptc~r-CD,3complcx via focal atlhcsion kinasc nnd the MAP kinasc signalling cascade. Mcdiatcs atfhesion of hacmopoeitic stem cclls to marrow stroma and hcncc hlood ccll Jiffcrcntiatinn.
Distribution Most Icucoytcs including T ly~nphocytcs [hut not platelets and ncutrophils), h;lctnopocitic p r c c u r s o r ~ ' ? . ~ ~rnucclc J~, ;lnJ sonic othcr nonhacniopocitic tissues'".
Disease association OMIM I92975
Knockout MG1:966OL3 T11cC;(,nc*k'l~ockoufFr~ctsNook~~, p. 621. Embryonic lethal mutation with failure of placentation in half of the cmhryos due to failurc of fusion of the VCAM-I +vc allantois with the intcgrin cu,+vc chorion. Surviving cmhryos tlic d i ~ ct o disruption of the intcgrin tt,+vc cpic;irdiiun ant1 unclcrlying coronary vcsscls-Y'~". Experiments with rr, -1- cclls have contirn~ctithe rcquircmcnt for this intcgrin in lv~nphoidhrmiing to Pcycr's patches".
Amino acid sequence of human integrin a, MFPTESAWLG KRGANPGPEA AVRETVMLLL CLGVPTGRP
.
1
-.,
-
,
,
.-
-.
-8
.
,
L
.
,
'
. ' - - % \
I I
I
.
. . .
.
. I
I.)
1
7 ' .
.
'
-
> . ...
-
..
'
-- -
- .
.
....
1
. . .. ...:-
1
...
.
I 1
I
. I
Protcolytic clcavagc site at position 597.
-
.\.
Integrin Family
Database accession EMRL/C,cnRnnk Sw~qsProt
X 16083 Pl.3612
References Sznho, M. and McIntyrc, I3 W. (1995)MoI. Immunc~l.62, 1453-1454 Ruhlo, M. ut a1 (19971 Eur 1. Immunol. 22, 1090-1 102. Tdkada, Y. ct al. I19X9) EMRO 1. X, 1,361-1.368. . I Tskada, Y. ct al. (19X7)Proc. Natl Acacl. Sci. USA 84, .32.39-*324;1. Hcmlcr, M E. ct al. (19H7)J. Riol. Chcm. 262, 1 1478-1 1485. A T t l x ~ d o J. , et al. (1992)J. Biol. Chcm. 267, 1786-1 791. Parkcr, C.M. ct al. { 19901 J. Riol. Chcm. 268, 7028-70.35. Putadcs, C. ct al. (1996)Riachem. J. 313,899-908. EIICCS,M.J. ct 81. (1990)Ccll 60, 577-5R4. Wayncr, E.A. ct al. I I9XYl J.Ccll Riol, 109, 1,321-lL326. M(mld, A.P. and Hu~nphrics,M J. (1991)EMRO J. 10, 4089-409s. Lol-rh, R.R. and Hcmlcr, M.E. (19941J. Clin. Invest. 94, 1722-1728 K~lgcr,G. ct nl. (199il J. R~ol.Chcm. 270, 5979-59X4. l J Rott, L.S. c t 81. (14961J. Immunol. 156, 3727--37.31,. IF Erlc, D.1. ct al. (199417. Imlnunol. 15.3, 51 7-528. 1" Rcrlin, C. ct al. (199.31 Ccll 74, 185-195. 'I Springer, T . A . (1994)CelI 76,.iOl-*3 14. IRRoscn, G D ct a]. (1'1921Ccll 69, 1 107-1 T 19. Iy Mak, T . W . (19981 Thc Gcnc Knockout FactsRr>ok. Acndcm~c Prcss, Lr~ndnn. 2n Ynnq, 1.T. ct 31. (1Y9il Dcvclopmcnt 121, 549-560. 2 i Arroyo, A.G. ct al. I 19961 Cell 85, 997-8,75. Yanq, 1.T. ct al. (19961 J. Ccll RloI. 135, X29-K.35.
"
CD49e, VLA5, fibronectin receptor --
Family Integrin
Structure Molecular weights Amino acids Polypeptide
1049 114508
SDS-PAGE reduced
135,25 kDa (155 kDa unreducedl
Carbohydrate N-linked sites 0-linked sites
14
Gene location
12q11-q13
Gene structure Alternative forms
9v
PPW PPPPSP PPPP dbbb bbbbbd bbbi m4wc029
Structure The type I memhrane glycoprotein intcgrin a; chain*+' associates with p, to form the non-covalently linked a i p I heterodimer. The ai chain falls into the subclass of intcgrin n chains without an inserted I domain, and is posttranslationally proteolytically cleaved into heavy and light chains that are disulphide bonded. Rotary shadowing electron microscopy of purified a,@, has provided a stnlctural model for all integrin dimers in the absence of crystallography or NMR data" The a;chain contains five potential divalent cation binding sites.
Ligands Major receptor for fihronectin, via RGD sequence and alternative ancillary domainsb.'. a$, also interacts with the neural adhesion molecule, LIR and the bacterial coat protein, invasin9.
Function Mediates fibronectin assembly into the extracellular matrix, and fihronectin-dependent cell adhesion, spreading, migration and signal transduction'. It acts as a co-stimulatory molecule t o the T cell receptor-CD3 complex in T cell activation and enhances phagocytosis of opsonized particles by monocytesy". a+, is also involved in rnonocyte migration" and alp,-mediated adhesion t o collagen is enhanced by aip,'2. There is extensive evidence for pl intcgrin dimers being involved in signal transduction and several general reviews are provided in the 'Integrins' section in Chapter 2 (p. 16).
Integrin Family
Distribution Widcsprca~l in cmhryonic ;ind ; ~ d u l ttissuesu. Exprcsscd hy hlood cclls, inclutlinfi rnonocytcs, platelets and lymphocytes, cspccially in R and T cclls ;~ftcr; ~ c t i v a t i o n ~ ~ - ~ ~ .
Disease association OMlM 1.35620
Knockout MGI:96604 TlicbC;r3nrbKnoc.lir)ri~Ftrc.t.sRookl', p. 611. Emhryos die at day 10-1 1 of xcstation with vascular dcfccts in thc embryonic ;~nci cxtril-cmhryonic circulation; thc posterior t n d of thc cinhryo fails t o develop properly. Intcgrin ru; n ~ i l l fihrohlasts function rctnrlrkahly nclrnially In rfitm, adhering and spreading o n fihrrmcctin, and asscmhling fihroncctin-rich cxtr:iccllular matrix, ctc. Thus, thc phenotype is miltlcr than sccn with fihrcmcctin null micc, implying intcgrin rcccptor rc~lunciancyfor intcr;lction with fihroncctin1"lv.
Amino acid sequence of human intcgrin n; MGSRTPESPL HAVQLRWGPR RRPPLVPLLL LLVPPPPRVG G. -
.
. .. -..
.
--
. -. - . .- .-. ?
.
-
.. . . . . .
-
Protcolytic c l c n v : ~ ~sitc c at position X93.
Database accession EMRLjGcnlk~nk SwissPrc~t
XOhl56 POS61X
References Argravcs, W.S. ct :iI. 119871 J. Ccll Rial, 10.5, 11Xd-1 190. Fitzgcrald, L.A. ct 31. {lr)X7IRiochem. 26, X I 58-X 165. Argnrvcs, 1Y.S. ct :I]. 119861 J. Riol. Chcm. 261, 12922-12924.
?
Takada, Y. ct al. (1987) Proc. Natl Acad. Sci. USA 84, 32393243. Ncrmut, M.N. ct al. (1988) EMRO 1. 7,40934099. Hemler, M.E. (19901Annu. Rev. Immunol. 114,365-400. Hyncs, R.O. (1992)Ccll 69, 11-25. Ruppert, M. et al. (199.5)J. Cell Riol. 131, 1881-1891. Ishcrg, R.R. and Lcong, 1.M. (1990)Cell 60, 861-871. lo Wright, S.D. et al. (1984)1. Cell Riol. 99, 336-3.39. l1 Wcbcr, C. ct al. (19961 J. Ccll Riol. 134, 1063-1073. l2 Pacifici, R. et al. (19941J. Immunol. 153, 2222-2233. Sanchez-Madr~d,F. and Corhi, A.L. (19931 Scmin. Cell Riol. 3, 199-110. l4 Hcmlcr, M.E. (1990)Annu. Rcv. Immunol. 8,365-400. l5 Shlmizu, Y. et al. 11990)Nature 345, 250-253. '"Raard, L.L. e t al. (1991)Clin. Exp. Immunol. 84, 336-346. I' Mak, T.W. (1998) The Gene Knockout FactsBook. Academic Press, London. I V a n g , J.T.et al. (19931Development 119, 1093-1 105. l9 Yang, J.T.ct al. (19961Mol. Riol. Cell 7, 1737-1 748. J
Family Intqrin
Structure Molecular weights A I I ~ I I ~ 6O
~
~
~
I'olvpcpt~clc
I 07.1 I I 7 26.3 [ A b~jr~iil, I 1 ~ shC) ) 113 berm\ ~
~
\
/r
e4
';I)\-I'AC;E
rcrli~ccd
*-
120, .30 k l ) ~1 I40 kD,l ~~nrcducc~ll
Carbahvdmte \ ' - l ~ n k c d\ltc\ 0 - l ~ n k c i \ire\ l
s
Gene location
<:hromo\ornc 2
Gene structure
CD4911CD29
Alternative forms T w o ; ~ l t c r ~ i ; ~ t ~ vspl~ccrl clv RNA torms with dittcriny cytplopl;ls~iictails ( t ~ , , * \ ;111cl
Structure Intc,qrin (I,.'-.' csicth ;IS ; ~ l t ~ r ~ i( ;l i~mt c~ r s(~,.[3, , [VLAOI ;ln11 rr,,(3, \see entry tor (3,/C:L310-11. T h e C - t c r m ~ n u sis phosl~Iioryl;~tctl. t r , is most holiiologo,qoi~.;t o t h e intcyrin C Y , cli;lin. I t is c l c ; ~ v c ~po\t-tr;lnsl;~tir~~i;llk l to proc1~1ce ;I c l i ~ i ~ l ~ ~ l i i c l ~ - I ~ ot r~ ci cl lii;~~c ~l n , rloc.; not cont;lln ;In ~nscrtcclI clom;~in.T h e t t , , cli;lin c o n t ; ~ i n s seven I i r r n o l o g o ~ ~repcat s ~lom;~in.;,the three most n~cml.rr;uicproxim;~lli;~ving~ l i v ; ~ l c ncation t hinrlinx scqucncc.;; n t o ~ ~ r site th is Ioc;ltc~lhct\vccn rcpc;lt ~ l o r r l ; ~ ~I I nI s;~nclIV.
tu,,
intcgrin climcrs, tu,.l3, ; ~ n dtr,.13,, ;Ire receptors for 1;lminini ".
Function cu,,P, t1icrli;itc~p l ~ t c l c tintcrsction
with .sul1cnrlothcli;11 h;lscmcnt mcrnhr;lnc 1;lminin c s p o s c ~ lo n hlood vrsscl rla~nagc.I'latclct hintlinr: of laminin via tu,.('l. I-c~1uirr.i m;~gncsiurlihilt 11c1tc;llciuni c;~tions.O n T Ivmphocytcs tu,,P, I S ;I co-ctimul:~tory~ n o l c c u l cfor T cell act1v:ition. t ~ , , piortns , spcci;~lixxl ;~rlhc.;ivc intcr;~vtions in t h t hctniJcstnororncs c ~ tstr;~tificrl cpithcli;l, Scli\t.;~nn cull.;, ctc., whurv ~t is csscnti;~l tor t h e structurnl intcxrity of cell-matrix intcr;lctions lscc I~cIoM~I.
Integrin Family .
Distribution is expressed widely in epitheliaJ0,and in haemopoeitic tissues is found on monocytes, platelets and 1 y r n p h o c y t e ~ ~ ~Activation lJ. increases expression levels in T c ~ l l s 2 ~The ~ 6 . A form is found in lung, liver, spleen and cervix, whereas the R form is expressed in hrain, kidney and ovary. In other tissues, both forms are co-expressed. a,P, is found in stratified epithelia, Schwann cells and some endothelia.
a,P,
Disease association OMIM 147556 Mutations in integrin a,give rise to junctional epidermolysis bullosa with pylnric atresiaI2.
Knockout MGI:96605 The Gene Knockout FactsRookl", p. 623. Embryos die neontally due to detachment of epithelia (epidermis and simple epithelium of mouth and oesophagus1 from the basement membrane. Exhihits a similar phenotype to integrin P, knockout mice and to the human blistering skin disease epidermiolysis hullosa with pyloric atresia (as with mutations in internin p,1'"J6.
Amino acid sequence of human integrin a, 1 HlUAGQLCLL YLSAGLLSRL GAA??!I,D??E 6 1 ~.:,i:.'~;:,.r.?r:? .:,I,F:,~;IF:..I~~': ~.:L.;S~CDTT.:, 12; sr)c?i:c;r7.-:: c?..~!P;'FGQo!~ '.T::I:OF~SPTI 1Q 1 GF!Ei.'.FGSCCIQ G'.~;i.:~.TT?:l:- H'I17,!F8J.?~PGT :a'.! GETSf!3ZSL,'.. ?'~.'?AIJS?L~.~F -SLDSGF'C!','S 30: LLFRKI?DC:T GT,A.?SFGI'D'.' :~.',-.'nI.?lYIl~':: 361 I.,'!l?F!?PIP,LIJ G T ? ~ S b : F ~ S I ? . ,~!EfIIG3I?:QD 4 2 1 ?TQl.'L?GI-CP YFGVSIAG:!'~! DLDPI:SYF?'.' 4 P : rDLPOV.'?ACG APSGICLOI'K SCFFYTR?!P.\ 5 4 1 iIC)GSE?F:':'TO EI.TI,I:?,OK~V. \'CMFETLT:!LQ 5 0 1 ?E'.'LPIL!I.SP E?KTAHID'!E FLP:EGCG?I?:I 6 6 1 '.'FEL',",KDC~K D1ALETT';TTI SPS!J??:IP;P 7 2 1 FYQLSC7.',4!:Q 1:GSQADCELC IIPFKP,PIStF,"!' 7 P 1 ?JLi?ITAYAV, 7.-,*I';LLLS'.tS G','AU.PSQl,"I'F 84 1 RPLT1ILGT.a.T L11T07r:PY:EIS ?JGFi$'LLVL;7K 301 R P E I T R K Q I D D?IF.I:FSLFAE PK'iQTL?!CSJl 961 ?LEEYSKLF:Y L D I L M R A F I D ','TAA.SC?!I?L 1 0 2 1 A 1 LAGILNLA LLt!FI LWKCG FF:P,I!L:IT3,"1'
P:!'.'TPI:YG??
GSLFGFSLA!.!
H!.!QT,Q?EDV?. EDQP::.*G'.~T~.'Q D:':SFCI?GPLP 'rr??!:?C 17,'P','E QP:PJI:TFF9?!!: I FEDGPYE'JG KDCI'!'F'r'SC;.:< PDAP!HSC.ii.~r'~!' LLKF,DMKSRH gDTyU'TG.APg?' FU!?DGE:'GGA ;'V',':I!CPIC)QGR G?PDIA'v'GA? YD3LGE'.'=IV HGSAP?G,I:"'I At'GS;SDS','" IFRSPP'.'IEII OKTIT','TP?lR GYF!PSJSI'.'G TTEAEEERRK SGLSSPI!OFR U?!I?DULRPI PIT.?iS'.'EIQE P.SSF.S?.\T:SL '.'CIJS?!LYLE'I' K?CTpEC-IJQ? YFS'iLP1QY.G DG3DhF:E:,KL I A T F P E T L T ? SAYRELP.h?P FYLJLS?TTE1.' T ? D T F Y 5 3 I ? ! LKLETTSElQ3 GPTV'JGEQ.\!.! IISEDF7,'CSL1 EYEFP!'IE!LG T~7ESVT,LELL'" CEPQKEIPISL ?!LTESHMSRK PP.TIC'??!TRCP LWGI,DSFASL IL?SRLiC!ST P?IAGTD'!R'!T '!?PSKTT.'AOY SG'.'F1bK2'I:LV ? G F C T P I E F D IID?,DPTSESI: FCPC':':LSOII LRIEDT'.:DGC
D.ATf'HL:..IEi.Y
AQPS3KERLT SDA
Proteolytic cleavage site at position 899. The above sequence is for intepin a,A, and the sequence in italics and undcrlincd is substituted as below to make the B form: n;
CGF!?XSP'?'D
DS'!PF.'I?IA'.'P
Database accession EMBLIGenBank SwissProt
X53586 P23229
IpKEE?EIYD
EPYIDNLEKK QT/.!ITKPpP!S!!E
SYS
Integrin Family
Rcf~rc?nces
" 1'
T;lmur;l, l1.N. ct al. (19'11 1 Proc. Natl Acad. Sci. USA XS, 101S,?-10187. Hogcruorst, F. ct 31. 11991 I Eur. I . Riochc~n.19'1, 425-4.3.3. Hcmlcr, M.E. ct ;I]. I 1')S9\ 1. In.
fi
Gcorgcs-L~l>rjucssc., E.N. c t ;I]. (lYI6I N;lti~rcGcnct. 1,3, .370-LZ?.?. Vn11 dcr N c i ~ t R. , e t ill. Il9'1hl Nilture Gcnet. 1.3, ,367-.369. 13owIi~ig,1. r t :I]. 1 lYL)61J. Cell lliol. 1.34, 559-,572.
Family Intcgrin
Structure Molecular weights Ammo acids Polypeptide
1137 120957
SDS-PAGE reduced
100,30 kDa (120 kDa)
0--
-
4
Carbohydrate N-linked sites 0-linked sites
5
Gene location
12q13
Gene structure
Alternative forms
lntegr~na,/pl
Two extracellular and three cytoplasmic variants have heen described'.
Structure Typical proteolytically cleaved, non-I domain containing integrin a chain that forms dimer with P, to form a+,.
Ligands Receptor for basement membrane laminin types 1, 2 and 4 (E8regionlZd.
Function Integrin a, is involved in muscle development? a , is also involved in the formation and function of muscle fihre to extracellular matrix linkage, distinct from that mcdiatcd by the dystrophin-dystroglycan complex (see entry on dystroglycan), at the muscle basement membrane, as exemplified by the phenotype seen in human and mouse mutations (see below].
Distribution Developmentally rcgulatcd expression and splice variant usage during myogenesisM, with integrin a , expressed in skeletal, smooth and cardiac m u ~ c l e 2 ~ 4 Additionally, ~~J~. a , is expressed in developing nervous system'. The a,A and B spliced forms of a, are concentrated in myotendinous and neuromuscular i ~ n c t i o n s ~ . ~ ~ .
Disease association OMIM 6005.36 Humnn mutations lend to congenital mvopathv and variable mental retardatronr2.
Knockout MGI: 102700 Viahlc mice at hirth despite its apparent role in myogcncsis, with later development of pathological and clinical features of muscular dystrophy'j.
Amino acid sequence of human integrin a,
1
Proteolytic cleavage site at position 882.
Database accession EMRLIGcnHank TrEMRL
L2342.3 (mouse1 Qhl7,38
References Vcllrnq, T. c.t n1 (19961Dcv. Dvn. 207, ,755-,371. Kmmcr, R.H. ct al. ( 1 991 1 Cell Rcgul. 2, 80i-817. Yao, C.C. et al. 119961 I. Rrol. Chcm. 271, 25598-2560,Z. Yao, C.C. et al. (1997)1. Cell Sci. 110, 1477-1487. Song, W.K. et al. ( 19921 1. Cell R~ol.1 17, 64,Z-657. "ong, W.K. ct nl. (199,311. Cell SCI.106, 11,39-1152. Ziehcr, R.L. ct 81. (199.311. Riol. Chcm. 268, 26773-26783. Leung, E. et al. (19981R~ochern.Riophvs. Res. Commun. 24.7, ,317-,325. ') Kmmcr, R.H. ct a1. [I9891 I. Riol. Chcm. 264, 15642-15649. von der Mark, H. et al. (199111. R~ol.Chcm. 266, 23593-23601. Martln, P.T. ct 31. Dcv. B~ol.j 19961 171, 125-1.39. Havash~,Y.K. ct al. (1998)Nature Gcnct. 19, 94-97. Mnver, U. ct al. (19971Naturc Gcnct. 17, ,3 18,323.
J J
Family Integrin
Structure Molecular weights Amino acids Polypeptide
1025 113612
SDS-PAGE reduced
Carbohydrate N-linked sites 0-linked sites
15
Gene location Gene structure Alternative forms Structure Integrin a, is expressed as a heterodimer with integrin P, chain to form a@,'. The a, chain is disulphidc bonded at post-translational proteolytic clcavagc site and has no 1 domain.
Ligands Osteopontin2, and fibroncctin, vetroncctin and tenascin".
Function Location of integin a, in smooth muscle and kidney is suggestive of a functional role. Osteopontin interacts with a,P, during kidncy morphogenesisz, where a#, appears to he involved in epithelial-mesenchymal interactionsd. In chick embryo it is predominantly cxprcsscd neural tissue5.
Distribution Predominantly expressed in smooth muscle and kidney.
Disease association OMlM 604063
Knockout MGI: 109442
Integrin Family
Amino acid sequence of human integrin a,
Protcrrlvt~cclc;lvngc sitc at position ShS
Database accession EMI\L C.cnH,lnl<
L3hi 7 I
C M ~ ~I
1;' 3-OY
~ I ~ T O I
References
'
Schnllpp, L.M. ct ill. 1 1L)L)511. Ccll Soi. 108, 3.37-314. Dcnds, 5 . ct i l l . (19L1K1Mol. Riol. Ccll 9, 1325-15.45. Schnnpp, L.M. ct ill. (IL)9.51I. Riol. C l i c ~ n 170, . 1(3196-2,3202. Mullcr, U. rt al. 119971 Ccll SS, hOL3-hl,Z. Hossy, I{, ct nl. 1 lL)L)l1 EMRO I. 1 0 , 2.37.5-1.3S.5.
Family Integrin
Structure Molecular weights Amino acids Polypeptide
1035 114 560
SDS-PAGE reduced
Carbohydrate N-linked sites 0-linked sites
11
Gene location
3p2 1.3
Gene structure Alternative forms Structure Integrin a, forms heterodimcr with integrin PI to form a,P,l. It is posttranslationally cleaved to form disulphide-bonded heavy and light a chains; the cleavage site is non-standard as in the a, chain1.
Ligands Type 111 fibronectin repeat of tenascin-C2, the N-tcrminal fragment of osteopontin through a cryptic site" and VCAM-14. Together with the related integrin, a,P,, crop,, rccogniscs tissue transglutaminasc, coagulation factor XI11 and von Willebranci factor pro-peptide5.
Function The function of a, remains to he fully clarificd, but it appears t o hc involved in a number of cvcnts in the epithelium of gut6 and respiratory tract.
Distribution Widely distributcd in epithelia (skin, airway), muscle (smooth, skeletal1 and liver'. Upregulated in lung and colon carcinoma'. Its expression is regulated in embryonic airway and intestinal ~ I c v e l o p m c n t ~ ~ ~ .
Disease association OMIM 603963
Knockout MGI: 104756 T l ~ cGenc Knockout FactsRook9, p. 624. Livc offspring arc produced at birth hut thcsc die in the first postnatal wcck with respiratory failure due to chylothorax as integrin a, expression is critical for thoracic duct development (D. Sheppard, unpublished\.
Amino acid sequence of human integrin a,
Proteolvtic cleavage site at position 565.
Database accession EMI{L/GcnI
L24158 QILZ707
References Palmer, E.L. ct al. (1993)1. Cell B~ol.113, 1289-1297. Yokosak1,Y. ct al. (19981 1. Rlol. Chcm. 273, 11423-1 1428. Smlth, L.L. et al. (19961 J. R~ol.Chem. 271, 28485-28491. Taooka, Y. ct al. (19991 J. Ccll R~ol.14.5, 413-420. Takahashi, N. ct al. (2000)J. R~ol.Chem., in press. W c s l o g c s , N. ct 81. (19981 1. Ccll Blochem. 71, 536-545. ' Basora, N. ct al. (19981 Int. 1. Cancer 7.5, 738-743. Wang, A. et al. ( 1905) Dev. Dvn. 204, 42 1-43 1. Mak, T.W. (19981 Thc Gcnc Knockout FactsBook. Academic Press, London.
?
Family Integrin
Structure Molecular weights Amino acids Polypeptide
1167 127 574
SDS-PAGE reduced
160 kDa
Carbohydrate N-linked sites 0-linked sites
10
Gene location
lq21
Gene structure
17 exons
Alternative forms Structure
The intcgrin a,, chain forms a dimer with PI to form a,,P, Integrin a,, is most homologous to integrin chains a 1 and a2, and to the uncleaved, I domain-containing subgroup of integrin cu chains1.
Ligands Collagen type I1 building integrin in chondrocytesl.
Function Unknown.
Distribution Chondrocytes. Widely expressed with high levels in skeletal muscle and heart2.
Disease association OMIM 604042
1Knockout
Amino acid sequence of human integrin a,,
.
LpLVFLTGLC SP: " : : :::: :. ' :?:, -.7 -,::,..77 . .',.?' . . ,,.,:..-;; :,;, ,:. ..;........ .. . . . . . . . . . . . . . . . . . . . , . . ., . . ,. .., , . . . . .. . ....., _. _..........,.. , . ,., . ..,,..(:;: ,-I : . : : ~ , . : - , . .. . . . . .. ..., . . .. ., . . . .. . .. . .. . . . . . . . .- . . . .. . ... , ........ . . , .., ._.. ._-..,,, . . . . . . . . . . . . . . _ . . . . .". . .,..-,. . ..,-. . .. . .. . :.., .... . : .;. ... ........... .... ......... . .. .. .. . .. .. . . . - ... . .. . , . . .. . . . . . .. . , . :,. . .. .. . . . . ... .,.. .. ...... , :.. . . . . . . . . . .. " ..I: 7.' : : . ._ . .. .. ... .. ._. : : , _ .: . .../... . .. . . _ .. . ..._ ., , _ . . . . . . . . . . . .. . ... . . . .; . . -. ...-. - .. ... , - ...... ,,-.-,:., . -. . . . ... .. ... . .. . ....... -., . . . , . ,.. ... ..,,..,: .. . . . .. . . .* . . ,. . . . . . ... ... . ... . . .,., . .- . .,. . . . . . . . . . . . . ....... .. . ..,., ........ -.-...,:![?:,.. !.:,L9,':.., . ::.*,rr . . . . . .. .. ..: .. . . . . . ... .. . .. . .. . . .. .. .. . .. .. . . . , .,. :,,?. ,,,,,,, . '1'''' .:! g::'7:,(:;,, '-'--:,.,;-:0"'.-.--... -. . r . . .....-...........(-.# ; ;,2 :-;-: -........ . . . . . . . . . .. . . . . . .- , .. . ‘ . . . . ..L' . ~ . . ."". . " . :," ,.:::,;,, :., ' ". "" ,,..:-.1 ">:,:I: ',,,I>;:. .. .. . .. .. ' , .:,,: . . . . . . . ., .., . .. . .. i . " . . . . . "... " ".... . . ,-,,, . . .. ... . . . . .... . . . ,. . .. .. .. . . . . . . . . . . . . ..~. . . . . . ,:.. ... .. . . ,- -!,F" ::.,, . :.. , . . .. ... . . . . ..z7..,.-.-.....-. ,~ , . . . ................... ,.- . . . ... .. ., .. .'I . . , 'l::';'T:,(-: . . ,.!,.,... . - , . , ,;- .,r I:. - . . . . .. ..... .:. ...;..: ....... ..... ..... . ..- .. , ........... -. ...L. ;. : :.,.., -....: .. :,-:::,::-; -..-.r-I., ,. -. . - ,. , ,.-. ., . . -.. .~. .. . . ...-..,-.,. . . . .....-... ........... .-,.,, ................. "I,i',.. "". [".,'L' .......... .. . . . . . _ . . . . . . . . . ,. . . . ; > : . . . . . . . . - . . .,., . . ., , . . . . I .. .,. . - ,., , , :,:::;... ..:;. . . ...... "-. . . . . ," . ',"',." ........ . . . ". . ".. ... . r !,,? . .. .. . ... . ... . "... ... ... ................. . . .. -, .. .~-. . . ..... . . ;:'..:.: ::,.:.l.lv .. .',. -, . . . . . . . . . ....;.. . . ........ . , . , . : ,,n . ... ,; : "'.!,". .::: '".-. : ; .;. 'I.',,7.:.,. .-. ,-[ ,-,.-.. .-'. . . : ". . . ,.(. . ." ..7 ". ' . ' : - I ; , . ,. ,.. ,. . . . . . - " ~ " ' ..;....... " : : .. . .. . , , , ......... -. .,::-..:. . .... . . .,.----.,. . . . . . . . . . ...-.. ..... .., , , , , , . .-..-,,. . . . ....- ..: ,:r;,:,rr.;:-r . . ...... . :., ,- . -,.r ; --.. . . . . . . .. . . .. . . .. . . . .. . . . . . . . . ... .-C. .;.......-?-. . . . . . ,. . . _ . ..,-. . ..; . .- <.,... . . . . . . '. ' ._I' MELp-HLF
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I domain position 140-3,Z7.
Database accession EMRL/GenRank SwissProt
AF074015 075578
Reference Camper, L. et nl. (199811. Riol. Chcm. 173, 20.783-20389. Lchncrt, K . ct al. 119991 Cytogcnct. Cell Gcnct. 87, 238-244.
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CD41,platelet glycoprotein gpIIb
Family Integrin
Structure Molecular weights Amino acids Polypeptide
1039 110 019
SDS-PAGE reduced
125,22 kDa (140 kDa unreduccd)
-
Carbohydrate N-linked sites 0-linked sites
7
Gene location
1Jq21.32, in thesarne region as 83
Gene structure
17 kb, 30 exons
Alternative forms
'i
1111 1111
'
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m-*
i i l ~ ~11ii i 111111
1111
CD41lCD61
Alternatively spliced variant with extracellular domain 34 amino acid deletion, which stops surface expression'.
Structure Integrin a,,, is a type I membrane glycoprotein integrin u chain24 forming a non-covalently linked dimcr with P, (CDbl), u,,,P,. a,,,, is proteolytically cleaved and disulph~debonded. Conformational changes in a,,hoccur on coactivation through signals mediated via the cytoplasmic tail leading to high-affinity ligand binding and exposure of antibody-defined neo-epitopes (see entry for integrin P,)cyO.Rotary shadowing electron microscopy has led to the development of a consensus structural model for integrinsyl.A model for the distribution of intramolecular disulphide bonding has been proposcdI2.
Ligands The a,lhP,dimer (CD41/61, platelet gpTIbIIIa1 is the platelet receptor for the adhcsivc proteins fihrinogcn, fihronectin, vitronectln, thrornhospondin and von Willebrand facto? 'I. Binding occurs through an Arg-Gly-Asp (RGD) interaction sequence in matrix/serum proteins (see also integrin a,)6.13J4; with fibrinogen is via an alternate sequence, HHLGGAKQAGDV (the H12 sequence) in thc fibrinogen y chainJslh. Adhesion is enhanced by costimulation, trimered by the agonists thromhin, ABP or collagen, leading to integrin receptor activation, high-affinity adhcsion to solublc ligand and platelet aggregatior~~.~~.'~.
Function a,,,@,is the major intcgrin in platelets. Essential for normal platelet
adhesion to d a m a ~ c dvascular cndothclium and platclct aggregation. RGD pcptidc-hased inhihitory dmgs havc hccn cicvclopcd for clinical use in a variety of cardiovascular rlis~ascs whcrc thcrc is cxccssivc platclct aggregation and thromho~is1','~.
Distribution Expression is limited to platelets and mcgakaryocytcs"?
Disease association OMIM 273800 Mutations in cr,,,,2"-pJ cause one form of Glanzmann's thromhasthenin (type A\ (see also OMlM 17.1470, entry for integrin p,/CDhl), which causes an inherited disordcr of mucocutnncous hlcuding. Polymorphism at the position 874 (scrX74 to ilel forms the HPA-3/Rak/Lek platelet alloantigen system and is involved in neonatal t h r o m h o c y t ~ p e n i a ? ~ . ~ ~ .
Knockout
I
Amino acid sequence of human integrin a,,,
Protcolytic clcavagc sitc at position 901.
Database accession EMRL1C;cnRnnk Swl~sProt
102764 POX5 14
-.-
Integrin Family -.--
References Bray, P.F. ct al. (1990)J. Riol. Chem. 265, 9587-9590. Poncz, M. et al. (1987)J. Biol. Chem. 262, 8476-8482. " Frachet, P. et al. (19901Mol. Riol. Rep. 14, 2733. Charo, I.F.et al. (1986)Proc. Natl Acad. Sci. USA 83, 8351-8355. "relinger, A.L. et al. (1991)J. Biol. Chem. 266, 17106-171 11. Du,X. et al. (1991)Ccll65, 409416. Loftus, J.C. et al. (1990)Science 249, 915-918. Frelinger, A.L. ct al. (1990)J. Biol. Chem. 265, 634(&352. Frelinger, A.L. et al. (1988)J. Biol. Chem. 263, 12397-12402. l" Mondoro, T.H. et al. (1996)Rload 88,3824-3830. 11 Carrell, N.A. et al. (19851J. Riol. Chem. 260, 1743-1 749. Calvete, J.J. et al. (1989)Biochcm. J. 261, 561-568. l1 Phillips, D.R. et al. (1991)Cell 65, 359-362. I4 Ginsberg, M.H. ct al. (1993)Thromb. Haemost. 70,87-93. l5 DISauza, S.E. et al. (1991)Nature 350,6C-8. I b Savage, B. et al. (1995)J. Riol. Chem. 270, 28812-28817. l7 Fcrguson, 1.1. and Zaqqa, M. (1999)Drugs 58,965-982. l R Wang, W. et al. (2000)Cum. Mcd. Chem. 7,437453. I q Kieffcr, N. and Phillips, D.R. (19901Annu. Rev. Cell Biol. 6 , 3 2 9 3 5 7 . Rray, P.F. (1994)Thromh. Hacmost. 72, 492-502. 2' Poncz, M. et al. (1994)1. Clin. Invcst. 93, 172-179. 22 Wilcox, D.A. et al. (1994)J. Biol. Chem. 269, 4450-4457. z1 Wilcox, D.A. et al. (1995)J.Clin. Invcst. 95, 1553-1560. 24 Tadokoro, S. ct al. (1998)Rlood 92, 2750-2758. 25 Calvete, J.J. and Muniz-Diaz, E. (1993)FERS Lett. 328, 3034. ZL Lyman, S, et al. (19901Blood 75, 2343-2348.
CD51,vitronectin receptor
-
-
--
-
Family Integrin
Structure Molecular weights Ammo acids Polypcptidc
1048 116051
SDS-PAGE reduccd
125,25 kDa ( 165 kDa unrcduccdl
Carbohydrate N-linked sitcs 0-linked sitcs
13
Gene location
2q3 1 4 3 2
Gene structure Alternative forms CD51ICD61
Structure lntcgrin a, is a typc I memhranc glycoprotein of the integrin subclass with The a, chain is post-translationally cleaved into a no I [inserted) heavy and light chain, which is cxprcsscd on the cell surfacc as a disulphidehonded polypeptide. a , is a promiscuous integrin cr chain forming dimcrs with many integrin p chains: p, (CD291,p, (CD61),pi,ph and p,.
Ligands Most a,. intcgrins rccognizc the Arg-Gly-Asp (RGD) amino acid sequence. RGD-dependent interactions have heen shown with many extracellular matrix and serum proteins.'-5, thc specificity depending upon which a , integrin is utilized. These include, for example, for a , p , [see also entries for intcgrins p,, P6, Pul, vitronectinn.', fihroncctin, fihrinogcn, thromhospondin, ostcopontin, hone sialopmtein and von Willehrand factor. Unlike the other p, dimcr, platelet allhP,, ligand hinding is constitutivcly activated. In contrast, a,$, is a fihroncctin/vitroncctin rcccptol-R. Scveral protcins whcn in their native conformation fail to interact, for example laminin9 and collagcn type I, hut do so if 'dcnaturcd'. Othcr matrix intcractions with a,@, are not dependent on RGD, such as with the neural cell adhesion molecule L1 (scc cntryll"; a$, also mcdiatcs intcrccllular (lcucocytc-cndothclium) adhesion via interaction with CDL31(scc cntry)u*12.
Function A role in normal honc rcsorptinn and hcncc honc turnovcr has been extensively demonstrated for a,,p,y3, a finding that is being exploited
pharmaceutically. Likewise a\,@,integrins play an important regulatory role in angiogenesis in various pathological conditions such as in tumours~4-15. Recent evidence shows reciprocal involvement of a,Pi and avP, dimers in angiogenesis in experimental models, with a,Pi being regulated by vascular , modulated by bFGFjh. Experiments in factors such as VEGF, whereas a , @is mice have shown that a @ ,can act as a co-stimulatory molecule for T cell activation. It is upregulated on inflammatory monocytes, where it is involved, with CD36, in the recognition of apoptotic neutmphils (see CD36 entry). There are a number of membrane molecules associated with a,@, that are involved in signal transduction and regulating activation, for example, CD371'.1R. Melanoma cells express high levels of a,p, in vivo, and this integrin dimer is probably involved in tumour progression and invasionyv(for example, via cell-endothelial adhesion via CD3 1 ). It thus has a rolc in melanoma invasion in the clinical situation due to upregulation of a,P, in neoplastic versus normal melanocytesM.
0
Distribution Low levels of a$, integrin are found in a number of tissues, including cndothclium, smooth muscle, some activatcd macrophages and T cells, and platelet+. Very high amounts are expressed constitutively by osteoclasts in bone'". Most cultured, adherent cell lines are a,,positive.
Disease association OMIM:193210
Knockout MGT:96608 The Gene Knockout FnctsRookZ1,p. 625 Eighty per cent of embryos die at E10.5-12.5. The remainder survive to birth but rapidly die with brain haemorrhage due to malformation of the cerebral vasculature. The unexpectedly 'mild' phenotype points to a complex role of a,, integrins in development and angiogenesis (leading to fatal intracerebral and intestinal haemorrhage)2'.
Amino acid sequence of human integrin a, 1 MAFPPRRRLR LGPRGLPLLL SGLLLPLCRA FIIL?.'DSP>.E YSCPEGS'r'FG 6 1 :':;?:.!?,:;';4 ':',A;:;-~-I~I;I ',I' :i:~'''L:'_:) !:SST?OCOpI :EXTT:!:!DS 12 1 f!O>:X.&AS?C L:07':IL&C.A? L'iI!>::-TCF!F'.O EREF','GTC?I, @CG?YTVEYA I R I C:X:FCOGGFS :cT:~.:,n?~.'L ; r ; r . ~ ~ : . ~ ~ i ' : : ~T.O!,:SD~-Y;..E ~ I':SY-{~?*P;Y 2 4 1 PT?.,T~I:!CD~-: ;&.y::r.hz:,~ ! . ! ~ ? G S D C Y L ~E::G~.:s:I'sL~ 3 6 1 Lf?GFF?.'F>,?F G??sIj,,F X71, DTDG'?!7:,:+1 ;..,?,,?'>'GGF2!'?: GI3,.*'i:F?!G.RS 421 >EGC!*:;&,,?,PC!.! ?F'SPC'I';'Mt:G :30:7':? DLI',,'C,?iFS','3 R;..IL'P?? LIIFV?ELLLD 541 ALFLLYS3T'S tiSi'::?~1TTSFr; CLI.!QCFELT.', YLDDFSFFPI) PT,T?TTTFKE 6 0 1 TTGLOPIL!:Q ?TP.~.IIIT?Q.~.UI:,LDCGTJT! ".'C!'PVLF.'?',.' DSDOF'K.:IVIG 6 6 1 .iO>!OCi.'CA'?'1: IiEL:'.'ST P: O A3FIC'.".'3:!I! F?LA?Lf C:\F VTTE9TPOW
FAVDFFVPSA ,AED3p',EFKS
PCRSODIDAD
s IKV~J:!QL.J.T ?.!SSLYYFTGE P.:,SGDFOTTV TGLP:>,',v'PS@I ITV!:ACLT,.'Y Y.LKOYCAIP,R YPL[JYPTAA3 DD?.IPLTLI'JK CDLGEIP!?Y.AG
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Proteolytic cleavage s i t ~ a t position 889.
Database accession EMRLIGenRank SwissProt
M 14648 PO6756
References Suzukl, S. et al. (19861Proc. Natl Acad. Sci. USA 83, 8614-8618. Suzukl, S. ct a1. (1987)J. R~ol.Chem. 262, 1408&14085. N. and Phillips, D.R. (1990)Annu. Rev. Cell R~ol.h, 329-357. "eiffer, 4 Ginsberg, M.H. et al. (1993)Thromh. Hacmost. 70, 87-93. Horton, M.A. (1997)Int. J. Riochem. Cell Riol. 29, 721-725. Pvtcla, R. ct al. (19851 Proc. Natl Acad. Sci. USA 82, 5766-5770. ' Cheresh, D.A. (1987)Proc. Natl Acad. Sci. USA 84, 6471-6475. Voge1,R.E. et al. [1990)J. Riol. Chem. 265, 59345937. Kramer, R.H. ct al. (1990)J. Cell Riol. 11 1, 1233-1243. IDEbelrng, 0,et al. (1996)Eur. J. Immunol. 26, 2508-25 16. I1 Piall, L. c t al. (199511. Cell Riol. 130, 451-460. Ruckley, C.D. et al. (1996)1. Cell Sci. 109, 437-455. " Hclfrich, M.H+and Horton, M.A. (19991Dynamics of Bone and Cartrlage Metabolism, Scibcl, M.I., Rohins, S.P. and Rilez~kian,J.P., eds. Academlc Press, London, pp. 11 1-1 25. Vamer, J.A. and Cheresh, D.A. (1996)Curr. Opin. Cell Riol. 8, 724-730. 15 Vamer, 1.A. ct al. (1995)Cell Adhes. Comm. 3, ,367-.174. InFriedlandcr, M. ct al. (1995) Sciencc 270, 1500-1502. I' Lindherg, F.P. et al. 119961 J. Cell Riol. 134, 1313-1322. lR Gao, A.G. et al. (19961 J. Cell Biol. 135, 533-544. Johnson, J.P ( 1999)Cancer Metastasis Rev. 18,345357. IYScftor, R.E. ct al. (1992)Proc. Natl Acad. Sci. USA 89, 1557-1561. 2"Mak, T.W. (19981 The Gene Knockout FactsRook. Academic Press, London. Rader, R.L. et al. 11998) Cell 95, 507-5 19. 2
Family Integrin
Structure Molecular weights Amino acids Polypeptide
1178 129714
SDS-PAGE rcduccd
150,25 kDa ( 175 kDa unreduced)
Y-
*
i
Carbohydrate N-linkcd srtcs 0-linked sltes
11
Gene location
17ql.3
*, .*
t-
w
J.
Gene structure Alternative forms
COl03(nE~
Structure Intcgrin a, {CD103) is a type I membrane g l y ~ o p r o t e i n 'which ~ exists as a dimer with p. t o form aEp,. It has an N-terminal I or inserted domain characteristic of a subclass of intcgrin a chains, hut, unusually, it is also post-translationally clcavcd into two polypcptidcs (an N-tcrminal 25 kDa and larger C-terminal 150 kDa fragment], which are disulphide bonded. An cxtra scquencc (the 'X' domain) of 55 amino acids (16 are acidic) is found immcdiatcly N-terminal to the I domain and is the site of proteolytic clcavagci.
0
Ligands E-Cadhcrin (cadherin-I)Mon epithelium.
Function Adhesion of intraepithelial lymphocytes, a subset of T cells, t o the basolatcral surface of intestinal cpithclial ccllsg. Prcsumcd role in lymphocyte homing to e p i t h e l i u ~ n ~ - ~ ~ f ~ ,
Distribution Intcgrin a, was defincd as the HML-1 antigen by the M290 antihody in the mouse in the early literature. It is expressed on the majority of intraepithelial lymphocytes in thc intestine and other epithelia (bronchi, skin, breast, tumours], and a suhpopulation of T cells in thc lamina propria. Lcss than 5% of circulating lymphocytes express a,,hut this is increased by TGFPI",".
Integrin Family
Disease association OMIM 604682
Knockout MGI:1298377 The function of a, has been defined in p,-deficient mice (see entry) and in a, knoclzout mice", where intraepithelial lymphocyte numbers are reduced, sparing T cell levels in tissues such as spleen and Peyer's patches.
Amino acid sequence of human integrin cx, 1 61 121 181 241 301 361 421 481 541 601 661 721 781 841 901
961 1021 1081 1141
MWLFHTLLCI KRTPGPLHRC LTGTCSLLGP KEEEEDKEEE ALVQYGGVIQ KASKWLT DETHAFKVTN GAFDWSGGAL QYKHHGAVFE HGEEGRVYVY EGFGADDGAS DITVGTLGQA EALLNFTLDV NASVKVSYQL QELWGLTKE VLIMNCRIGH RHGFVAVLSK KKLTRTQAST KDVTELQILG ILVILFKCGF
ASLALLAAFN SLVQDEILCH DLRPQAQANF EDEEEEEAGT TEFDLRDSQD DGGIFEDPLN YMALDGLLSK LYDTRSRRGR LQKEGREASF RLSEQDGSFS FGSVYIYNGH WFRSRPWR DVGKQRRRLQ QTPEGQTDHP LTLNINLTNS PVLKRSSAHV PSIMYVNTGQ VCTWSQERAC EISFNKSLYE FKRKYQQLNL
VDVARPWLTP PVEHVPIQGE FDLENLLDPD EIAIILDGSG VMASLARVQN LTTVINSPKM LRYNIISMEG FLNQTAAAAA LPVLEGEQMG LARILSGHPG WDGLSASPSQ LKVSMAFTPS CSDVRSCLGC QPILDRYTEP GEDSYMTSMA SWQLEENA GLSHHKEFLF AYSSVQHVEE GLNAENHRTK ESIRKAQLKS
KGGAPFVLSS APGSDRCPEP ARVDTGDCYS SIDPPDFQRA ITQVGSVTKT QGVERFAIGV TVGDALHYQL DAEAAQYSYL SYFGSELCPV FTNARFGFAM RIRASTVAPG ALPIGFNGW LREWSSGSQL FAIFQLPYEK LNYPRNLQLK FPNRTADITV HVHGENLFGA WHSVSCVIAS ITWFLKDEK ENLLEEEN
LLHQDPSTNQ PRCFDMHSSA NKEGGGEDDV KDFISNMMRN ASAMQHVLDS GEEFKSARTA AQIGFSAQIL GYAVAVLHKT DIDMDGSTDF AAMGDLSQDK LQYFGMSMAG NVRLCFEISS CEDLLLMPTE ACKNKLFCVA RMQKPPSPNI TVTNSNERRS EYQLQICVPT DKENVTVAAE YHSLPIIIKG
TWLLVTSPRT GPAPHSLSSE NTARQRRALE FYEKCFECNF IFTSSHGSRR RELNLIASDP DERQVLLGAV CSLSYVAGAP LLVAAPFYHV LTDVAIGAPL GFDISGDGLA VTTASESGLR GELCEEDCFS ELQLATTVSQ QCDDPQPVAS LANETHTLQF KLRGLQVAAV ISWDHSEELL SVGGLLVLIV
Proteolytic cleavage site at position 176. 1 domain position 199-390 and an 'XI domain position 144-198.
Database accession EMBLIGenBank SwissProt
L2585 1 P38570
References Shaw, S.K. et al. (1994)J. Biol. Chem. 269, 6016-6025. Micklem, K.J. et al. (1991)Am. J. Pathol. 139, 1297-1301. Parker, C.M. et al. (1992)Proc. Natl Acad. Sci. USA 89, 1924-1928. Kilshaw, P.J. and Murant S.J. (1990)Eur. J. Immunol. 20, 2201. 5 Cepek, K.L. et al. (1994)Nature 372, 190-193. Higgins, J.M. et al. (1998)J. Cell Biol. 140, 197-210. Karecla, P.I. et al. (1995)Eur. J. Immunol. 25, 852-856. Karecla, P. et al. (1996)J. Biol. Chem. 271, 30909-30915. Cepek, K.L. et al. (1993)J. Immunol. 150, 3459-3470. lo Shaw, S.K. and Brenner, M.B. (1995)Semin. Immunol. 7,335-342. l1 Schieferdecker, H.L. et al. (1990)J. Immunol. 144, 2541-2549. l2 Scon, M.P. et al. (1999)J. Immunol. 162, 6641-6649. 2
CD29, platelet gp IIa
Family Integrin
P chain
Structure Molecular weights Amino acids Polypeptide
798 88 465 ( 4 isoforms with polypeptides varying by approx. 4 kDa)
SDS-PAGE reduced
115 kDa (130 kDa unreducedl
Carbohydrate N-linked sites 0-linked sites
12
Gene location
lop1 1.2
Gene structure
30 kb, 7 exons
Alternative forms Four alternate RNA splice variants producing different C-termini with differential tissue expre~sion'-~.
Structure p, is the prototype integrin P chain (fibronectin receptor, a,P,)? It is a type I membrane glycoprotein that associates with a large number of integrin a chains forming non-covalently linked dimers with a , , a,, a,, a,, a,, a,, a,, a,, a,, a,, and a,. p,, like all integrin P chains, is cyteine-rich (56 residues in four repeat regions) and internally disulphide bonded. The N-terminal part of the p chain is involved in ligand interaction and shows homology with the von Willebrand factor A-domain5.
Ligands Ligand specificity depends upon the exact integrin dimer formed (see individual a-chain entries for details). For example, a , and a, form dimers with P1 that bind laminin, alp, is a collagen receptor and a,P, is the major fibronectin receptor.
Function See individual a-chain entries for details. P, integrins mediate a broad range of cell-matrix and intercellular interactions6. The P, integrin is activated for ligand binding by divalent cation exposure and 'inside-out' cell signalling7s8.
Integrin Family
Distribution Widespread in most tissues during embryogensis and adult life as the common @ chain of the large @,subclass of integrins6 (see individual achain entries for details of individual dimer tissue distribution). The @chain splice forms show different tissue expression: the B variant1 is found in placenta, lymphoid tissues, liver and endothelium; the C isoform3 is expressed by some subpopulations of haemopoietic cells; the D variant4 is found only in slzeletal muscle and heart.
Disease association OMIM 135630
Knockout MGI:966 10 The Gene Knockout FactsBook9,p. 626. Embryos implant but die at around E5.5 due to defective inner cell mass endoderm morphogenesis following normal blastocyst development and trophoblast functionlo-".
Amino acid sequence of human integrin p, 1 MNLQPIFWIG LISSVCCVFA QTDENRCLKA NAKSCGECIQ AGPNCGWCTN STFLQEGMPT 61 121 181 241 301 361 421 481 541 601 661 721 781
SARCDDLEAL LRLRSGEPQT RIGFGSFVEK ISGNLDSPEG CHLENNMYTM SANSSNVIQL GDEVQFEISI NGTFECGACR RDNTNEIYSG ASNGQICNGR CTQECSYFNI PECPTGPDII PIYKSAVTTV
KKKGCPPDDI FTLKFKRAED TVMPYISTTP GFDAIMQVAV SHYYDYPSIA IIDAYNSLSS TSNKCPKKDS CNEGRVGRHC KFCECDNFNC GICECGVCKC TKVESRDKLP PIVAGVVAGI VNPKYEGK
ENPRGSKDIK YPIDLYYLMD AKLRNPCTSE CGSLIGWRNV HLVQKLSENN EVILENGKLS DSFKIRPLGF ECSTDEVNSE DRSNGLICGG TDPKFQGQTC QPVQPDPVSH VLIGLALLLI
KNKNVTNRSK LSYSMKDDLE QNCTTPFSYK TRLLVFSTDA IQTIFAVTEE EGVTISYKSY TEEVEVILQY DMDAYCRKEN NGVCKCRVCE EMCQTCLGVC CKEKDVDDCW WKLLMIIHDR
GTAEKLKPED NVKSLGTDLM NVLSLTNKGE GFHFAGDGKL FQPVYKELKN CKNGVNGTGE ICECECQSEG SSEICSNNGE CNPNYTGSAC AEHKECVQCR FYFTYSVNGN REFAKFEKEK
IHQIQPQQLV NEMRRITSDF VFNELVGKQR GGIVLPNDGQ LIPKSAVGTL NGRKCSNISI IPESPKCHEG CVCGQCVCRK DCSLDTSTCE AFNKGEKKDT NEVMVHWEN MNAKWDTEN
Integrin @ lexists in four cytoplasmic tail splice variants. The A isoform is illustrated in italics and underlined and is replaced by the following after T777: B: VSYKTSKKQS GL C: SLSVAQPGVQ WCDISSLQPL TSRQQFSCLS LPSTWDYRVK ILFIRVP D: QENPIYKSPI NNFKNPNYGR KAGL
Database accession EMBLIGenBank SwissProt
A form: X07979; B form: U33879; C form: U33882; D form: U33880 PO5556
Integrin Family
References
lo
JZ
Balzac, F. et al. (1993)J. Cell Biol. 121, 171-178. Argraves, W.S. et al. (1987)J. Cell Biol. 105, 1183-1190. Languino, R.L. and Ruoslahti, E. (1992)J. Biol. Chem. 267, 71 16-7120. Belkin, A.M. et al. (1996)J. Cell Biol. 132, 21 1-216. Tuckwell, D.S. and Humphries, M.J. (1997)FEBS Lett. 400, 297-303. Hemler, M.E. (1990)Annu. Rev. Immunol. 114, 365-400. Shimizu, Y. et al. (1990)Nature 345, 250-253. Schwartz, M.A. et al. (1995)Annu. Rev. Cell Dev. Biol. 11, 549-599. Mak, T.W. (1998) The Gene Knockout FactsBook. Academic Press, London. Stephens, L.E. et al. (1995)Genes Dev. 9, 1883-1895. Fassler, R. and Meyer, M. (1995)Genes Dev. 9, 1896-1908. Brakebusch, C. et al. (1997)J. Cell Sci. 110, 2895-2904.
Family Integrin
Structure Molecular weights Amino acids Polypeptide SDS-PAGE reduced
95 kDa (90 kDa unreduced)
Carbohydrate N-linked sites 0-linked sites
Gene location Gene structure Alternative forms Structure Integrin p, is a type I membrane glycoproteinl-3 of the general integrin p chain structure (see p,) that forms dimers with four a chains (CDlla-d). The cytoplasmic tail of p, contains eight potential posphorylation sites.
Ligands See individual entries for a,, a,, a, and a, (CDlla-d) molecules for details of p, ligands. p, integrins also recognize several microbial ligands including those from Histoplasma sp., Legionella sp. and Leishmania spG7.
Function Adhesion and signalling in haemopoietic cells. For details of function, see entries for individual a chains, a,, a,, a, and a, (CDl la-d) integrins. The cytoplasmic tail of p, is important in regulating signal transduction from the individual dimer via cytoskeletal interactions and cytoplasmic tail phosphorylations.9. Ligand binding is regulated by receptor activation as with several other integrinsl0jH.
Distribution Integrin P, (CD18) is expressed by all leuc0cytes~~~l3 with the four leucointegrin dimers being differentially expressed - see individual entries for a,, a,, a, and a, (CDlla-d) integrins for details.
Integrin Family
Disease association OMIM 116920 Leucocyte adhesion deficiency syndrome (LAD-1)is caused by mutations in the p2 gene (see also LAD-2, in entry for selectins) in which patients suffer from varying severity of disease owing to recurrent bacterial infections due to defective leucocyte (granulocytes, monocytes, lymphocytes) adhesion1"17; in part this relates to the molecular defect and its impact upon the level of p, integrin expression in the cell membrane
Knockout MGI:96611 p2 (CD18)knockout micefs show similar deficits in inflammation as in the human disease, underscoring the importance of P, integrins in normal immune function. An inherited disease with similar features was observed in Holstein cattle due to point mutations in the bovine p, genef9l2O.
Amino acid sequence of human integrin p, 1 61 121 181 241 301 361 421 481 541 601 661 721
MLGLRPPLLA RCDTRPQLLM RAKGYPIDLY NTHPDKLRNP MQVAACPEEI YPSVGQLAHK NKLSSRVFLD IQEQSFVIRA CECQTQGRSS CERYNGQVCG CECHSGYQLP TCKERDSEGC WKALIHLS
LVGLLSLGCV RGCAADDIMD YLMDLSYSML CPNKEKECQP GWRNVTRLLV LAENNIQPIF HNALPDTLKV LGFTDIVTVQ QELEGSCRKD GPGRGLCFCG LCQECPGCPS WAYTLEQQD DLREYRRFEK
LSQECTKFKV PTSLAZTQED DDLRWJKKLG PFAFRHVLKL FATDDGFHFA AVTSRMVKTY TYDSFCSNGV VLPQCECRCR NNSIICSGLG KCRCHPGFEG PCGKYISCAE GMDRYLIYVD EKLKSQWNND
SSCRECIESG HNGGQKQLSP GDLLRALNEI TNNSNQFQTE GDGKLGAILT EKLTEIIPKS THRNQPRGDC DQSRDRSLCH DCVCGQCLCH SACQCERTTE CLKFEKGPFG ESRECVAGPN NPLFKSATTT
PGCTWCQKLN QKVTLYLRPG TESGRIGFGS VGKQLISGNL PNDGRCHLED AVGELSEDSS DGVQINVPIT GKGFLECGIC TSDVPGKLIY GCLNPRRVEC KNCSAACPGL IAAIVGGTVA VMNPKFAES
FTGPGDPDSI QAAAFNVTFR FVDKTVLPFV DAPEGGLDAM NLYKRSNEFD NWHLIKNAY FQVKVTATEC RCDTGYIGKN GQYCECDTIN SGRGRCRCNV QLSNNPVKGR GIVLIGILLL
Database accession EMBLIGenBank SwissProt
YO005 7 PO5107
References
lo
"
"
Law, S.K.A. et al. (1987)EMBO J. 6,915-919. Weitzman, J.B. et al. (1991)FEBS Lett. 294, 97-103. Kishimoto, T.K. et al. (1987)Cell 48, 681-690. Aderem, A. and Underhill, D.M. (1999) Annu. Rev. Immunol. 17, 593-623. Mosser, D.M. et al. (1992)J. Cell Biol. 116, 51 1-520. Rosenthal, L.A. et al. (1996)Infect. Immun. 64, 2206-2215. Talamas-Rohana, P. et al. (1990)J. Immunol. 144, 4817-4824. Pavalko, F.M. and LaRoche, S.M. (1993)J. Immunol. 151,3795-3807. Sharma, C.P. et al. (1995)J. Immunol. 154, 3461-3470. Ortlepp, S. et al. (1995)Eur. J. Immunol. 25, 637-643. Petruzzelli, L. et al. (1995)J. Immunol. 155, 854-866. Larson, R.S. and Springer, T.A. ( 1990)Immunol. Rev. 114, 181-2 17.
l3
14 j5
l6 l7
19
Patarroyo, M. et al. (1990)Immunol. Rev. 114, 67-108. Nelson, C. et al. (1992)J. Biol. Chem. 267, 33513357, Wardlaw, A.J. et al. (1990)1. Exp. Med. 172, 335-345. Arnaout, M.A. et al. (1990)J. Clin. Invest. 85, 977-981. Kishimoto, T.K. et al. (1987)Cell 50, 193-202. Wilson, R.W. (1993)J. Immunol. 151, 1571-1578. Shuster, D.E. et al. (1992)Proc. Natl Acad. Sci. USA 89, 9225-9229. Shier, P. et al. (1996)J. Immunol. 157, 5375-5386.
CD61, platelet glycoprotein gpIIIa
Family Integrin
Structure Molecular weights Amino acids Polypeptide
788 87213
SDS-PAGE reduced
105 kDa (90 kDa unreduced)
Y*
w0
-
-a
Carbohydrate N-linked sites 0-linked sites
6
Gene location
17q21-23 near aIIb
Gene structure
60 kb, 14 exons
Alternative forms
CD41/CD61
There are at least three cytoplasmic tail alternate splice forms1, with one form having reduced ligand binding2.
Structure Integrin P3 is a typical integrin P chain type I g l y ~ p r o t e i n ~that - ~ dimerizes and a,, to form aIIpp,and avP3,respectively. with two alternate a chains, aIIp Point mutations lead to polymorphisms, and deletions or mutations to an inherited bleeding disorder (see below). Tyr 773 is potentially phophorylated and is deleted by RNA splicing. A model for intramolecular disulphide bond usage has been proposed6.
Ligands The two 6, integrin dimers, a,& and a I I p ~ ,bind , different ligands (see individual a, and a,,bentries for details).
Function See individual a, and a,,,,entries for details of
P3 function.
Distribution p, expression in tissues follows that of the exact integrin dimer formed. a,P, (CD51/CD61) is found in several tissues (see entry for integrin a,).In contrast, a,1pp,(CD41/CD61, gpIIbIIIa) expression is restricted to the platelet/megakaryocyte lineage7, where it plays a key role in platelet aggregation and hence haemostasis (see entry for aIIp).
Integrin Family
Disease association OMIM 173470 Glanzmann's thrombasthenia (type B) (see also OMIM 273800, and entry which causes an inherited haemorrhagic diathesis, is due to for integrin qIp) mutation (cytoplasmic tail truncation due to stop codon leading to altered signalling to, and interaction with, platelet actin cytoskeleton) or major deletions (Iraqi-Jewish form) in the P, gene8-ll. The significance of functional regions within the p, chain important in ligand binding have been exemplified by certain mutations in Glanzmann's thrombasthenia'22'3, which lead to loss of binding activity. Alloantigens on the P, chain include Zw/P1 (a), Pen and Mo lead to neonatal and post-transfusion p u r p ~ r a ~ ~ . ~ ~ ~ ~ ~ .
Knockout MGI:96612 The Gene Knockout F a c t ~ B o o kp. ~ ~627. , Mice are viable at birth with bleeding diathesisis due to a platelet defect, the murine homologue of Glanzmann's thrombasthenia. As predicted from studies of the a,P, integrin (vitronectin receptor), there is some evidence of an osteoclast functional defect in the bones of mutant mice1'.
Amino acid sequence of human integrin (3, 1 61 121 181 241 301 361
421 481 541 601 661 721 781
MRARPRPRPL SPRCDLKENL DDSKNFSIQV AFVDKPVSPY NRDAPEGGFD VGSDNHYSAS MDSSNVLQLI VSFSIEAKVR FECGVCRCGP KITGKYCECD CSGRGKCECG CRDEIESVKE WLLSVMGAI TNITYRGT
WVTVLALGAL LKDNCAPESI RQVEDYPVDI MYISPPEALE AIMQATVCDE TTMDYPSLGL VUAYGKIKSK GCPQEKEKSF GWLGSQCECS DFSCVRYKGE SCVCIQPGSY LKDTGKDAVN LLIGLAALLI
AGVGVGGPNI EFPVSZARVL YYLMDLSYSM NPCYDMKTTC KIGWRNDASH MTEKLSQKNI
CTTRGVSSCQ EDRPLSDKGS KDDLWSIQNL LPMFGYKHVL LLVFTTDAKT NLIFAVTENV
VELEVRDLPE ELSLSFNATC
TIKPVGFKDS EEDYRPSQQD MCSGHGQCSC GDTCEKCPTC CTYKNZDDCV WKLLITIHDR
LIVQVTFDCD ECSPREGQPV GDCLCDSDWT PDACTFKKEC VRFQYYEDSS KEFAKFEEER
QCLAVSPMCA GDSSQVTQVS GTKLATQMRK TLTDQVTRFN HIALDGRLAG VNLYQNYSEL LNNEVIPGLK CACQAQAEPN CSQRGECLCG GYYCNCTTRT VECKKFDREP GKSILYWEE ARAKWDTANN
WCSDEALPLG PQRIALRLRP LTSNLRIGFG EEVKKQSVSR IVQPNDGQCH IPGTTVGVLS SCMGLKIGDT SHRCNNGNGT QCVCHSSDFG DTCMSSNGLL YMTENTCNRY PECPKGPDG PLYKEATSTF
Database accession EMBLIGenBank SwissProt
U95204 PO5106
References van Kuppevelt, T.H. et al. (1989) Proc. Natl Acad. Sci. USA 86, 5414-5418. Kumar, C.S. et al. (1997)J. Biol. Chem. 272, 16390-16397. Fitzgerald, L.A. et al. (1987)J. Biol. Chem. 262,3936-3939. Frachet, P. et al. (1990)Mol. Biol. Rep. 14, 27-33. Zimrin, A.B. et al. (1988)J. Clin. Invest. 81, 1470-1475. Calvete, J.J. et al. (1991)Biochem. J. 274, 63-71.
Integrin Family
7
lo
" " 13
l4 '5 l6
j7
Kieffer, N. and Phillips, D.R. (1990)Annu. Rev. Cell Biol. 6, 334-357. Wang, R. et al. (1992)J. Clin. Invest. 89, 1995-2004. Simsek, S. et al. (1993)Blood 81, 2044-2049. Kuijpers, R.W.A.M. et al. (1993)Blood 81, 70-76. Lanza, F. et al. (1990)J. Biol. Chem. 265, 18098-18103. Loftus, J.C. et al. (1990)Science 249, 915-918. Bajt, M.L. et al. (1992)J. Biol. Chem. 267,3789-3794. Newman, P.J. et al. (1989)J. Clin. Invest. 83, 1778-1 78 1. Wang, R. et al. (1992)J. Clin. Invest. 90, 2038-2043. Mak, T.W. (1998) The Gene Knockout FactsBook. Academic Press, London. Hodivala-Dilke, K.M. et al. (1999)J. Clin. Invest. 103, 229-238.
Family Intugrin
Structure Molecular weights Amino acids Polypeptide
1875 208 024
SDS-PAGE rcduccd
220 kDa
Carbohydrate N-linked sitcs 0-linked sitcs
3
Gene location
17qll-qter
Gene structure
CD49flC0104
Alternative forms Three RNA spllcc varlants rcpnrtcd [with two alternate cytoplasmic inscrtinns at positions 1.370 or 1.520 between the second and third type 111 fihroncctin rcpcats) nr ncithcrl-1.
Structure Intcgrin P, forms a hctcrodimcr with intcgrin a, chain'-< to form a$,. Unique amongst intcgrin P chains, (3, contains a large 118 kDa (apprnximatcly 1000 aminn acid) cytoplasmic domain with four fihrnncctin type 111 repeats. It has only 4R of the usual 56 cysteine residues conserved across most intcgrin p chains. Interacts via unique cytnplasmic tail with keratin cytc~skclctnl filamunts, rather than actin as found with other intcgrinskR.
Ligands Laminin 5'J0.
Function Its distribution on the basal surface of keratinocytes and association with hemidesmosomal cytoskclcton in stratified and transitional epithclia indicates that the receptor is involved in adhesion to hasement membrane matrix proteinsl1J2 (see below for effect of mutation in P, upon epithelial integrity and adhesion). In vitro experiments and evidence from 0, knockout mice also suEest a role for P, integrin in cpithclial prolifcration and signal transduction, the latter mediated specifically via its unique cytoplasmic tail. A cytoplasmic insert at position 1,170 (insert 1) is found in carcinoma cell lines supgesting a variant-related function7Jq.
Distribution p, (CD104) is expressed hy hasal keratinocytes in association with . ' ~ some h e m i d e s m o s o m e s ~and in simple epithelia, Schwann ~ e l l s ~ land endothelium, which do not have h c m i d e s m ~ s o m e s ~ ~ .
Disease association OMIM 147557 Mutations in p, lead to a variant of epidermolysis hullosa with pyloric atrcsialhJR.
Knockout MGI:966 13 Extensive epithelial detachment a t birth and consequent death, features similar to thc human disc as^^.'^.
Amino acid sequence of human integrin p, 1 M&GPRPSPWA RLLLAALISV SLSGTLAtdPC V!:,4Pv,'YSC3"C','P','DPDCS':' 61 (:t:7Q:,!?L:,:li CCOP:;'SI',..x.'!.! r S C 7 0 I T E R T O I D ? T L P P r O !.!CF'OGLF'.'P, 111 F'?F"?LESP'~.' DL'I'ILYDFSFI SHS3DLDMLK Y!4GOHL':P'.'L SCLTS3':'T'IG 1R1 POTI)V!RPETI, KFP1;!PtTS0PP FSFPN'!TSI.T WRPDSTHLLV FSTESAFHVE '%'FLL~ZYIIIJLI PIF;I7>'TNYS'i' 3 6 1 EAF:IFI?SML DIF;h.LDSPPG L?TEVTSK?!F 4 2 1 TF'.'COI,PEDO KGPITHLKPSF SW,LKM?XC;T 4 R 1 CSFG!':SGOTC NCSTGSLSDT OPCL3FGFDX 541 FOCPPTSGFL CHDFGPCSFAG OCVCE?G1:TG 6 0 1 Ct:CffOQSLYT DTlCEIP?YS.*, :IHPCI,CEDLP 661 Lh'PAl;'t::'.l'p CSFRDEDDDC T Y S Y T M X D G 721 LLFLLALLL; LCI*?tc.YCACCK ACLr\LLPCC:I 781 SG7.!LP'GPP.'~: P.:':F;.:TF!NMQR PGFATHMSI 84 1 AQL?QF:EEN LVEVVFQISG !!HKLQQTKCY 901 €.TF.)iV.'FaQl: FHn?.Ki:APC-'i YTLT.;*l7aDP 9 6 1 Ll,'CirI DT,'P,;!S TATLGPRLVN IT1 IKEO.:iP,3 1021 KSp:rSYPTpD GT.~LOG'T~D?IP:JEGI?SLFOP 109 1 L'QLS'.!PFFPA HLGOPHSTTI T TRDPDELDP 1 1 4 1 ?TIIiFPX~:;FP SGPPMGYRVK ViW:OGDSESE 12 n 1 ?:OGEGPYSSL :'SCFTI1~~'v'P SEPGFLAF!!'.: 1 3 6 1 PID!IIIF.PIGF!~I YKT'LS7D'\'PYPJ R Y L L I E?JL?,E 13 2 1 P:RP.h!l;I P I I P DI P I 1'D:IQSG EEJYDSFLh!Y.?
2 4 1 @T.';CT?DIG 3 0 1 TQD':'P.S':PTL
13 R l
.
r:'-- > >. . 2:2'--. . .., ,' .cL.p.7c>;;>::;
L-dL
1'14 1 [!:,-.-.],.:!.P':>!....
: :y - ,' .,,
$:.-!>:(:;.-?:-:>.:,
::-.-
:
D3!'LFS?SGS
CTDFMFPDP? PP';FCQHFFL FGYF':DF",'S',' @CEnT?C'!!dn ? + P F C G c 7 l T : , !~!.C?I1nEFC!?!, DTTGT!'TQ?? ?'.'SSLC.'.'LOE DSS!:I..'ELLE P,?'I:E':f;I'iQ'! QLP.:<.LEFi;'DC: I.:F'.'?SAPCSF !!T;DF':CGOC3. GUC'.'C'r'GFt'!?.*C'r'C-Lt* P?lGAGI'!CPEP E?tI I?!LZ.TQP OF F.71 :qF?TG CGlrr.KFE?LLG
!:'>.:7.--..>;'.'?
.:>.:;,:T.:L.:>-
E3'L!nEFPP11'l, :Ax>.tT.'I,?~GT
SY'fCELHTYT QVTP,TCSFH: :Cn?!CTCE:,Q PCSGPGECOC FSCDC?LS!:A SC'.'OCOAI.:CT APGPtl-CT','I,',' P,GH!T,'CFKFD ?IPTEL'.'PYGL QQ??!.iG'.:?On G'T'.'EFOFC."F 'm.",'SFCOPEF,C GE;'I!*IYELO'!V SFTSO"1,SSQ AlltLPS!:','P5 '.'SST;'TOLSih! SQ?Y?YT'L'P:A
. ... .-.-. ... : ' 3
:.-.:
:
.:+
".. . . .
-.
-: &-:?rL-? ;;.:7,;r
..
..
rl':'::.-:.T'..-:'li
T w o splice v;lri;lnts are marker1 {undcrlinerl nntl in itnlics1.
Database accession EMRLiGcnR;lnk Sw~c
Xi1 SJI 1'16143
References Hogcrvc~rst,F. ct al. 119901 EMRO 1. 9, 765-770. Suzuki, S. and Naitoh, Y. {I9901EMIiO I. 9, 757-76,'r. T;unur;l, R.N. ct ill. 119901 1. Ccll Riol. 1 1 1 , 159.7-1604. Kniiii, S. ct nl. (19H9l EMRO I. 8, 67,Z-680. Hcmlcr, M.E. ct ai. Il9S91 1. Riol. Chcm. 264, 6529-1,5;i.5. " Garrod, D.R. ( 199.31 Curr. Opin. Ccll Riol. 5, 30-40. Dowling, I. ct nl. 119961 1. Ccll Riol. 1,Z4, 559-572. Nicsscn, C.M. et 31. 119941 Exp. Cell Res. 21 1, ,360-.367. " Lotz, M.M. et :I]. 119~)01Ccll Rcgul. 1, 249-157. I N Lee, E.C. et ;I!. 119921 1. Ccll Riol. 117, 671-678. Sonncnhcrg, A. et 31. (19901 1. Cell Sci. 96, 207-217. Sonncnherg, A. et ;I]. \I9911 I. Cell Riol. 113, 907-017. Shaw, L.M. et al. 119971 Ccll 9 I, 949-960. I.' Nntnli, P.G. ct a]. 119911 J. Cell Sci. 10,3, 1243-1247. l 5 Kennel, S.1. et al. (19c)211. Cell Sci. 101, 145-150. I" Vidal, F. ct al. (19951 Natiirc Gcnct. 10, 120-234. 'I Pulkkinen, L. ct ill. IIC)98al Am. 1. Hum. Gcnct. 6.3, 1.376-1,3K7. In I'i~lkkincn,L. ct i l l . (199Khl Am. I. I'athol. 151, 157-166. I" Murgi;~,C. et nl. ( I9081 EMRO 1. 17, .3930-.3951.
Family Intcgrin
Structure Molecular weights Amino acids I'olypcptidc
HX 053
SDS-PAGE rcduccd
100 kDa
700
Carbohydrate N-linked sites 0-linked sitcs
8
Gene location
> 3
Gene structure
rxvlps
Alternative forms T w o alternately spliced
P ; transcripts1 havc hccn dcscrihcd ((3;A and &RI.
Structure lntcgrin p; is highly homologous (56'X1) to the first integrin discovcrcd, P,, and forms the n,P; dimcrz-5.
(1,
partner
Ligands Vitroncctin? and pcnton hasc of adcnovirus"
Function Cell adhesion to, and nligrntion on, vitroncctin and other extracellular matrix s u b s t r a t ~ s ~ ~ ~ . T Iis ' ~ ccinta r c for a rcdc for cr,@; in vitronectin endocytosis'.". Recent evidcncc shows reciprocal involvcmcnt of n,Pi and a,@, in angiogencsis in cxpcrimcntal modcls, with n,P; being regulated by vascular factors such ns VEGF, whcrcns a,$, is modulntcd by bFGFP.
Distribution c-u,Pi is more widely spread in tissues than the related
rrv intcgrin, n,P, Expression of n,P; is regulated in angiogcncsis in tumours and at other sites of pathologicnl new vcsscl formation.
Disease association OMIM 147561
Knockout MG1:966 14
Amino acid sequence of human integrin p, MPRAPAPLYA CLLGLCALLP RLA
Database accession EMRL (;c~il<.ln Cu.~\\l'rc>t
X i 3001 PI SOSJ
References
-I
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%li;lng, 1. ct ;)I, ll9C)Sl l
Family Integrin
Structure Molecular weights Amino acids Polypcptidc
788 85 975
SDS-PAGE rcduccd
105 kDa v -,?
-
Carbohydrate N-linkcd sites 0-linked sites
9
Gene location
2q24-cl3 1
m-.e
-%
Gene structure Alternative forms Structure Intcgrin p, dimcrizcs with thc intcgrin
a, chain to form a,P,'. It has high degree of homology with other integrin P chains but has a unique 11 amino acid cytoplasmic extension, which 1s conscrvcd across speciesr.
Ligands hinds fihronectin'a, tcnascin5 and vitroncctinh. Recent findings have indicated that TGFp-associated latency-associntcd pcptidc (LAP)is a ligand for crVp,'.
a,@,
Function a,,@& is involved in the response of epithelium to inflammatory stimuli and injury, such as in asthma. Regulation of epithelial proliferation in vitroRand wound healing9.
Distribution Epithelial cells, including carcinomas. In vicw of thc phenotype of the knockout mouse (see helowl the distribution of a,@,, in airway epithelium has been extensively studicds.
Disease association OMIM 147558
Knockout MGI:966 15 T11cGene Knockout Fact rook", pp. 628-629. Mutant micc arc normal at birth, hut dcvclop alopccia aftcr minor trauma
ant! show ; ~ i r ~ v nhyper-rcsponsivcncss y and 'asthma'. Roth arc associated with an ahnormal intlammatc~rycell infiltration and suhsrql~cntfibrosis".
Amino acid sequence of human integrin p , MGIELLCLFF LFLGRNDS
Database accession EMIZL/ClcnH;lnk SwiwProt
M,3519X PIS364
References
lo
"
Shcpp;~rd,13. ct ;I]. ( 1 9901 I. Hiol. C h c ~ n76.5, . I 1502-1 1507. Husk, M. cr ;I]. (19921 I. Riol. Chcni. 267, 5790-5796. Clicn, 1. ct ;I!. 11996l Ccll Adlics. Comrnun. (1, LZ7-250. Wcinnckcr, A. ct al. I IC)931I. Riol. Chcm. 269, 69.10-6948. Wcinnckcr. A. ct ;I]. 119951 Am. 1. Rcspir. Ccll Mol. Riol. 12, 547-556. Huang, X, ct ;iI. (I99SI 1. Cell Sci. 1 11, 71X9-2.195. M i i n ~ c r 1.S. , ct ill. 119991 Cell 96, L319-tZ18. A,qrc=, M. ct ;I]. i19c)ll 1. Cell Riol. 177, 557-556. Rrc~iss,1.M. ct ;I]. jI00.5J J. Cell Sci. IOX, 141-151. Mak, T.W. il99S1 Tlic Gcnc Knockout FactsRook. Acatlcmic Prcss, Lonrlon. Hunng, X. c t a!. ( 1 9961 1. Cell Hiol. l,Z,3, 021 -91%.
Family Integrin
Structure Molecular weights Amino acids Polypeptide
798 86 903
SDS-PAGE reduced
110 kDa
-a
-
Carbohydrate N-linkcti sitcs 0-linked sites
8
Gene location
12q13.13
Gene structure
10 kb, 14 cxons
,f 0.-
*- *
J-
--a
Alternative forms aqCW9dm7
Structure A Pz-integrin-related p chainJ.2 that combines with the integrin a, chain (CD49dl t o form a,PTor with a, (CD103)to form a,P- (HML-1")(see entries for a, and a,). The cytoplasmic tail contains two potential tyrosine phosphorylation sitcs. P, contains 54 instead of the usual 56 cysteine residues found in most P subunit^'.^.
Ligands a,P, binds VCAM-1 (CD106l and thc CS1 domain of fibronectin, a,P, integrin4."; additionally, a$, binds M A ~ C A M - I ~a$, .~.
as does the recognizes
epithelial E-cadherin (cadherin-1)GJO.
Function a,p7 mediates lymphocyte adhesion to MAdCAM-1 on high venular endothelial cells and is involved in lymphocytc homing to intestinal Peyer's patchesh7. It is predicted that the interaction of a&, with Ecadherin betwccn lymphocytes and epithelium is likewise involved in intestinal targeting of lymphocyte subpopulationsRJf.
Distribution p7 was isolated from T lymphocytes. In its a$, form it is expressed by mucosal lymphocytesJ2, NK cells and eosinophilsl3. In contrast, a,P- is highly expressed by intraepithelial lymphocytesJ2 and only by a small rnlnority of peripheral blood lymphocytes. Endothelial cellslJ.
Disease association OMIM l473.+)
Knockout MGI:9hh I 6
Amino acid sequence of human integrin
P,
MVALPMVLVL LLVLSRGES
.
.
. - . -
-
Database accession EMRL/C;cnl<;lnk Swissl'rot
SS0.3.3.5 PZ60 1 0
References
!
.'
It
J4
Erlc, U.J. ct ill. (199111. Riol. C l ~ c m266, . 11009-1 1016. Y;~un,Q. ct al. (19901 Int. Imniunol. 2, 1097-1 108. Micklcm, K.1. ct al. (19911 Am. 1. Pnthol. 1,39,1197-1,301. Lohh, K.K.; ~ n dHemlcr, H.E. (19941 1. Clin. Invcst. 94, 1712-1 718. Kilgcr, C.. ct al. (I993l I. Hiol. C h c m , 270, ,3979-5984. Rcrlin, C. ct al. (199.31Ccll 74, I X.5-195. Rott, L.S. ct ill. (1996l 1. I m m i ~ n o l .156, c37Z7-,37.Z6. Ccpck, K.L. ct ill. (1994) N i ~ t u r c371, 190-19.3. Hiwins, J.M. ct 31. (19l)Kl 1. Ccll Riol. 140, 197-210. Karccla, P.ct al. (19961 I. Riol. Chcm. 171, 30909-.109l3. Ccpck, K.L. ct al. (l99,711. Itnmi~nol.150, .3459-,3470. h r k c r , C.M. ct al. (I992I Proc. Nntl Acad. Sci. USA X9, 1924-1918. Erlc, D.I. ct a]. 11994) 1. Immunol. l5,3, 517-528. l
Family Integrin
Structure Molecular weights Ammo aclds
769
Polypeptide
85631
SDS-PAGE reduced
95 kDa
** ,# /
Carbohydrate N-linked sites 0-linked sites
a, 'Y
7
-Y
A
Y
Gene location Gene structure Alternative forms avlpa
Structure Integrin P, dimerizes with the integrin a, chain to form a,@,. The PRchain
sequence is divergent from other P chains' especially in the cytoplasmic tail, which does not interact with cytoskeletonz.
Ligands a$, binds to vitronectin in addition to fibronectin, laminin and Type IV
~ollagen~.~.
Function There is increasing evidence for a role for avP,in neural f u n c t i ~ n ~ . ~ .
Distribution Placenta, kidney, brain, ovary, uterus; transformed cell lines. Early oligodendrocyte precursors express avP, at high levels, reducing during differentiation"; it is also expressed in synapses and glia of selected areas of the adult brains.
Disease association OMIM
Knockout MGI: 1338035
604160
Amino acid sequence of human integrin p, MCGSALAFFT RAFVCLQNDR RGPASFLWM WVFSLVLGLG QG-
.. .,
..
.
.
.
,
-
_
'5
'
7
.
-
.,
, , l
-
_
>
,
.
Database accewian EMRL GenRank Sw~\\Prot
M7.3780 P260 1 2
References Moyle, M. ct al. (199117. Riol. Chcm. 266, 19650-19658. Nishimum, S.L. ct al. (199411. Riol. Chern. 269, 28708-2871 5. Venstrom, K. and Rcichardt, L. I, 19951 Mol. Riol. Ccll 6, 41 9-43 1. Milner, R. et al. [I9971Clia 21, ,350-.360. Nishimur;i, S.L. ct al. 119981 Rrnin Rcs. 791, 171-182.
'
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Selectins
This Page Intentionally Left Blank
CD62E, endothelial leucocyte adhesion molecule-1, ELAM-1
Family Sclcctin (Ca' -dependent, C-type lcctinl
Structure Molecular weights Amino acids Polypeptide
h 10
SDS-PAGE rcduccd
97, 107, 1 15 kDa
66 655
Carbohydrate N-linked sites 0-linked sitcs
11
Gene location
I ~13.~-~125
Gene structure
approximately 13 kh, 14 cxons
Alternative Forms
COOH
Structure The extraccllul;ir domain of E-sclectin consists of an N-terminal C-type lcctin domain, nn EGF-likc domain and six complcmcnt control protein domains. The crystal stnicture of the C-type lcctin and EGF domain has been solvedr. Activation of endothelial cells leads to association of Esclectin with the actin cytoskelcton2.
Ligands E-sclcctin displays calcium-dcpcndcnt, low-affinity hinding to oligosaccharidc scqucnccs related to sinlylatcd Lcwis x (sLcX,CDlSsl, particularly 3-sialyl di-Ley, via the C-type lcctin domainJ-7,4. Well cstahlished lig;lnds are ESL-I on mvcloid cells, PSCL-1 on ncutrophils, monocytes and most lymphocytes, and leucocvte L - ~ c l e c t i n ~ ~ ~ ~ ~ .
Function E-sclcctin mediates the rolling and tethering of Icucocytcs on activated cntlothclial surfaces.
Distribution E-sclcctin is m:~inly cxprcsscd on activated endothelial cells and on cndothclium in chronic intlammatory lesions of thc skin and synovium7. In
--
-selectin
-
-
-
Family -
-
-
addition, E-selectin is detected on non-inflamed endothclia in the skin, placenta and hone marrow. Soluhle E-selcctin forms arc found in plnsmaR.
Disease association OMIM 131210 In addition to its role in leucocytc-cndothclial interactions, E-sclcctin may play n role in tumour metastasis since carcinoma cells have heen shown to express E-sclcctin ligands and hind activated cndothclium9. Patients with LAD-2 syndrome, who lack the sialyl Lewis x component on their selectins, suffer pyogcnic infections (see Knockout\.
Knockout MGI:98278 Tllc Gcrlc Knockout FoctsRnokJ0,p. 935. E-sclcctin-deficient mice display n o gross abnormalities or overt inflammatory or immunological deficiencies despite circulating lcucocytcs showing a decreased adhesion to activatcd cndotheliau-1" However, mice dcficicnt in hoth E- and P-selcctin have scverc defects in leucocyte recruitment into inflan~matory sites and are highly susceptible to opportunistic bacturial infcctic~ns,suggesting overlapping rolcs for thcsc two family mcmhcrs.
Amino acid sequence of human E-selectin
Database accession EMRLIGcnRank SwissProt
M24736 P16581
References Graves, R.J. et al. (1994) Nature 367, 532-538. Yoshida, M. ct al. (19961J. Ccll Riol. 133, 445-455. Varki, A. ct al., (1994)Proc. Natl Acad. Sci. USA 91, 7390-7397. Patel, T.P. ct 31. (1994)Biochemistry 33, 14815-14824. McEver, R.P. et 81. (199.5)J. Riol. Chem. 270, 11025-1 1028. V e s t w e h e r , D. and Blanks, I.E. (1999)Physiol. Rev. 79, 181-213. ' Tcddcr, T.F. ct al. (1995)FASER J. 9, 866-873. "caring, A.T.H. and Ncwman, W. (1993)Immunol. Today 14,506-512.
Selectin Family
"
"' " j3
Aruffo, A , c't al. ( I 9 9 l l Proc. Natl Acat!. Sci. USA 81, 11L)1-1196. Mnk, T.W. (1'IL)XI Thc Gcnc Knockout FactsRook. Acndcmic Prcss, L(lnr1on. Frcncttc, P.S. c t al. (19961Ccll X J , 5hx3-.i7J. Hcvilacqu;l, M.P. c t ;]I. (19S91Scicncc 13,3, 1160-1 16.5. Lill~otv,M.A. ct 31. (19941Imrntlnity 1, 709-720.
--
--
CD62L, LECAM-I, MEL-14, LAM-1
Family Selectin (Ca"-dependent, C-type lectin)
Structure Molecular weights Amino acids Polypcptidc
3 72 42 187
SDS-PAGE reduced
74 kDa, 90-100 kDa
Carbohydrate N-linked sites 0-linked sites
7 0
Gene location
1 q23-q25
Gene structure
>30 kh, at least 10 exons
Alternative forms COOH
Structure The extracellular domain consists of an N-terminal lectin C-type domain, an EGF-like domain, two complement control protein domains and a 15 amino acid spacer containing a proteolytic clcavagc site to generate a solublc L-selectin'. Thc cytoplasmic domain mediates association with a complex of cytoskeletal proteins including a-actinin2 and calmodulin'.
Ligands L-selectin hinds with low affinity to oligosaccharide sequences related to sialylatcd Lewis x (sLcv,C D l i s l via the C-type lcctin domain: which are presented on the maior ligands CD34, GlyCAM- 1, MAdCAM- 1 and PSGLIn addition, L-selectin hinds PLCP19 unrelated anionic carbohydrates such as heparan sulphated.
Function
(
L-sclectin mcdiatcs the rolling and tethering of lcucocytcs on cndothclial surfaces, which is a prerequisite for leucocyte adhesion and extravasation5. In particular, L-sclcctin mcdiatcs homing of naivc lymphocytcs via high endothelial venules to peripheral lymph nodes and Peyer's patches. L-selectin also plays a role in rccniitincnt of Itucocytes to inflammatory sites"In. In vitro, association of L-selectin with GlyCAM-1 can activate P, integrins".
Distribution L-sclcctin is cxprcscsrl hv most hac~n;~topoictic cclls a t some st;~gcof ~liffcrcntiation'.In tlicsc cclls the localization of L-sclcctin of the tips ot the inicrovilli is rctluircd tor optirn;~l :~tlhcsion'~.Activation of Icucocytcs c ; ~ ~ ~shcrldin!: scs of L.sclcctini.
Disease association OMIM 15,3140
Knockout MGI:OX779 Thr' C:runtbKnockout F r ~ r . cRor~k", t p. 9.W.
L-sclcctin-deficient micc arc vinhlc ant1 fcrtile, Imt cxhihit n o Icucocytu migration across thc high cnrlc~thclial vcni~lcs of peripheral lymph notics ;~ncl ;I rctl~~ccilIcucocvtc emigration into tissues ;it sitcs of in f l ; ~ ~ i i i n ; ~ t i o n I ~ - ~ ~ ~ .
Amino acid sequence of human L-selectin MIFPWKCQST QRDLWNIPKL WGWTMLCC
Database accession EMI3LjGcnllank Swi<\Prot
M7S2SO PlJlSl
Refcr~ncc~ Chcn, A. ct 31. (1903)J. Exp. Mcd. 182, ,319-5.30. P;iv;~lko,F.M. ct i l l . 1 199.51 1. Cell Biol. 129, I 1.55-1 164. K:~hn,1. ct al. 1I99SlCcll 92, X09-SIX. .' V;lrki, A. (10t)11 I'roc. Natl Acarl. Sci. USA '11, 7.300-7.307. Tcildcr, T.F. ct 31. ( I 9951 FASEIJ J. 9, S66-X7.7. " Lasky, L.A. ( 199il Annu. Rcv. IJic~chcm.64, 1 1.7-1.39. II(~scn, S.D. ;~ncl13crtozz1,C.R. 119961 Curr. Rial. 6, 261-264. M'alchcck, R . c t ;I]. [ 19961 1. Clin. Invcst. 98, 1081-1087. " Snssctti, C. ct al. [199S\ J. Exp. Mcd. 1S7, 1965-1975. lo Hcmmcrich, S. ; ~ n d Roscn, S.U. 119931 Iliochcmistry .X3, 48.30-48.33. " Hwang, S.T. ct al., 119961 J. Exp. Mcd. 1H1, 1,73;h3-l,34X. von Antlrinn, U.1-I, ct al. l199.51 Cell X2, 989-999. iT Mak, T.W. ( 1 9 9 s ) T h c Gcnc Knockout F;~ctsKook. Ac;~dcrnic I'rcss, Lontlon. Arhoncs. M.L. ct ;II. ( 1994) Immunity I , 147-260. Xu, 1. ct nl. (19961 J. E x p Mcd. IK3, SSc)-S9S. C ; ~ t ; ~ l i nM.D. ; ~ , ct al. (19961 J. Exp. Mctl. 184, 2.741-2L751 1
2
-
-
-
--
--
CD62P, GMP-140, PADGEM --
Family Selectin (Ca?+-depcndcnt,C-type lectin)
Structure Molecular weights Amino acids Polypeptide
8,30 90 844
SDS-PAGE reduced
140 kDa
Carbohydrate N-linked sites 0-linked sites
12
Gene location
1q21-c124
Gene structure
>.SO kh, 17 exons
Alternative forms Altcrnativc splicing rcsults in varlants lacking cxon 11, which cncodcs thc seventh complement control protein domain, or lacking cxon 14, which rcsults in a soluhlc P-sclcctin form',2.
Structure The cxtraccllular domain consists of an N-terminal C-type lectin domain, an EGF-likc domain and ninc complemcnt control protein domains. The cytoplasmic domain is phosphorylated on Ser, Thr, Tyr and His residues following platelet activation'. Cys807 in the cytoplasmic domain is acylated with palmitic and stcaric acid.
Ligands P-sclcctin binds with low affinity to oligosaccharidc scqucnccs rclatcd to sialylated Lewis x (sLev,CD15s) via the C-type lectin domaind, which are presented on the major P-sclcctin ligands, PSGL-IQnd CD24n.
Function 1'-sclcctin mcdi;itcs Icucocvtc .ind j1l;itclct rollin,q o n ;~ctiv;~tctl cndothcliiim. Platc,lct 1'-sclcctin promotes Icucocytc ;~cciuiiul;~tionin tliroml>i'.
Distribution P-selcctin is toiind on mc,qak;il~ocytcs,activ;itctl pl;~tclcts; ~ n d;ict~vatcd cnilothclial cells. P-sclcctin is storcrl in secretory gr;~nulcs(Wcil,cl-P;~l;i~lc h{~dicsl and is rapidly transportccl t o t h e pl;~siii;i nicrnl>rauc upon ;ictic.ation2. R;lpid intcrn;ilization iron1 t h c pl:ism;~ n ~ e m h r ; ~ nattcnuntcs c t h c tr;insicnt cxprcssion.
Disease association OMlM 17.7hll)
Constittltivc P-sclcctin cxprcssion in intl;lnimation Inay contrihutc t o tissiic tlcstruction, ntlicro~cncsisand tliromhosis. Patients with t h e lifclon!: hlccding ilisortlcr, ,
Knockout MC1:OHZSO The C;rnc I(r~oc.I;out F(1c.l \liool<".17. 941. Micc dcficicnt in P-sclcctin dcvclop norninlly ; ~ n t l;lrc fertile, hut show rcduccrl I c u c o c ~ t r rt~lling and dcl;~ycd rccruitnicnt i n t o i n f l a ~ n m a t o r y sitcstN. Mice dcficicnt in hot11 P- ;inti E-sclcctin h ; ~ v cm i ~ c hmore scvcrc clcfccts in Icucocyte cxtr;ivas;ition ;ind a high susccptihility t o opportunistic infcctic)ns" siigycsting ;in ovcrl;ippit~crole for tlicsc fn~nily111cli1hcrs. Micc dcficicnt in hot11 P- and L-sclcctin arc viahlc and fcrtilc w i t h a phcnotypc si1nil;ir to that ohscrvcd in t h e P-sclcctin - / - micct'. Micc dcficicnt in 311 thrcu sclcctins ;ire viahlc and fcrtilc, hilt with scvcrc lcucocytr~sis;~nrlhigh s u s c c p t i h i l i t ~to opportiuiistic infections, si~nil;irt o that ohscrvcd in t h e Psclcctin/E-sclcctin - !- niicct2.
Amino acid sequence of human P-selectin MANCQIAILY Q R F Q R W F G I SQLLCFSALI SELTNQKEVA A
. .
Selectin Family
Database accession EMRL/GenRank SwissProt
M25322 P16109
References johnston, G.I. ct al. (19901J. Riol. Chcm. 265, 21381-21385. McEvcr, R.P. ct al. (1995)J. Riol. Chcm. 270, 11025-1 1028. Crovcllo, C.S. ct al. (1995)Ccll 82, 279-286. Varki, A. (1994) Proc. Natl Acad. Sci. USA 91, 7390-7397. Roscn, S.D. and Rcrtozzi, C.R. (19961Curr. Riol. 6, 261-264. Sammar, M. et al. (1994)Int. Immunol. 6, 1027-1036. ' Tcddcr, T.F. ct 81. (19951FASER 1. 9, 866-873. Mazurov, A.V. et al. (1996)Eur. 1. Haematol. 57, 3 8 4 1 . Mak, T.W. (1998) The Gene Knockout FactsBook. Acadcmic Prcss, London. 1" Mayadas, T.N. ct al. (1993)Ccll74, 541-554. " Frenctte, P.S. et al. (19961Ccll 84, 563-574. Robinson, S.D. ct al. (1999)Proc. Natl Acad. Sci. USA 96, 11452-1 1457.
Syndecans
This Page Intentionally Left Blank
Family Svndecan
Structure Molecular weights Amino acids Polypeptide
310 3 2 476
SDS-PAGE reduced
85-95 kDa
Carbohydrate N-linkcd sitcs 0-linked sites GAG
1 prohahly 5
Gene location
2p24.1
Gene structure
5 exons
++
+ GAG
Alternative forms Structure
COOH
Syndecan-1, like other memhers of the syndecan family, is a type I transmembrane protein with an extracellular domain, which has consensus sequences for the attachment of glycosaminoglycans (GAGsl and 0-linked sugars. This extraccllular domain can hc shcd hv memhrane proximal proteolytic cleavage. The transmemhrane and short cytoplasmic domains are highly conserved hetween the four family memhers. The cytoplasmic domains of all syndecan family memhers can be divided into three regions: a membrane proximal constant (C11region, a variable (V)region, and a carhoxyltcrminal constmt (C21 region. The C2 region has a consensus sequence for hinding proteins with class I1 PDZ domains and such an association would rcsult in the formation of an adhesive/sipalling complcx'4. In syndccan-1 the GAG attachment sites occur in two clusters: the three N-tcrminal sitcs arc usually modified by hcparnn sulphatc, while the membrane proximal sites are usually modified hv chondroitin sulphatc". Thc differing molecular weights of syndccan-1 from different tissues suggests that GAG modifications can be cell-type specificn. Functional assays indicate that syndecan-1 can associate with the actin cytoskeleton', and an association of syndecan-1 with two such proteins, CASK and svntenin, has been d e m ~ n s t r a t e d ~ , ~ .
Ligands
U
Syndecans can hind a wide variety of extracellular components via their heparan sulphatc side chains. These include growth factors, extracellular matrix components Ifihronectin, laminin, collagens), other adhesion receptors (L-selectin, NCAM, CD.111 and enzymes2.
Function Svndccans plav an important role in n~odulatingthe biological activity of heparin binding growth factors. In addition, they can inctliatc cell-ccll and cell-matrix interactions. Binding is strengthened either hv cliistcring of the syndccnns ant1 other ailhcsion receptors, such as intcgrins, by stabilizing other rcccptor-ligand interactions and/or thc inductic~n of signal trnnsduction cascades2.J. In vitro sturlics have dcmonstratcd that loss of svndccnn-1 cxprcssion results in the I(~ssof a polarized cpithclial phenotype ; ~ n d;~cquisitionof anchorage-indcpcndcnt growthJn.
Distribution Syndcc;ln-l is prcdomin:intly cxprcsscd on the hnsolntcral s ~ ~ r f a of c cepithelial cclls. In addition, cxprcssion is found on vnsciilar smooth musclc cclls, cnil~~thclium, neural cclls, prc-R cclls, immatlrrc R cclls and plasma ccllsf.
Disease association OMIM 186355 Syndccan-l cxprcssion is rcclucctl in many epithelial t ~ ~ i n o u r;lnd s the aillount of loss correlates with tumour progressionf1.
Knockout MGI: 1,349I62
Amino acid sequence of human syndecan-1 MRRAALWLWL CALALS 1 '
. .. . .
j
I
..
1.81
I
]I
' I 1 .
">,
Database accession EMBL/C;cnRan k 105,392 SwissProt
P 1 8827
References Rcrnficld, M. ct al. 119921 Annu. Rev. Cell Riol. H, .765-.79,3. T a r c v , D.J. (1997) Riochcm. 1. 327, 1-16. Rapracger, A.C. and O t t , V.L. (1998I Curr. Opin. Cell Riol. 10, 620-638. Woods, A. and Couchman, 1.R. ( 19981Trcntls Ccl I Riol. 8, 189- 192. Kokcnvcsi, R. and Rcrnficld, M. (1994)1. Riol. Chcm. 269, 12304-1L309. Knto, M. ct al. (19941 1. Riol. Chcm. 269, 18881-18890. ' Carey, D.J. et al. 119941 1. Cell Riol. 124, 161-170. Grootjans, 1.1. ct al. (19971 Proc. Natl Acnd. Sci. USA 94, 1,3(,X,3-1.368X. Cohcn, A.R. et al. (1998)I. Cell Riol. 143, 129-l,38. Kato, M. et al. (19951 Mol. Riol. Cell 6, 559-576. Inki, P. and ];ilkanen, M. 119961 Ann. Mcd. 28, 6.3-67.
J J
I
Fihmglvcan, heparan sulphate protenglycan, HSPG
Family Synilccan
Structure Molecular weights A m ~ n oa c ~ d s Polypcptldc
10 1 11 171
SDS-PAGE reduced
36 kDa
& GAG
Carbohydrate N-l~nkcdsitcs 0-linked sites GAG
0 prohahly +
Gene location
Sq??-Kq?4
Gene structure
.icxons
-3 COOH
Alternative forms Structure Syntlccan-2, like othcr mcmhcrs of the syndtlcan family, is a type I transmcrnhranc protein with an cxtrnccllular domain, which has conscnsus scqucnccs for thc attach~ncnt of GAGS and 0-linkcd sugars. This cxtmccllular domain can hc shed hv mcmhranc proximal protcolytic clcavagc. Thc trans~ncmhrancand short cytoplas~nicdomains arc highly conserved llctwccn thc fnur family mcmhcrs. Thc cytnplasmic dnmains of all svndccan family mcmhcrs can hc dividcii into thrcc r c ~ i n n s : a mcmhranc proximal constant (Cll rcgion, a variahlc (V)region, and a carhoxyl-tcrminal constant (C11 rcgion. The C2 rcgion has a conscnsus scqucncc for hinding proteins with class 11 PDZ domains anti such an association ~ v o ~ i l result d in the formation of an atlhcsivc/signallinfi~lling complext4. In svndccan-2 the hcparnn sulphatc sttachmcnt sitcs arc cltistcrcd at thc N-terminus, Within the cytoplastnic domain, an assnciaticln of syndccan-2 with the PDZ domain containing proteins CASK and synteninG' and with czrinH has hccn dcmonstratcd. In additinn, syndccan-2 cnntsins a unique scrinc phosphorylation site, ivhich is a targct for protcin kinasc Cv.
Ligands Syndccans can hind a widc variety of cxtraccllular cnmponcnts via their hcparan sulphatc sidc chains. Thcsc includc growth factors, t.xtraccllular matrix components ifihroncctin, Iaminin, colla~cnsl, othcr adhcsion rcccptors [L-sclcctin, NCAM, CD.3 I 1 and cnzymcs2.
--
--
--
Syndeenn Family
Function Syndccans play an important role in modulating the hiological activity of heparin binding growth factors. In addition, they can mctii;~tccell-cell and cell-matrix interactions. Rintling is strcngthcncti either hy clustering of the syndccans and other adhcsicin rcccptcirs, such as intcgrins, hy stabilizing other receptor-lignnd intcriictions and/or the induction of signal transduction c;iscades',J. Syndccan-2 plays a critical role in the development of dcndritic spines whose morphological changes provide a structural hasis for learning and m c m o r ~ ~ ~ .
Distribution In adults, syndccan-2 is thc maior svndccan in fihrohlasts. During development svntlccan-2 is dctcctcd predominantly on mcscnchymal cells that represent the hard and conncctivc tissuc precursor cells, such as those in prcchondrogcnic ;ind prcostcogcnic mcscnchvmal contlcnsation areas". Syndccnn-7 is also intli~cctlon primnry human ii~onocytcsin response to diffcrcntiaticlnir~ctivation".
Disease association OMIM I47460
Knockout MGI: 1,749165
Amino acid sequence of human syndecan-2 MRRAWILLTL GLVACVSA .
I
'
1..
1
"
.
-
jf-I
Data base accession EMRL/GcnRank SwissProt
JO4611 P,3474 1
References Rernfcld, M. ct al. (1992)Annu. Rev. Ccll Iliol. 8 , L365-,19.1. Carey, D.T. (19971 Riochem, 7. ,717,1-16. .' Rapraugcr, A.C. snd Ott, V.L. (19981Curr. Opin. Ccll Riol. 10, (120-628. Woods, A. and Couchman, J.R. 119981Trends Cell Riol. 8, 189-192. 5 Grootians, 1.1. ct 31. (19971 Proc. Natl Acatl. Sci. USA 94, I,?(ltl,?-l,Zh8tl. " Cohcn, A.R. ct al. (1998)7. Cell Riol. 142, 129-1.38. ' Hsuch, Y.P.ct al. 11998) J. Ccll Rinl. 142, 1<39-151. Cranes, F. ct al. (20001 J. Ccll Sci. 11.3, 1267-1276. " Itano, N.K. ct al. (19961Riochcm. 1. 315, 925-9.30. I" Ethcll, I, and Ynmaguchi, Y. (1999)J. Cell Riol. 144, 575-586. Davit!, G. ct nl. (199,7)Dcvclopincnt 119, 841-854. l2Claspcr, S. (19991 J. Riol. Chctn. 774, 241 13-24123. 2
,
,
Family Syndecan
Structure Molecular weights Amino acids Polypeptide
442 45919
SDS-PAGE reduced
100-1 20 kDa
Carbohydrate N-linked sites 0-linked sites GAG
0 probably
Gene location
Chromosome 1
Gene structure
5 cxons
++
A
Alternative forms
COOH
Structure Syndecan--3, like other mcmhcrs of the syndccan family, is a type I transmemhrane protein with an extracellular domain, which has consensus sequences for the attachment of GAGS and 0-linked sugars. This extracellular domain can he shed by membrane proximal protcolytic cleavage. The transmemhrane and short cytoplasmic domains arc highly conserved hetween the four family members. The cytoplasmic domains of a11 syndccan family members can hc divided into three regions: a membrane proximal constant (C11 region, a variahle ( V ) region, and a carhoxvl-terminal constant (C21 region. The C 2 region has a consensus sequence for binding proteins with class I1 PDZ domains and such an association would result in the formation of an atlhesivc/signalling compl~x'~.
Ligands Svndccans can bind a wide varlcty of extracellular components via thcir hcparan sulphate sidc chains. Thesc include growth factors, cutraccllular matrix components (fibroncctin, laminin, collagcns), other adhesion receptors (L-sclectin, NCAM, CD.11) and enzymesz.
Syndecan Family -
--
- --
- -
-
Function Syndecans play an important rolc in modulating thc biological activity of heparin binding growth factors. In addition, they can mediate cell-cell and cell-matrix interactions. Binding is strengthened either by clustering of the syndecans and other adhesion receptors, such as integrins, hy stabilizing other receptor-ligand interactions and/or the induction of signal transduction cascade^^.^. A variety of studies have indicate that syndecan-3 is involved in aspects of limh morphogenesis, skeletal dcvelopmcnt and skclctal musclc diffcrcntiation"'.
Distribution In adults, syndecan-3 is the major syndecan in neuronal cells. During dcvclopmcnt, high lcvcls of syndecan-3 are found in neonataI brain, heart and Schwann cclls. Expression in thc hrain riscs rapidly at birth, pcaks on postnatal day 7 and thcn dcclincs in the adult nervous systcmz. Syndccan-3 is also expressed transiently during embryonic limh development8 and by proliferating immature chondrocytes.
Disease association OMIM 186357
Knockout Amino acid sequence of rat syndecan-3 1 MKPGPPRRGT AQGQRVDTAT HGPGARGLLL PPLLLLLLAG RAAGAOR'L'P,FJ T?:F -? ?'.'DL!? ,.... v m .,:F! . , T T rrj :;'.L.'..:I*:':IPI E.!I.PTT:IOP':
6 1 ~ ~ ~ - . . l , ! , r , , - ~ 7:.,. . . 1l 8 A -, ,, ~ , f , ~ , r F ~ [-.,-. r ~ s :..'I. .:: .~.:..-.(-. :
1: 1 1RI 741 3 (? 1
~ T ~ " . ' F F I , : , , - T:iy;'rrs.Tr" ::;'TF'.T? 7' PA'?A?>TTAI'.C T?AliPPAT>.T T;?DIPTTr:IO I?TEk?T?Fr.' ?IT?t,"SFPFAL P??'.'TTQcPr ~ ~ f ~ ? ~ p r , ~i:r;p:;i:!>~l::~ - p ? ; 01,rr7'-r 3 . 1 1 . 4
.
' I '
q
EF?TI\UAT:: ~ ~ T : c T ~ , > , T.~T,~;P.,,T~,:,,.,.TI:, T-LLP[,PLTTA ATAKA'rTrA PF!'I":'T'-'T'?12 '.'AI;PSTLPL,G ?TAPCPTT:.?I @T!'T?rSJ,I,T ?:P:.".'i'.'TG.?\,I. :&,KPSP!'T,CT:, FPCAPPCl,Cl,
Database accession EMRL/GenRank SwissProt
US2825 P33671
References
'
Rernfield, M. et al. (1992) Annu. Rev. Cell Riol. 8, 365393. Carcy, D.J. et al. (1997)J. Riol. Chem. 272,2873-2879. Rapraeger, A.C. and Ott, V.L. (19981Curr. Opin. Cell Riol. 10,620-628. Woods, A. and Couchman, J.R. (1998)Trends Cell Riol. 8, 189-192. Carey, D.J. (1997)Riochem. J. 327, 1-16. Kosher, R.A. (1998)Microsc. Res. Techn. 43, 123-130. Fuentcalba, L. et al. (1999)J. Biol. Chcm. 274,37876-37884. Gould, S.E. et al. (19951Dev. Riol. 168, 438-451.
Family Syndccnn
Structure Molecular weights Amino acids Pol ypcptidc
19% 21 641
SDS-PAGE rcduccrl:
.3.'; kDa
Carbohydrate N-linkctl sites 0-linked sites GAT,
0 prohahly 4
Gene location
ZOq 12-2Orl 1<3
Gene structure
5 cxons
COOH
Alternative forms Stn~cture Syndccan-4, likc other mcmhcrs of the syndccan faillily, is A type I tr;msmcmhranc protcin with ;In cxtraccllular dnmilin, which has consensus sctlllcnccs for the attachment ot' GAGS and O-linked sugars. This cxtracclluli~r domain can hc shed hv niemhr;inc proximal protcnlytic clcava,qc. T h c transmcrnhranu and short cytclplasmic domains arc highly conscrvcd hctwccn thc four family mcinhcrs. Thc cytoplasmic domains of all svndccan family lncmhcrs can hc ditfidcd into thrcu rugions: a ~ n c m h r a n c proximul constant (C11region, a variable (VI region, and a carhnxvl-terminal . h e C2 rtgion hns n consensus scclucncc for binding conwlnt [C2) r c ~ i n n T prt~tcinsw i t h C I ~ 11 S PDZ rlomains and such an association would rcsult in the forniiition of ;In ntlhcsivc/signnlling ~ o m p l c x ' ~ . In synr1cc;m-4 the hcpnran sulphatc uttacli~ncntsitcs arc clustcrcd at thc N-terminus. Unlikc t l ~ cothcr t ; ~ ~ n i l mcmhcrs, y the V region in the syndccan-4 cvtc~plasniic domain can hind activated protcin kinasu Ca [PKCtul : ~ n dPIPJC.", ;lnd, uni~suallv,this hinriing is via the PKCn catalytic dom:~in'.Thc C 2 region c ~ ftlic cvtoplasmic rloniain can hind thc PDZcont:~ininsprotcin, syntcninx.".
Ligands
.
Syndccans can hind n wide vuricty of cxtr:iccllular coi1iponcnts via their hcparan sulphatc side chains. Thcsc include growth fnctors, t.xtracellular m;itrix components (fihmncctin, laminin, collancnsl, othcr adhcsion rcccptorc (L-sclcctin, NCAM, C D \ l l \ and enzymes?.
Function Syndccans play an important rt~luin niorlulatin~thc hiological activity of hcpiarin binding g r t ~ w t hfactors. I11 addition, thcy can mccli;~tccell-ccll and cell-matrix iiltcractions. Binding is strcngthcncli cithcr hy clustering of thc
-
-
---
--
Syndecan Family
syntiecans and othcr adhcsion receptors, such as integrins, hy stabilizing othcr receptor-ligand interactions and/or thc induction of signal transduction cascade~'.J.~. A numhcr of studics havc indicated that syndccan-4 may havc a unique function among the syndecan family in regulating focal adhcsion formation and hence intcgrin-hascd ccll adhcsion p r o c c ~ s c s ~However, ~~. in recent studies it has llccn dcmonstratcil that syndccan-4 -1- fihrohlasts derived from nockout micc [see helowl can form focal adhesions with terminating actin fihrcs whcn platcd on fihronectin. Dcfccts in focal adhcsion formation were only detected whcn the heparin-binding domain of fihroncctin was added in a soluhlc form'".
Distribution Syndccan-4 is usually present in lower amounts than the other syndccans hut it is more widespread in its distribution, hcing found on many epithelial and fihrohlastic cclls. Syndccan-4 is uniquc among the family memhers as it is localized to focal adhesionsr1 and this localization is dependent on PKC activationf2.
Disease association OMIM 60001 7
Knockout MCI: 1349 I64 No gross abnormalities arc dctcctcd in syndccan-4 syndecan-4 -1- fihrohlasts platcd onto fihroncctinl".
-/-
micc or in
Amino acid sequence of human syndecan-4 MAPARLPALL L L W G G V A 3
,
-r
- ..-
-.,L
~1
b.
r
t
-
L
1'
,[ 1 - ---
1 1 1 1 "
I
r - L
i.
1 1 I
I I
1
1
I'
-r
I"1i171
' I
Data base accession EMBL/C;cnBank SwissProt
X670 16 P.3 14.3 1
References
ln l1 l2
Rcrnficld, M. ct al. (1992)Annu. Rev. Cell Riol. 8, 365-,19,1. Carey, D.J. (1997)Riochem. J. 327, 1-16. Rapracgcr, A.C. and Ott, V.L. (1998)Curr. Opin. Cell Riol. 10, 620-628. Woods, A. and Couchman, 1.R. (19981Trends Cell Riol. 8, 189-192. Oh, E.S. ct al. (1998) 1. R~ol.Chcm. 273, 10624-10629. Lee, D. et al. (1998)1. Riol. Chcm. 27,3, 13022-13029. Oh, E.S. et al. (1997)1. Riol. Chcm. 272, 81.3.3-81%36. Crootians, 1.1. ct al. (1997)Proc. Natl Acarl. Sci. USA 94, 13683-1,3688. Couchman, I.R. and Woods, A. (1999)J. Cell Sci. 1 12, 3415-%3420. Ishiguro, K. ct al. (2000)1. Riol. Chcm. 275, 5249-5252. Woods, A. and Couchman, 1.R. (1994)Mol. Riol. Cell 5, 18<3-192. Raciu, P.C.and Goctlnck, P.F. (1995)Mol. Riol. Cell 6, 150,Z-1513.
Other Molecules
This Page Intentionally Left Blank
--
m
>
e
s
i
o
-
moIecuIe oil Jia, Na.,K.-ATPase 112 polypeptide'
n
--
-
-
Family ATPasc
Structure Molecular weights Amino acids Polypeptide
33 344
SDS-PAGE reduced
45-50 kDa
190
coo"\ IIIII IIIII
Carbohydrate N-11nkcd sites 0-linked sites
7
Gene location
17p (human), chromosome 11 (mouscl
Gene structure
7 kh
NH7
Alternative forms Structure AMOG is a type 2 integral membrane glycoprotein of glial cells with homology to the non-catalytic P, subunit of Na+,K'-ATPase associated part of a multigene enzyme with thc cr subunit in the active family with t~ssuc-specificfunctions.
Ligands Unknown.
Function Non-catalytic component of plasma memhranc ATP-dcpendcnt N a ' , K' exchanger. Involved in calcium-independent cell adhcsion bctwccn ncurons and glia, and migration of neurons and a s t r o c ~ t e s ~ ~ ~ .
Distribution Dcvclopmcntally rcpilatcd expression6. Central nervous system neurons and astrocytes'.
Disease association OMIM 1823,11
Knockout Motor incoordination and paralysis with death hy 18 days post-nataln.
Amino acid sequence of mouse AMOG
Database accession EMRL/GcnRank SwissProt
XI6645 [ ~ n t ~ ~ ~ s c ) PI423 1 [~ntntsc)
References Pagliusi, S. ct al. (1989)J. Ncurnsci. Rcs. 22, 113-1 19. Martin-Vasall(~,P. u t al. (1989)J. Riol. Chcm. 164, 46134618. Glnnr, S.M.u t al. (1990)1. Ccll Riol. 110, 165-174. -IAntonicek, H. ct al. (1987)1. Ccll Riol. 104, 1587-1595. Mullcr-Husmann, C . ct al. ( 1 Y9,31 J. R i d . Chem. 268,26260-26267. "ccuona, E. ct al. (1996)Brain Rcs. RulI. 40, 167-174. Pagliusi, S.R. ct al. 11990) Eur. J. Ncurosci. 2, 471-580. Magyar, J.P. ct al. (1994)J. Cell Riol. 127, K15-845. 2
Family Sc:~vcngcrreceptor cystcinc-rich xroup R
Structure Molecular weights Amino acids Polypcptitlc SDS-PAGE rctluccd
Carbohydrate N-linked s ~ t c s 0-linked sitcs
Gene location
I lql.3
Gene structure
>
25 kh, - 1.3 cxons
COOH
Alternative forms ~ h 1;1rfic c cytoplasmic domain can hc alternatively spliccdr-'.
Structure Tlic extensivelv glvco.;yl;~tcd CL>6 cxtraccllular cionlain contains three sc;Ivenger receptor cystcine-rich domains ;lnd nn (1-glvcosylatcd mcmhranc proxim;~lstalk. T h e third scilvcngcr receptor domnin contains rhc ALCAM (CDl66l hinrling T h e Inrsc cytopl;ismic domain cclntains multiple SH1 and SH.3 hindins sitcs.
Ligands CD(; is the countc,r-receptor for ALCAM ICDI 661'.
Function Associiltion ot Cl>h lvith ALCAM [CDI66) cxprcqscd in the thymus may play n rolc in T ccll maturation ;ind regulation of T ccll nctivation". In addition, the C D 6 cvtoplnsmic domain hccomcs phosphorylatcd following T ccll receptor s t i m u l a t ~ o ns, u ~ q c c t i n ga signalling rolc for CDhV.
Distribution C D 6 is cxprcsscd on tlie tnnioritv o i pcriphcral hlood T cells ant1 n s ~ l h s e ot t H cells. Exprccsiotl on i m m ; ~ t u r cthymocytcs is low hut increfiscs with m ; ~ t u r ; ~ t i oCD6 n . cxprc.;.;ion h;ls also hccn dctcctcd in thc brain2.
Disease association OMIM 186720 CD6 may he involvcd in graft versus host discasc. In hone marrow transplants, CD6+ T cclls are sorted out t o reduce graft versus host discasc. Exprcssion is found in chronic ly~nphocyticlcukacmia R cells.
Knockout MGI: 103566
Amino acid sequence of human CD6 ;,..; ;-;,L,;,---J. - . - :..:;rrL.k.:.~..~.. WWLFFGITGL LTAALSGHPS PAPP:IVL':::' .<..-!.,.;;.,L>:i . . .,. . ...,.;.; ..(. ,:-.-...,. .,..,,.:.~.,,.>~, . . - ..>. , .,>I... :,;?,.~..,,:..-c;. . . . ..,. ~..,",,.. . .. , . , . :. (l:" :-: .';i-:.\:..?l>:,.-.:'l . . ..,: . . . . .. . . .. ...:>. , ,... , ,-.--8,.,-~,.,,-,: ... . r,--,!?>,-7~,-~".. ' :;Y{;.; 'pz?: ,:,:., .',,I>' :' !-:!!.':;? :. : ?I,' .n8:?,;,-,.,;,.;p' 'T.'!!I~F.:~!,: , ,. .r-n,,.. ,, , , T ' y:::>::'F'~~ I)! ( -,c(::::.' 'l;l.'.] , j <;:,::I j r:v r . ~j j-n ? ~ - : , ' - , ~ r ; ~ ~ ; . - . - ~ , ~ : ' ? l . ; .:I,~3,7?Jl!7,~c~; 14?7:>,->c:.'. '(:,? :.':lQ,y>,'":. (:,: ..,,!j~~:~:,:c,. .!... L:I-2,-. ...-. , ...,....r. .... ... #..?.~r'.:.,-zr:.r ?I..,
7
8
F..7.7-r,
7r,y.r>>,-7..2T..-Trrr..-.-.:, . >., .
;: 5n,7:,:::.:,,; F Y I , : :yp;.'.'
,- .
,!:,]::,:,,(:.! 01 7.:'7p:.p.;,,;..
T!?,.:Tr-r.
..
. .
. 1 :
... . , , . . . .. . . ,.. , .- , --,,--... l
l . ,
..?..?.,
,-T
7
7 - - .
. l . , . ' . . ? \
Y.7-T: ;,;.,/.y! ,:..'C7>''?:--: Y F . ': ,.,' : ',;,' ' (; ,.,,I : ! r. 7;-:,;,, , -. yp\8:.:,!::.:(.:: :: ;, ?:!-L., : :, .,.,, . ~,.'<::T;)!I:::J'. '1 )1!7'' ',?r?:,!; + ,.-
;.,!,;,.,':,y,';;:yc!;[
.
:,~-,:~:,.,.l,.::.,.. . ,.. . ,. .,.....r .
,
, :.:, (:;y,'f:!;,p::
,!rm'-;u:-':.TT,,
- - r.,1.C -. .,. .,.. ,-r.
?:I $ : , ~ : : ~ ~ . ' y - , ' ..:~.-.-:,y-~; ,~IIC. C..,>T..,IP,]T~T ,?0lrr
'.:,C-,~:,~;IT~Y ;.'--??).~.i
,.;
:.?;.+:;>[
:>:jr),:
;!::,'?:'
'
:.'!:, :L,
:;::':~~;:::':.";~y,
;y:y.:;:>>;,c;.:, :
!!::;;,~>JP$T~
:
.
!#.,',!:8s>--T,
Database accession EMRLIGenRank SwissProt
.. . p:?!::,!:(;,F.;.8
,& ? > 1,
F?;I!'I:,-.;~,-:~~
UL3462.1 P3020,1
References Robinson, W.H. ct a]. (1995)Eur. J. Immunol. 25, 2765-2769. Aruffo, A. et al. (1991 ) 1. Exp. Med. 174, 949-952. Rowcn, M.A. et al. (1997)J. Immunol. 158, 949-952. Rowen, M.A. et al. (19961 1. Riol. Chem. 271, 17,390-17396. Rotlian, D.L.ct al. (1997)Riochcmistry 36, 26.37-2641. Skonier, J.E. et al. (1997)Protein Eng. 10, 943-947. ' Aruffo, A. ct al. (1997)Immunol. Today 18, 498-504. Osorio, L.M. (19981 Immunology 93, 358-365. Koharg, 1. ct al. (1997)Eur. J. Irnmunol. 27, 2971-2980.
.-!v>?~,cyr,p!ri
Family Calcium-dependent C-tvpe Icctin
Structure Molecular weights Amino acidc Polypeptide
32 I .36 46s
SDS-PACE reduced
4.5 kDn 14.5 kDa ~~nrcdilccdl
Carbohydrate N - l ~ n k c dsite.; 0 - l i n k e d sites
1 Prohahl y .
Gene location
I 9p I <3.,3
Gene structure
1.3 l
Alternative forms
N H NH2 ~ NH2
Multiple soluhlc torms of molccu1;lr weight 37, 33 and 17 kDa produced hy proteolytic clc;lvagcf; these retain their lcctin domains intact. T w o turthcr c splicing resulting in d i f i c r i n ~ forms exist ;IS ;I result of ; ~ l t c r n ; ~ tRNA cytopliismic t;iil sequences in the first nine mino no ;~cids jdilc to 5 ' untranslatcd region splicingl'.
Structure CD1,I is n type I1 mcmhranc glycoprcrtcin th;lt cxists as ;I hornotrin1cr'~'~J. T h c cxtraccllulnr C-terminal pnrt of CD2.3 contains onc C-typc lcctin dom;1in5 tlint mcdi;~tcs lig;lnd interaction. Thrcc mcmhranc proxilnal repeats of 11 mino no ;lcids torm stalk region tli;~tis involvcd in noncovillcnt trimcrization.
Ligands Low-;~ffinityrcccptor tor IgE1. CD1.3 is ; ~ l s oil counter-rcccptor for the this occilrs in part via intcgrins tr,,pl and t r , P , hut not tu,(3,""; cilrhohydrntc-lcctin intcractioti. CD1.7 ; ~ l s o hinds C D l l [complcnicnt rrccptor CR2, C,lrl reccptorl".
Function It hns a m;lior rolc in the negative iccdhack r c ~ u l a t i o nof IgE synthcsisl", and R lymphocyte prolitcration, diftcrcntiation and survival; ilprcgulatcd hy IL-4 and many other cytokincs jsce rcf.1 l for detailed discussionl. T h e intcr:lct~on hetween CDL3 : ~ n d i n t c ~ r i n sis thought t o pl;ly ;I rolc in monocvtc f i ~ t i \ ~ ; l t i o n ~ , ~ .
Distribution Widcsprcad cxprcssion by thc majority of Icucocytcs, including R lvmphocytcs9 monocytcs, tissue macrophagcs and follicular dcndritic cells, and more wcakly on othcrsll. The CD2;Sa spl~ccform is restrtcted to rcsting B cclls.
Disease association OMIM 15 1445 Surface cxprcssion and plasma levels of CD2.Z arc a prognostic marker for ruduccd survival in chronic lymphocvtic Icukacmia"JJ.
Knockout The Gene Knockout Fr~ctsRot)li'$,p 156 CD23 knockout mice have low circulating lcvcls of IgE and reduced IgEmcdiatcd immunc
Amino acid sequence of human CD23 <::,,:":,:,,.:' .'.' ......,'.'' .'., - .. ..........!l:.:: . .'.' 1 :: ;).-:.,.v:.~r P;. ..,. .. . ., : , ' * :.. . , - ., . .. . . .- .: .. .. , ' I , ;: ;:::: ?!I.:: OArl;. .-,. - - . .,-.rr l..F:-,J1.i;.... . .,.. r.- ...: ;-: .... .-. ~,l,L-,'~;'"'.' -. ;,,.:-.-:>::,:.-;; -. :.:, , ... '- . : .. . . .. ." . . ,':.8:..7.:,.;;!t.. . . ! r/.,ri;
. ...,~:!.{;,J.!'<~,r[.
'
..,
2.
.
] v:
..
, A .
.
, 11:
F,.
;.~J~]''::<)..'~Y?:
!>?l,::(-,
:>:.,
d:..'.,
:y(J::'!j;,p.i-;,
,,-.l,.,,,,.-,<. ! ,,.,; ,,,:
-..>
' T '
.
:,;'FF:::, ::\,*)!:', <*:,
L'i):)::k:(;(J;,-.s
. :!!,;!':!Ff.>,!>;, :, ':y!;;,,::t!
~:~~p~();:..:Lf.:~; ;.:.::>,::-1:;,,:,;:: G;7!>?;!<:>!>?[)[;[ > [ l,'::>:-;:.:3:,!? :; L,d,
I
,-.,~l.~~:.
8 ,
rf.::',,'
:':(:;.,',,'
"
'
'
! , ::,p::: "'
:>::'r ~!7::,;'.'~c<:~','
~:lQ:.;..,;',~-p p:,,-~(c~;.,~,-!,!
Database accession EMRLIGcnBank M 15059 SwissProt
PO6734
References Sutton, R.J and Gould, H.J. (199.31 Naturc ,366, 421428. Stengelin, S. et al. (19881 EMRO J. 7, 1053-1059. Kikutanl, H, ct al. (19861Cell 47, 657-665. Ludin, C. et al. (19871EMRO 1. 6 , 109-1 14. Ikuta, K. et al. (19871 Proc. Natl Acad. Sci. USA 84, 819-82.1. W u ~ a sR., ct al. (1995)Immunol. Today, 16, 574-580. ' Lccoanct-Hctlchoz, S. ct al. 119951 Immunity 3, 119-125. Ronncfoy, 1.-Y.ct al. (1997)Int. Rev. Immunol. 16, 1 13-128. Auhry, 1.-P. ct al. (19921 Nature 358, 505-507. 1" Yu, P. ct al. (1994)Naturc ,369, 75.3-756. Fridman, W.H. (ed.)(19891 Chcmical Immunology, 47, 21-78. Sarfati, M. ct al. (1995)Lcucocyte Typing V, 5,30-55.3. Keating, M.J. (1999)Scmin. Oncol. 26, 107-1 14. I J D'Arcna, G . c t nl. (2000)Lcuk. Lymphoma 36, 225-2.37. ( 19981.The Gene Knockout FactsRook. Acadenlic Press, London. Mak, T.W. Lamcrs, M.C. and Yu, P. (1995)Immunol. Rev. 148, 71-95. I' Fuilwara, H. ct al. (1994)Proc. Natl Acad. Sci. USA 91, 6835-6839.
*
Family Sialomucin
Structure Molecular weights A m ~ n oacids Polvpcptide
,385 40716
SDS-PAGE reduced
90-120 kDa
Carbohydrate N-l~nkedsltcs 0-linked sites
9
Gene location
1 ~132
Gene structure
-26 kh, 8 cxons
A++
COOH
Alternative forms Alternat~vespl~cingresults in an isoform with a truncated 16 amino acid c)rtoplasmic doma~n',?.
Structure Thc N-terminal portion of the CD34 extraccllular domain is cxtcnsivcly Nand O-glycosylated. In the mcmhrane proximal region there are six cysteine residues for potential disulphide bond formation. The 73 amino acid fulllength cytoplasmic domain hccc~mcsscrine phosphorylatcd in rcsponsc t o protein kinase C activ;ltionl.
Ligands L-selectin hinds to sialoglycoconiugates present on CD34; this hinding CD34 requires sulphation and probably f ~ c o s y l a t i o n ~ . ~Variable . glycosvlation results in L-sclcctin hinding to CD*Z4from high cndothelial vcnulcs but not to CD.34 on other vascular or haematopoietic cells. CD.34 can also act as an E-selcctin ligand".
Function The ahility of endothclial CD31 to mediate attachment and rolling of leucocytes in r7itro suggests a role in leucocyte trafficking6. The similar stnicturc and expression pattern of PCLP (podocalyxin-like protein1 and
.-
.
-.
~~
Other Molecules
- ..-
-
CD34 suggests that thcy may havc redundant or overlapping physiological roles, and that PCLP may compensate in the CD34 -1- mice, which show no defects in lymphocyte recruitment to secondary sites7. Experiments in which CD34 has been cctopically expressed also s u a c s t a function in haematopoietic cells in promoting adhesion t o hone marrow s t r o m a b n d initiation of signal transduction pathways9. Like all mucins, CD34 may also have a cytoprotective andlor antiadhesivc function.
Distribution CD34 is expressed by hacmatopoictic stcm and progenitor cells, hone marrow stromal cells, a suhset of endothelium and some nervous tissue.
Disease association OMIM 142230 As discussed by Suthcrland ct al.fn,thcrc are potcntial clinical applications in using CD34 to select for hacmatopoietic stem cell progenitors from tumour contaminated bonc marrow in preparation for transplantation and/or gcnc manipulation in gcnc thcrapy.
Knockout MGI:88.329 The Gene Knockout Factsi3ook1l, p168 CD34 -1- animals dcvclop normally and display no ahnormalities in lcucocyte traffick~ng. In one knockout straln, there is evidence for a decrease in number and in colony-forming activity of hacmatopoietic progcnitor cells12. The other strain1"isplayed no abnormalities in haematopoiesis but defects in eosinophil trafficking in the lung.
Amino acid sequence of human CD34 1 MLVRRGARAG PRMPRGWTAL CLLSLLPSGP . , , . ..,- r.jXGt! F,.:TY 1 1 : rk:?'? ,I : ,- y :, .,- . , .,!:. 1?1 FTTP?%!!'..S?P ET1'1,I:r'TLTP G:.",'.53LZTT.? 1E 1 ?E':Y:LT3~~IC LEr3CIF:TFSCA EF?:Y3P.?EGL ?
.?41
()CLLL'.'LIII!D
3 11? Lfi','TGITC't'F hl
'." . - ..(>...,-,-';> : ,#-, 8
T?TI;5b'L,O!-,b: L,P*!!:?RC?!C??
?i'?OSDI.WI. GE?L,GEDP'l':'
MST.n:J?lCT.k'? ','KFTSTSL'T? T5L?:TS?'?K? :iPTVLCGECQ;! GII.DFTEOW,.'
TENGGGVGY S
?EI,?TOG'?F.'; !F.'STI!'.'.S'IOE S'v"~C~lT~l.5,S'.v QFQTS','TST',' '?'TSFC?ILTII IX,'IEI'.:C5GI D.iD.~..GAO'.'C.C LLLhQ5E':F.P Ia.SFOS'!'CO?T I.I;II,'.'T.SGAL SG'GTSPE?,,O C)I.liT'.'!rdf~:::l;)
: ! : : f ! ~ > , V ~ ) ! ? ' . " ,:nTEL, ~,'
Database accession EMRL/GenRank SwissProt
M8 1945 P28906
References 2
4
Satterthwaitc, A.R. ct al. (19921Genomics 12, 788-794. Nakamura, Y. et al. (1993)Exp. Hematol. 21, 236-242. Facklcr, M.J. et al. (19901J. Riol. Chem. 265, 110.56-1 1061. Raumhueter, S. et al. (1993)Science 262, 436-438.
.-
Other Molecules
Rnscn, S. ant1 Rcrtozzi, C.R. (1996)Curr. Rinl. 6, 261-264. V u r i , K.D. ct al. (199.511. Ccll Riol. 131 261-270. Snssctti, C. ct al. ( 1 9981 J. Exp. Mcd. 187, 1965-1975. V d y , L. ct al. 11995) Proc. Natl Acad. Sci. USA 92, 12240-12244. Tada, 1. c t 31. (19991Rlood 9.3, .373<3-3735. Suthcrlantl, D.R. c t al. (199.31Stcm Cclls 1 1 (Suppl. 31, 50-57. I J M~ak, T.W. I 19981 Thc Gcnc Knockout FactsRook. Academic Prcss, London. Chcng, J. ct al. 11996) Rlood 87, 479-490. " Suzuki, A. ct a1. ( 19961 Blood 87, 3550-,iS(i2.
-
-
gpIV or gpyb,PAS IV, milk fat globule membrane protein] -
--
--
-
Family CD36 family
Structure Molecular weights Amino acids Polypeptide
47 1 52 922
SDS-PAGE reduccd
80-90 kDa (80-90 kDa unreducedl
Carbohydrate N-linked sites 0-linked sites
+
Gene Iocation
7q11.2
Gene structure
32 kh, 15 exons
10
Alternative forms Two altcrnatcly spliced variants, and a short 57 kDa form due to exon skippingf.
Structure CD,76 is a type I transmemhrane heavily glycosylated protein; it is possible that the N-terminus also forms a mcmhrane-spanning domain and/or that the extracellular unclcaved hydrophohic signal sequence intcracts with the external face of the plasma membranez". The two putative cytoplasmic tails arc palrnitoylated* and the two mcmhrane-spanning model may he incorrect". CD36 is a member of a superfamily that includes a further lipoprotein receptor, SR-BIICLA-14sh.Platelet glycoprotein IV (gpIV or gplIIh) and leucocyte CD36 are immunologically related. Threonine 92 is phosphorylated and may he involved with CD36 interaction with intracellular src family protein tyrosine kinase signalling pathways.
Ligands Several extracellular matrix ligands for CD36 have been identified including collagen Types I, rV and V, and thrombo~pondin"'~.Acts as a macrophagc scavenger receptor for oxidized low-density lipoproteinsff.12, various lipids and long-chain fatty acidsJ'.JJ, and apoptotic neutrophils via interaction with thromhospondin [the latter role in association with intcgrin nvp,)'5Jh.
Function Maior platelet receptor for collagcn involved in calcium-dependent platelet adhesion and interaction of platelets with leucocytes and tumour cells. Adhesion of leucocytcs to collagcn and thromhospondin. Role in
nthcrogcncsis vin accun~ulation and differentiation of macrophages in arterial wall. Recognition, and phagocvtosis, of apoptotic ncutrophils. Mcdistes cytoadhcsion of Plasmodium f(r1cipilrurn parasitized erythrocytes to cndothcliumR.'. A role in atherogenesis via CD36 acting as s scavenger rcccptor on mncrophagcs for oxidizcd low-dcnsitv lipoproteins has hecn sugjicstcd"~".
Distribution Platclcts, monocytcs and macrophages, endotheIia1 cells, ndipocytes, dcvclopln~,crythrnhlasts, activated kcrat~nocytcsand somc other cp~thclial cells1R,and small vessel endothelium'.
Disease association OMIM 173510 A family with a mutant form nf CD.76 has been described with a mild hlccding diathcsis similar to Rcrnard-Soulicr syndromc'9.2" Dcficicncv of CD.36 in a tmnsfuscd patient lcd t c ~thc discovery of the Nak(a1 platelet alloantigcn". Three per cent of [apancsc and Africans have CD3h dcficicncy - in part this may he due to selection fnr resistance to malarial intection. Thcrc is a strong link in Tapancsc populations hrtwccn CD36 dcficicncy and coronary heart disease and hypertrophic cnrdiomyopnthy22. A similar relationship hctwccn insulin resistance type I1 diahctcs, hypcrtcnsion and CD<36 (Fat genel pnlvmorphism is found in the 'spontaneously hypertensive' (SHRI rat2?.
Knockout MG1: 107899
Amino acid sequence of human CD36 . . ... .. .. :,
.., -. . ..,. .. .,...... . ., . . . .-,-. .,., . i"
.. . ., . .
,
.
.. -, , . . ,
,
L
,,....:; .;,,:... . , , .,-.,,.T,>,-,;,,r7.;
. . -- . -.,. . . ,-.
,
,,,-
.,
?,:,'', ,
...,
' %
.
,: ,.*..;.;.,;;.; . ...;. . , -. . :I.. ..,..-..,.,,.. I: - . . .. . _. . .... . . .... r , . _ _ _ * _ _. . .._ ..._. -.. .. .. ,..._._..: ..,.-. . , , .,. . . ., .. , ,. . . . . , , .... .,,. . , . _ . , . , < , ........ . _ _ . . _ ....... . .. . . .. .____.._._.__... . . _.) .... -. .,. . ., . . . . . ., . . ::: . . . : . :: '-. : . . :
__
. . _ __. I
.
Database accession EMRL/CenRank SwissProt
MU795 Pl6671
References Tavlor, K.T. ct a]. 11993) Gcnc 133, 705-212. Tandon, N.N. ct al. (1989a11. Einl. Chcm. 264, 7570-7575. Wyler, R. ct al, ( 1 99,11 Thromh. Hacmost. 70, 500-505. Tao, N. ct al. (1996)1. Rlol. Chcm. 271, 22315-22,320.
Other Moleollcr -
-
-
-
5 Pearce, S.F.A. ct a!. (1994)Blood 84, 384,389. "latt, N. ct al. (19981Trcnds Ccll Riol. 8, ,165372. Asch, A.S. et 31. (1987)1. Clin. Invcst. 79, 1054-1061. Oqucndo, P. ct al. (1989)Ccll 58, 95-101. " Ockcnhousc, C.F. ct nl. (1989)Science 243, 1469-1471. lo Tandon, N.N. ct al. (1989h) 1. Riol. Cllcm. 264, 7576-7583. Endc~nann,G. ct al. [199,3)J. Riol. Chem. 268, 1181 1-1 1816. I? Kricgcr, M. and Hcrz, J. (1994)Annu. Rcv. Rlochcm. 6,1, 601-(i37. Nozaki, S. ct al. (1995)J. C l ~ nInvest. . 96, 1859-1865. l J Ihrah~mi,A. ct al. (1996) Proc. Natl Acad. Sci. USA 93, 2646-2651. l5 Savill, J. et al. (1993)Immrlnol. Today 14, 1<31-136. Navazo, M.D.P. ct nl. (19%) J. Riol. Chem. 271, 15,381-15385. I' Rigotti, A. ct al. (l9r1.5)J. Biol. Chcm. 270, 1622 1-16224. Grccnwalt. D.E. ct al. ( 1992) Rlood 80, 1 10i-1 1 15. Yamalnoto, N. ct al. [I9941Rlood 8,1, ,192397. 2Vash1wagi, H. et a]. (19951 J. Clin. Invest. 95, 1040-1046. Ikeda, H. et ;I\. [ 1980) Vox Sang. 57, 213-2.1 7. 22 Tanaka, T. et al. (19971 J. Molcc. Ccll Cnrdiol. 29, 121-127. 2' Altmnn, T.J.ct al. (1999)Nature Ccnct. 21, 7(-83. I J
m
V a s c ~ ~ lATP a r diphosphohydrolase, ecto-apyrase (EC 3.6.1.5)
Family CD.3') gene family
Structure Molecular weights Amino acids Polypeptide
510 579 654
SDS-PAGE reduced
78 kDa
Carbohydrate N-linked sites 0-linked sites
6
Gene location
1 Oq2.3.1-24.1
NH2
COOH
Gene structure Alternative forms Malor $3.2 kh KNA and other tissue forms; at least four structural variants (CD.39Ll-4)in human and clthcr species indicating a gene family1.
Structure CD.39 has amino acid homology (fnur regions) to ecto-apyrase enzymes from animals, lower organisms and plants'. Functional studies show that CD.39 is a vascular ATP diphnsphohydrolasc/ecto-;ipyrase (EC 3.6.1.5) family member' with typical enzymatic activity towards ATP and ADPaS. The amino acid sequence c ~ fCD,39 contains three hydrophobic strctchcs sumcsting a two-mcmhrane span molecule, although the N-terminal segment is unusually short; its exact topolohy is thus 11nclcar3.
Ligands CD.39.
Function CD39 is a metlintor of activated R cell homotypic adhesion". Regulation o f platelet activation hy surface expression of CD.39 (cndothelial ATP diphosphohydrolasc, ccto-apyrasc C 6 . which hydrolyscs extracellular ATP and ADP to AMP, and is further degraded to adenosine hy annther enzyme 5'-nuc~cotidasc;adenosine, is a stimulant of platelet atlhcsion to endothclium. A similar mechanism may reduce cxtraccllular ATP hy enzymatic hydolysis, which at high lcvels is toxic t o cclls.
Distribution Activated R and NK cclls, and suhscts of sctivatcd T cclls [it was first itluntifiud on Epstcin-Rarr vims-trsnsformcd lymphncytes'), hut nnt resting lymphncytcs, and hy some other hacinopoictic cclls. Mnntle and pnracnrtical zones of lymph nndcs h u t not gcrminal cuntrus. Entioth~lial"~ and neural cells also express CD,399.
Disease association OMIM 601751
Knockout MGI: 102,405 I
Amino acid sequence of human CD39 \,,),.,,
,
J
..&,~c..,..,.
,
,
,
. ..,,'. , ,,. ..,,! ,
,I,.,:;,
.,
,,.,.,,..,;.,
- ,... . .
I
.
, .;..,.
. I L A I L G F S S I I A V I ALLAVGLTCi'! :c':":.':!'f'1.-'.';
' I'~','L.'~
L. ,
. I
.. .
, .,:,.I>
,; ,
.
, I,.,:
:,,-7.,..,.,: :,',',:I.~...r'r.',. '
,-..,,,,..
,.,.,:, ',',."
."&.',.'
~..,,,,(.,,:').:>:.
:
:
1
j'.
I ' ',,'#I.'
,.
. .;., . ,
...,..,,,: .
. ..::.::.::: ,
. .. . ...; ., ., 1'"' . ,.L..,.,
W F S L V L F T VAIIGLLIF:?
1
:
I,
1 , :
...
r.r,<,
,.,. .
.., . . ..... , ' > . 'r,:.'
:;.,
,
,
...
, , [ ,:&..-. (.,r.-
(..rr .I,,,
..
. . . ..
.;: ,
:.~.-,;':,l,,
''1
".'I
. ..,,' ..; '.,I.'
. , .., ., . . L",":,:
'";:
:
I,:'; r,'
:-b!'.'[
.
L.8.)
.
:r
.
. .!'-r
v.;.:;
;,.,
,:-
>.
,
,,, . , I
,
.
! ~'.11>1:;:'1!1'
,,..' . ,.,::."., , . . .:.:>!'(, . <:(,!:j.:<;;,'*'('...
..,,.I
, : . r ,>*;-., (IT'!: - ..
';.'~;!,!;~:'~v',' ','~!',.:'~,~,'~~~'~~j
. : ,,., ,...,.:,.,. .> , ,"r.l:.:,!.:!,
- , ,; ';,'I,::;
.
.
, : ;...,:"'.! "'-;-'!,<<'.,
.,...,..,.... . ,. , :
! ,:: \,.:,.: l)<'!.,T: !:;I::<),:?,,;> 1 ; !,
.: .,!:,.v!:v.;;,F: : [:I,
1
~,l,(.l,:>,:c:.-.!
.
[
;,:;, !!.-.....FL ,. 1
.
v,..(.?,.!;(:.r.,.: ;,
*'-'
Database accession EMRLICcnRsnk SwissProt
S7.3813 P4996 1
References Chadwick, R.P. and Frischauf, A.-M. (19981Genomics 50, 357-367. Handa, M. and Guidotti, C. (1996)Riochem. Riophys. Rcs. Commun. 218, 916-923. Maliszewski, C.R. ct nl. (1994)1. Immunol. IS,?, 3574,3583. Kaczmarek, E. ct al. (1996)J. Riol. Chcm. 271,331 1633122. Wang, T.F. and Guidotti, C . (19961J. R i d . Chcm. 271, 9898-9901. " Kansns, G.S. ct al. (1991)J. Immunol. 146, 2235-2244. ' Rowe, M. et a]. 119811 Int. 1. Cancer 79,37.7-,78 1. Goutcfangcas, C. ut al. (1992)Eur. I. Immunol. 22, 2681-2685. Wang, T.F. and Cuidotti, C. (19981Rrain Rcs. 790, .7 18322.
Family Leucine-rich gIycoprotcin/ CD42 family
Structure Molecular weights A m ~ n oa c ~ d s Polvpcpt~dc SDS-PAGE reduced
177
19046 32 kDa 1 17-22 kDa unrcduccrll
Carbohydate A'-l~nl
1
Gene location
Chromosome 3
Gene structure
6 kh, 2 cxons
Alternative farms
COOH
Structure CD42a is a single-chain tvpc 1 integral membrane glycoprotcinl,' that forms a non-covalently linked complex with CD42h, CD42c and CD42db5. The extracellular part ot CD42a is characterized hy a singlc 24 amino acid leucine-rich domainq; as such it shows homology t o CD42c (gplhpl. CD42n is possihly mvristolatctlh and has a single N-glycc>svlation sitc (lactosamine chain). CD32a is linked to the platclct actin cvtoskelcton (as part of the gpIX-~pIhcomplcxl.
Ligands The CD32 complcx forms n rcccptor for von Willcbrand factorJ and thromhin'on platclcts [the binding sitc lies In CD42hlgplha).
Function CD12a rncdiatcs adhcsion to suhcndothelial matrix exposed upon cndothelial damage at high hloc~d flow rates, and modulates platelet
. -. --
--
-.
Other Malect~les
aggregation when ;ictivntcd hy thromhinJ. It maintenance of Ilacmostasis in the arterial system.
is essential for thc
Distribution Platclcts and mcgakarvocytcs5.
Disease association O M l M 17.75 15 mutation^^,^ and ahgcncc of CD42a (along with mut;itionz in CD42h ant! CD42c) lends to Rcrnnrcl-Soulicr syndrome (OMIM 2312001, n hlccding disorder chnractcrizcd hy giant platclcts and thromhocytopc~~i;~.
0 Knockout Amino acid sequence of human CD42a I MPAWGALFLL WATAEA / I . r ; 1 , I I
-
r 3
Database accession EMRLICcnRnnk SwissProt
X51997 P 14770
References Hickcy, M.J. ct al. ( 1 9891 Proc, Natl Acarl. Sci. USA 86, 677.3-6777 Hickcy, M.J. ct al. (19901FERS Lett. 274, 189-192. Fox, J.E.R.c t al. (1988)J. Riol. Chctn. 26-7, 4882-4890. Roth, G.J. (1992)Immunol. Today 1,3, 100-105. Lopcz, J.A. ct a!. (1996)J. Riol. Chom. 269, 23716-2,3721. " Schick, P.K. and Walker, J. (19961Rlood 87, 1,377-1,384. ' Kawnsaki, T. ct nl. (1996)J. Riol. Clicm. 271, 106,75-10639. " Wright, S.D. ct al. ( 199.1) Rlood 81, 2.339-2.347. C I C I ~ I C ' ~J.M. S ( I ~ct, nl. (1994)Rlood 84, 1124-1 131.
r
I,, 1
1
-., "
Family Lcucinc-rich gIycoprotcin/CD42 family
Structure Molecular weights
repeats
Amino acids Polypcptidc
626 68 955
SDS-PAGE ruiiuccd
145 kDa (160 kDa unrcd~~ccdl
CD42b
Carbohydrate N-linkcti sites 0-linkcd sites
4
Gene location
1 7ptcr-p 12
approx. 4,1
Gene structure
zD42a
IIIII IIIII COOH
'*OH
COOH
Alternative forms T h e clcavcd N-terminal part of CD42h 1s found in serum, named glycocalic~n~.
Structure CD42h cxists as a disulphidc-hondcd hcterodimcr with CD42c2J, and hcncc a non-covalent stochiomctric complex with CD42n and d, the functional von Willchmnrl factor/ thromhin rcccptor on platclcts. The N-terminal, 30 amino acid long, ant! a 60 amino acid strctch C-terminal t o the lcucinc-rich repeat1 rcginn of CD42h share scqucncc similarity between members of the CD42 complcx mcmhcrs4. T h c extraccllular portion of CD42b is contains eight tandcm Icucine-rich repeats of 24 amino acids flanked by consensus scqucnccs of 22 amino acids. CD42h cxists in scvcral size polvmorphs, due t o the presence of 1-5 copies of a l \ Z amino acid long, thrconinc-rich and highly 0-glycosylatcdS, sequences each containing five 0-glycation sites accounting for its extended sizeh. There are three tyrosinc sulphation sites [Tyr 276, 178, 279) and CD42b is palmitoylated'. T h e region C-tcrminnl to the Icucinc-rich repeats contains thc von Willchrand factor hinding site. The C-tcrrninus intcracts with the actin-binding protein, filaminR,and thc
Other Molecules -
-
--
-
1 4 - 3 3 zeta protein9, which is disrupted upon platelet activation along with dissociation of the CD42 complcx on the cell membrane. The N-terminal extracellular part of CD42b is cleaved by calpain during platelet aggregation and rclcascd, as glycocalicin, into the serum. The synthesis and assemhly of the CD42a-d (gplh-IX-V)complex has recently been studicdfn.
Ligands Von Willehrand factor and thrombin via the N-terminal part of CD42h"f1.12.
Function CD42b mediates adhesion to subcndothclial matrix cxposcd upon endothelial damage at high hlood flow rates, and modulates platelet aggregation when activatcd hy thrombin7. It is esscntial for thc maintenance of haemoqtasis in the arterial system. Platelet activation conscrlucnt upon thrombin binding results in dissociation of thc CD42 complcx and disruption of the CD42h,c (gplh complex) interaction with the platclct actin cytoskclcton, and hcnce altcrcd adhcsion and spreading on thc damagcd cndothclium/subcndothclial matrix.
Distribution Platelets and mcgakaryocytcs2.
Disease association OMlM 2631200 Mutations in CD42b lead to Bcmard-Soulicr syndromc (scc CD42 cntrics; OMlM 2,31200). Mutations on the douhlc loop region result in increased von Willehrand factor binding - 'platelet type/pscudo von Willchrand's disease' - duc to reduced plasma half-life of von Willcbrand factor and thromhocytopenia'~.f-f.Single amino acid polymorphisms (Mctl45Thr, and Thrl61Mct) produce the K o and Stb[al alloantigcns, rcspectivcly, which can result in auto- and allo-immunc thrombocytopeniafs~'".
0 Knockout Amino acid sequence of human CD42b
-.
Other Molecules
Database accession EMRL/GcnRank SwissProt
102940 1'07159
--
References Clcmctmn K.J. ct al. (19821Proc. Natl Acad. Sci. 78, 2712-2716. Lnpcz, J.A. ct al. (1996)1. Riol. Chem. 269, 2.7716-23721. " Roth, G.J. (1992) Immunol. Today 13, 100-105. Lnpcz, [.A. ct al. (1987)Proc. Natl Acad. Sci. USA 84, 5615-5619. Lopcz, L.A. ct al. (1992) J. Rinl. Chcm. 267, 10055-10061. FOX,1.E.R. ct 31. [1988) J. Rid. Chcm. 263, 4882-4890. ' Schick, P.K. and Walker, J. (19961Rlood 87, 1.377-1.384. Fox, T.E. R. ct al. (1989)J. Biol. Chcm. 264, 9716-9719. Andrcws, R.K. ct al. (19981Biochemistry 37, 638-647. In Dong, J.F. ct al. [199X) J. Riol. Chem. 27.3, 31449-*3 1454. Harmon, J.T.and Jamieson, G.A. (1986) J. Riol. Chem. 261, 13224-13229. Michclson, A.D. ct al. (1986) Rlood 67, 19-26. l"usscll, S.D. and Roth, G.J. (1993) Blood 81, 1787-1791. IJ Murata, M. ct al. (19931 J. Clin. Invest. 91, 21,3,3-21,37. Murata, M. ct a]. (1992) Rlood 79, 3086-,3090. '"uiipers, R.W. ct al. (19921Blood 79, 283-288.
Family Lcucinc-rich glycoprotcin/CI>J2 f;imily
Structure Molecular weights
repeats
Anlino acids l'olypcptiilc
106 21 717
SDS-PACE reduced
1 3 kD;i
CD42b
Carbohydrate N-linked sites 0-linked sitcs
1
Gene location
12111 1.2
Gene structure
I kh, I cxon
Alternative forms Larger 41 1 amino acid form in cndothcliwn, owing to i ~ s cof nltcrnatc upstrearn start site.
Structure CD41c forms n 1:l disulphidc-hondctl covalcnt complex with CD42h/gpIhtr, and the gpIh coinplcxcs with CD42;i and d to form the functional platelet receptor tor von Willchrand factor and tliromhin'.2. Contains a single lcucinc-rich repcat ~ i o r n ; i i n ' . , ~ ~homologous to CD42a/gpIX.'.",'. Phospliorylatcd on intraccllular scrinc 191, sumcstivc of a role in cell signalling/cytoskelet:~linter;ictionR.
Ligands Von Willehrand factor and thrombin.
Other M~lecules
Function CD42c mcdiatcs adhcsinn to suhcndothclial matrix cxposcd upon cndothclinl d a ~ n a ~ntc high hlootl flow ratus, and modulates platclct aggregation whcn activated hv thromhin (scc other CD42 cntricsl. It is essential for thc mnintcnnnct. of hacmostasis in the arterial system. Platclct activation conscqucnt upcm thromhin binding results in dissociation of the CD42 complcx and disruption of the CD42h,c [gpJh complcx) interaction with the platelet actin cytcjskclcton, and hence altered adhesion and spreading on thc darnagcd cndothclium/suhcndothclialmatrix.
Distribution Platelets, rneg3karyocyt~s.Unlike other CD42 components that art. tissue rcstrictcd, C D l l c is cxprcsscd rn cndothclium, heart nnd bmlnY.
Disease association QMIM l.lX720 Mutations in CD42c result in Rcrnnrd-Sonllcr syndrome, 3 platelet haemostatic defect. Howcvcr, a dclction in 22~111.2rcsu1tt.d in n complex phenotype that nlso rcscmhlud vclocardinfac~alsyndrnmc'" (sce claudin 5 entry, whosc gene is localized to thc same gcnctic rcg~on).
0 Knockout Amino acid sequence of human CD42c : MGSGPRGALS LLLLLLAPPS
. . ] .
.. - .-
..
. - . , ,..
.
.
., . .... . .
. , . . ...,. ..... ,
. ,.. ., .. ..., .. ,. . .. . .,. ,
,::..:I
, ' -,
.. , ,-
.
. . , .. ., . - <. , .
.
., ,. . ., .
Database accession EMRL/GcnRank Sw~ssProt
J0>3259
PI11114
References Roth, G.1. (19921 Immunol. Today 1,3, 100-105. Lopez, \.A. et al. (19961 1. Riol. Chum. 269, 2,3716-2.3721. Lopcz, ].A. ct ul. (19871 Proc. Natl Acad. Sci. USA 84, 5615-5619. Lopcz, \,A. ct al. (19881 Proc. Nntl Acad. Sci. USA 85, 21,35-21.39. Kelly, M.D. ct al. (1'19311. Clin. Invcst. 9.7, 2417-1414. Fox, 1.E. ct al. (19881 \. Riol. Chcm. 26,3, 488248'1n. ' Canficld, V.A. ct al. (1987) Riochcm. Biophys. Rcs. Commun. 147, 526-5\34, Wardell, M.R. ct al. (19891 1. Riol. Chem. 164, 15656-15661. Rningopnlnn, V. ct a]. (19921 Rlood 80, 1.5.3-1 61. Rurdart, M.L. ct 31. (194.5)Hum. Mnlcc. Gcnct. 4, 7h,3-766.
Family Leucine-rich glycoprotein family
Structure Molecular weights Amino acids Polypeptide
SDS-PAGE reduced
82 kDa (82 kDa unreduced)
Carbohydrate N-linked sites 0-linked sites
Gene location Gene structure
Alternative forms 3 transcripts
Structure
COOH
CD42d is a single-chain integral membrane protein" that forms a noncovalent complex with CD42a,b and cs', and possibly enhances their membrane expressionR. Contains 15 leucine-rich repeat domains. CD42d contains a thromhin cleavage site that may be functionally relevant.
The CD42 complex binds von Willehrand factor and thrombin (see CD42 entries); the CD42d/gpV component may be essential for the formation of a high-affinity receptor for thrombin9.
Function Part of the platelet CD42 complex that binds von Willebrand factor and thrombin, and is crucial for maintaining haemostasis in the arterial circulation under high shear rates, and in the modulation of the platelet response to thromhin.
--
--
- -
- -
-
--
--
Other Molecules --
--
Distribution Platelets and megakaryncytes.
Disease association OMJM 17351 1 Absent from platelets in Bernard-Soulicr syndrome, where the entire CD42 complex is lacking; no causative mutations have been found in CD42d.
0 Knockout Amino acid sequence of human CD42d
Database accession EMRLIGenRank SwissProt
L11238 P40197
References Shimomura, T. et al. ( 1990) Blood 75, 2349-2356. Roth, G.J. et al. (19901Riochcm. Rlophys. Rcs. Cnmmun. 170, 153-161. Lanza, F. et al. (19931J. Biol. Chem. 268, 20801-20807. Hickey, M.T. et al. (1993)Proc. Natl Acad. Sci. 90, 8327-8331. Lopez, J.A. et al. (19961J. Riol. Chem. 269, 23716-23721. G.1. (19921Immunol. Today 13, 100-105. "oth, ' Modderman, P.W. et al. 119921 J. Rlol. Chem. 267,364-369. Calvcrley, D.C. ct al. (1995)Blood 86, 1361-1367. Dong, J.F. et al. (1997)Rlnod 89, 4355-4,763.
Leukosialin, sialophorin - -
Family Sialomucin
Structure Molecular weights Amino acids Polypeptide
400 40 322
SDS-PAGE reduced
neutrophils and platelets 115-135 kDa T cells and thymocytcs 95-1 15 kDa
Carbohydrate N-linked sites 0-linked sites
+++
1
Gene location
16q11.2
Gene structure
4.6 kb, 2 exons
Alternative forms
""1"' bbbb bbbb
Structure
COOH
The extracellular domain contains five repeats of an 18 amino acid sequence decorated with 70-85 sialylated 0-linked carhohydrates~, resulting in an extended 45 nm rod-like structure that could protrude above the glycocalyx2. The 124 amino acid cytoplasmic domain is constitutively phosphorylated, probably by protein kinase C1 and has been reported to hind members of the ERM family of membrane-cytoskeleton linker proteins4.*.The CD43 gene is unusual in that it contains a single 378 hp intron in the 5'-untranslated region and therefore the CD4d coding sequence is within a single exon6.
CD43 has been reported to bind ICAM-17but it is not known whether this represents a relevant physiological event.
Function CDd3 -1- leucocytes show enhanced homotypic adhesionR,and enhanced rolling and adhesion after chemotactic stimuliv, indicating a function for
CD4,Z as an antiadhesive moleculc inhibiting T cell interactions. This includes an inhibition of T cell killing and an incrcasc in thc threshold for T cell activation. Like all mucins, CD43 may also have a: cytoprotective function. However, neutrophil and monocyte infiltration into the peritoneum is significantly rcduccd in CD43 -/- mice as is lcucocytc emigration from thc vasculaturcg, indicating that CD43 has a n adhesive function in rrirm.
Distribution CD43 is a maior sialylglycoprotein on all leucocytes except resting R cells6Jn. In d~ffercntcell types thc molccular sizc of CD43 varies duc to differing degrees of 0-linked carbohydrate s i a l y l a t i ~ n ~ CDd3 ~. is protcolytically clcavcd from thc surface of stimulated lymphocytes and granulocyte^^^.
Disease association OMIM 182160 CD43 is defective in T cells from males with Wiskott-Aldrich syndrome. Affected individuals arc susccptiblc to opportunistic infections reflecting defects in cytotoxic and helper T cell functions. As the Wiskott-Aldrich syndrome is X-linked, defects in CD43 are not the primary genetic cause. Circulating anti-CD43 antibodies are found in many AIDS patients and may contribute to the severe immunodeficiency.
Knockout MGI:98384
The Gene Knockout FactsAook1?, p175 CD43 -1- mice dcvclop normally hut CD43 -1- T cells show enhanced proliferation in response to T cell activators and in alloreactivity tests, and enhanced homotypic adhesion" CD43 -/- leucocytes show impairments in trafficking through the vasculature9.
Amino acid sequence of human CD43 1 MATLLLLLGV LWSPDALGS TTA.'nTT"CT EP:,'.'STSF?I, r r-rr-7 ,. T,;;:Lf",FT,v , r , : ., - r .. . . . r r.:;., . ~. . L ? FPTT':'QE','.5I 12 1 "_ r'i""7. , . LJ;, rt-}!T' ' Tr:,;:: ITT:!.Tp ry,-Cy,:':?5p ','TT>,,:,S:LET ;;I
~
A
19: ,,'TCr_l?p','Tl.!:., T:'TLF;";';T T';P:','':'!1?'::> 2.1: 'T'.'pT?~JPp"I[CFGI..!LI''.'.i.'.' L'.'>.,LL:i'.'L"L 312: [l:,,!.,'-,,Cp\n','7 ;-cr;" " " . " : ::'' '. ;., : : :,Lr:,-Tc?,-1,L' . ~-:~r-:'l~,'v;,,??,-::.". ...: :..rn
.,-
-.
Database accession EMRL/GenRank SwissProt
704 168 P16150
:L[:pCST-Afr: ..'.I.LL',L!:?P.F ., , .,, . ., ...:T?PP Ep--#'~:'>?r;.?,,:..r
.
??:CS';'TOETF :p12:T_Cr_ll,[:LT F;Q:'Ss?'F:L'T r,ll.'9PTC:iL7.'L
5n??.:;n5?G7 EAT? EFi.'.'FI ].I;\?".':,E?'SI: M!.!CrT'STI.]:i SF'i:C:'P.Hr-'.-.'
T:-TFFT;?F?
s?~c~;.?,,!?FF
5:5?!4?T?Si'T
-
-
--
-
-
Other Moleculeq -
-
--
-
References I'allant, A. ct a]. (1989) Proc. Natl Acad. Sci. USA 86, 1.328-13.32. Cystcr, 1.G. ct al. (1991)EMRO 1. 10, 893-902. .3 Pillcr, V. ct al. (19891J. Riol. Chcm. 264, 18824-18831. Serrador, J.M. et al. (1998)Rlnod 91, 4632-4644. 5 Yoncmura, S. ct al. (1998)1. Ccll Riol. 140, 8%-895. ~ l i c l l c yC.S. , et al. (1990)Riochem. J. 270, 569-576. ' Rosenstein, Y. et a\. 11991) Naturc 354, 233-23.5. Manitmath, N. ct al. (1995)Nature 377, 535-538. Woodman, R.C. et al. (19981J. Exp. Mcd. 188,218 1-2186. In Nathan, C. ct al. (1993).J.Ccll Riol. 122, 243-256. I * Carlsson, S.R. ct al. (1986)1. Rio!. Chcm. 261, 12787-12795. l2 Razil, V. and Stromingcr, J.L. (199.3) Proc. Natl Acnd. Sci. USA 90, 37923796. Mak, T.W. (1998)The Gcnc Knockout FactsRook. Academic Prcss, London.
*
Family Hyaluronan receptor
Structure Molecular weights Amlno aclds Polypeptide
CD44s CD44v CD44s CD44v
361
up to 742 39 391 up t o 8 1 609 4-
SDS-PAGE reduced CD44s 80-100 kDa CD44v 100-200 kDa
0-linked sites GAG
I
1 1 1 1 1 IIIII 11111 11111
Carbohydrate N-linked sitcsl
variable exons inserted here
CD44s 7 CD44v 7-9 CD44s ++ COOH CD44v + + + CD44s variable chondro~tinsulphate CD44v chondroitin and heparan sulphate
Gene location
1 lpter-pl3
Gene structure
60 kb, 20 cxons
Alternative forms CD44s (standard, also called hacmatopoictic CD44, CD44H) is generated by exons 1-5, 16-18 and 20. CD44 variant (CD44v)isoforms results from the insertion of various combinations of nine variant exons (exons 7-15 = variant cxons 2-1011. An additional variant cxon (exon 6 = variant exon 1) can he inserted into murine CD44".
Structure CD44s contains a 341 extracellular domain with a hyaluronan-binding link domain at the N-terminus followed hy mucin-like stalk region which is subject to N-and 0-linked glycosylation and variable addition of chondroitin ~ulphate".~. The cytoplasmic domain is phosphorylated constitutively on a single serine residue5 and can associate with members of the ERM family of membrane-cytoskeletal linker proteins6.'. A large number of different CD44 isoforms have been detected resulting from the insertion of different combinations of variant cxons v2-v10. Thesc variant isoforms also encode mucin-like regions and can be extensively 0-glycosylated. In addition, exon v3 can he modified by heparan sulphate side chains. CD44 can he shed from the cell surface by a proteolytic mechanism and the efficiency of shedding can be modulated by the insertion of variant ex on^^,^.
Ligands CD44 is the principal cell surface receptor far the extracellular matrix glycosaminoglycan, hyaluronan"". The ability of CD44 to hind hyaluronan
is highly regulated depending on the state of CD44 glycosylation, insertion of variant exons and clustering in thc plane of thc membraneq. CD44 has also becn reported to hind collagen, fibronectin and laminin, hut these interactions are prohahly dependent on the chondroitin sulphate side chains rather than the core protein4. Variant forms of CD44 containing heparan sulphate modified exon v3 can hind growth factors, such as bFGF and FGF8'2-14. A number of other extracellular matrix and signalling molecule ligands have been r ~ p o r t e d ~although *~, the mechanism and physiological relevance of CD44 binding is not known.
Function A variety of functions have been ascribed to CD44 including mediating costimulatory signalling, leucocyte attachment to, and rolling on, endothelial cells, transmigration through lymphatic tissue, growth factor and cytokine presentation, cell migration and the internalization and degradation of hyaluronan4J.
Distribution CD44 is widely distributed, with CD44s being thc most abundant isoform. Expression of variant CD44 isoforms occurs normally in epithelial cells and at other sites in the hody. Expression of both CD44s and CD44 variant isoforms is transiently upregulated during lymphocyte and monocyte activation, and extensively in many pathological condition^^.^.
Disease association OMIM 107269
CD44-hyaluronan interactions have been implicated to play an important role in the progression of chronic inflammatory conditions, such as rheumatoid arthritis, and in tumour growth and metastatic p r o g r e ~ s i o n ~ ~ ~ + ~ ~ .
Knockout MGI:88338 The Gene Knockout Fclct~Rook~~, p177 CD44 -1- mice develop normally and exhibit no gross developmental or neurological dcfccts. However, progenitor cpcss from the bone marrow is defective and mice develop an exaggerated granuloma response to Crvosporidium parvum infectionj'.
Amino acid sequence of human CD44s 1
MDKFWWHAAW GLCLVPLSLA OT DLIIITCFF AC;?'FHT~:EKF:T: P Y S I SFTE!:A SI!'TPD THPt,IT;TCAi?H HTC;:'YTI,TSM AS,',:'Pf7?DCT S1,,'Ti7LPPI,?iFD CPTTITT\?!? DGTRYVOKGF: YF!'T?IPEDTYP GSSSEPSSTZ GG'tl F"iTFST "!!?I PDEIISP t!TTDZTDFT I' .XT?DQDTFHP ESX--I!S'r!SSO EGC.JP.ITTSGP 1PTPOT PFYT. T 1I,,\ZT.L,JT..?~ T.?L',.~CTX\?l Li~'It~SG~JGA'.'ED?PPSCL?.IG ~ A S Y S I J E ? , ~ ' . 'L'.'l!i-'??f !~ FTi' DOF:.'T:\I!TTP. :'
51 1,'1'-':,~1l.:F:'::,
121 1R 1
24 1 3 01 361
DLCKAFNSTL, TSWDTYCFN SNPTDDD?.!SS SGGSHTTHGS .SP.FRCGOvKK b!LONVDI+!KIG
CD44v isoforms are generated by the insertion of variants cxons after T222 (shown in hold).
~.62
0 Family Structure Molecular weights Carnohydrate cpitope SDS-PAGE reduced
Depends on the protein core on which the CD57 epitope is expressed
Carbohydrate
n/a
Gene location
11
Gene structure Alternative forms
Carbohydrate epitope present on many proteins, including L1, N-CAM, MAG, P(0)and contactin-1 (scc individual entries).
Structure CD57 is a oligosaccharide determinant expressed on a variety of core proteins, lipids and proteoglycans in a tissue-specific manner'2. The associated protein backhone structures have not been studied in detail. The sulfotransferase enzyme that generates the CD57 carbohydrate epitope has been cloned3.
Ligands Rinds to L- and P-selectin; E8 fragment of laminin; involved in homophylic interactions of P(O](see entry)'"'.
Function Unknown, although its expression on myelin-associated glycoprotcin (MAG, see entry) on motor, but not sensory, neurones, and involvement in homophylic interactions with P[O\ suggests a role in peripheral nerve f u n ~ t i o n Its ~ ~binding ~. to L-selectin (CD62L)and P-selectin (CD62P), hut not E-selectin (CDAZEJ, implies involvement in selective leucocyte cmmigration.
Distribution Surface antigen detected on natural killer cells and T lymphocytes, hut not other leucocytcs, and peripheral nerve axon~L2.~. CD57 is found on integrins in hick'.^,^.
Disease association OMTM 151290
Knockout n/a
Amino acid sequence n/a
Database accession nl a
References lungalwala, F.B. (1994)Neurochem. Res. 19, 945-957. Schachner, M. et al. (1995)Prog. Rrain Res. 105, 183-188. Schachner, M. and Martini, R. 11995)Trends Neurosci. 18, 183-191. Rakker, H. et al. (1997)1. Riol. Chem. 272, 29942-29946. Schubert, J. et al. (1989) In Leucocyte Typing IV (Knapp, W., ed.) Oxford University Press, Oxford, pp. 71 1-714.
Family Structure Molecular weights
t
Amino acids Polypeptide
529 57 944
SDS-PAGE reduccd
80 kDa ( + 41 kDa light chain] [ 125 kDa unreduced)
Carbohydrate N-linked sites
4 (80kDa chain; the 41 kDa
(40 kDa)
1111 1 11 1
b
1111 1111
NH2
chain is non-glycosylatedl 0-linked site
Gene location
llq13
Gene structure
X kh,
9 cxnns (hcavy chain]
Alternative forms Structure CD98 is a type 11 membrane protein consisting of a disulphide-linked hcterodimer of glycosylatcd hcavy chain (CD98114, and non-glycosylated light chains. First defined hy the 4F2 antihodyh.
Ligands Unknown.
Function Potential amino acid7 and Na+-Ca2+ exchangetd function IS based upon protein homology and functional studies with antibodies. CD98 is part of a family of proteins9 that associate to form functional amino acid ~~. transporters by associating with LAT-1 and LAT-2 p r n t c i n ~ ~ *CD9R expression on many actively proliferating cclls, including epithelial and fibroblast~ccells, and hy activated leucocytes at sites of inflammation, suggests invo!vcmcnt in cell activation and proliferation'2. A role in intercellular adhesion and cell fusion is implicated by induction of monocyte fusion by antibodies to CD98i%and its association with actin.
Distribution Widespread tissue distribution expressed at high lcvcls by monocytes but low amounts on other leucocytes; upregulated upon leucocyte activation; cxprcsscd early in h a e m o p o e i c s i ~ ~ - ~ ~ ~ ~ .
--
Other Molecules
Disease association OMlM 158070
Knockout Amino acid sequence of human CD98 (heavy chain)
Database accession CD1)K (hc;lvy chain - humnnl CDOS ( I ~ g hch;lln t - mouse)
FAYHI, /C;r.nRr~r~k Sn~1ssl'rr)t 1029s3Y PO8 195 AR01789 QYZ117
References Teixeir;~,S. et al. jl')S71 1. Riol. Chcm. 161, 9574-9580. Li~mnduc,T.A. et ill. I I9871 Proc. Natl Acad. Sci. USA 84, 9204-9108. Q ~ ~ n c k e n h u sE. h , et ;I!. {I9871Proc. Natl Acad. Sci. USA 84, 6526-65,30. C;ottcsdicncr, 1Z.M. ct al. (19881 Mol. Cell Riol. 8, ,3809-,381'). N;tk;~mura.E. et al. 1 IC1991 J. Riol. Chcm. 274, ,300')-t3016. " Hcmlcr, M.E. nnd S t r o m i n ~ c rI.L. , (19821 1. Inimun. 129, 6?<3-628. M;tstrr~herardino,L. et al. 1 lL1981Nature .395, 288-2C)1. Miclinlnk, M . ct al. (108611. Riol. Chcm. 161, 92-95. " Dcvcs, R. and Ijoyd, C.A. (10001 1. Mcnihr. Riol. 17%3,165-1 77. "'Pincda, M. ct al. (19
Family Sialomucin
Structure Molecular weights CD164
Amino acids Polypeptide CD16434 Amino acids Polypeptide CD1643.5 Amino acids Polypeptide
197 20 90.3 184 19 676 178 19 004
SDS-PAGE reduced non-reduced
80- 100 kDa 160 kDa
Carbohydrate N-linkcd sitcs 0-linked sites
9
Gene location
6q2 1
+++
COOH COOH
Alternative forms CDlh4 h so forms lacking exon 5, CD1 64(E35I1;lacking exon 4, C D l64(EA4); or containing all six cxons, CDl64lEl-h)/cndolyn2, have been identified. MGC-24' probahly represents a splice variant lacking the transmembrane domain and diverging from CDl64(EI-61 after L 174.
Structure
I
CDlh4 is a type I integral transmembrane protein containing two mucin domains, I (encoded by exon 1) and 11 (encodcd by exons 4, 5 and part of 6 ) interrupted by a cysteine-rich region (encoded by exons 2 and 31, which probably contains a disulphidc linkage. Thc remainder of exon 6 encodes the transmembrane and cytoplasmic domains. The heavy 0-glycosylation predicts that the mucin domains of CD164 would have an extended filamentous conformation. Western blotting under non-rcducing conditions revealed a 160 kDa form, which resolved at 80 kDa under reducing conditions, suggesting CD164 exists as a homodimcr. The cytoplasmic domain of CD164 terminates in the sequence YHTL, which is characteristic of lysosomal glycoprotcins1.2.
I
Ligands
I
Predicted to hind a lectin(s1 expressed on bone marrow stroma.
Other Molecules
rCmm
Function CDl64 can mediate adhesion of haernatopoietic progenitor cells to hone marrow stromal cells in vitro. In addition, antibody ligation results in the reduction of cells entering the cell cycle, suggesting that CD164 can function as a signalling molcculc with the capacity to suppress haematopoietic cell proliferationJ.5 Like all rnucins, CD164 may also have a cytoprotective and/or antiadhesivc function. A largc proportion of CD164 is localized intraccllularly hut thc function of this intracellular pool is not know.
Distribution CD164 is expressed in all tissues with high levels detected in liver. CD164 is cxprcsscd on CD34+ haernatopoietic progenitor cells throughout ontogeny and is down-regulated on mature neutrophils and ahsent from erythrocytes, hut maintained on monocytes and lymphoid suhscts in peripheral hlood. Monoclonal antihodies that define three different classes of epitopes on CDl64 (class I, I1 and 1111 have been identified. T w o react with glycosvlation-depcndent cpitopcs in mucin domain I, the third reacts with conformation epitopes in the cysteine-rich domain. All three epitopes are expressed on the surface of CD34+ cclls hut in adult lymphoid tissues the CDlh4 epitope classes are differentially expressed, with the class I epitopc occurring on lymphoid cclls, thc class 11 epitope on endothelial and basal epithelia, and the class 111 epitope on hoth sets of cellsJ4. As prcdictcd from the cytoplasmic domain sequence, a substantial proportion of CDlh4 is found intracellularly in endosomcs and lysosomes2.
Disease association OMIM 603.356
0 Knockout Amino acid sequence of human CD164 (El-6) : MSRLSRSLLW
AATCLGVLCV LSAP!':':'TO!I
.I
., ",. ,..-. b.r,T,.,~. 7 ."!>?---b.-, , . , , . , . . , . r.r. , .,.b,r, - . . .. .. ",,". . ., ,. J
.
.
"..
, ,
.rT.
.
.>~,"<;~r..7..r,.~,,..."
, . ,
..:.- . :,.. ;,r,..7 . . .. . . . . . ;..: r"~-"?,-.. , . ... ;, ..., ,., . . ..,
!!'.'?'?;'i!"": I'L [.>.
?!:;'TTL?\PIT
-.
,-'::!,?!,?.r..Z7,<(- ' !~s(:T~-Tl'J[-'-; .-
. . . 7<-r.<>-,.."?.7T . . J!
.
:: 7. r - v - .1< -. 1 .>..._I?
'.L..T
T
?
>
Amino acid sequence of human CD164(EA4) : MSRLSRSLLW AATCLGVLCV LSAr'L'"!T"'?!! . .. .. . . .. - . ,,...-l.....T-,. ....I./.,..:,,::..I . ,, . , . , ,L -,! . .,. ... . ,, .. ,. . ..,.., . ,..,.. .,,.... .,.. . , , . , .,.~, . '....r.g.:, . ., . .. .,. . : .., .. . . . . .. ..- .. , .., ,.... . , ., 8
A
_
A
.,
-
>'::';':":'I
,;I'
::-
r':;y?]F.,'..27:'
;,::['l,:'r:I.'y.
T!','":l;$":C;d
r : "-.-7 ...,--? .-
. .
(,..<:%!y-'3F,-:' ,.,$'p':3 ' r , : # v L l.q :>::..'f);:..':: v, ':y>l-.?,;L'rFF:
.---.
-
-
other Molecules -
Amino acid sequence of human CD164(EA5)
,
,,1 ,, 1
HSRLSRSLL" MTCLGVLCV LSw:.'!T"'(..,t:r ' y r'.' .,;:r: ."-,.:)" ' . . ., . . . ,. .... .. .., . -, . . . ' . . . . . ., . ,.,....7,r.,.. . . , pp::..-.-. . . ..
_
0:
;..
,;:-.. . 1 8 ,
.-(.,18":>Y'-
.I:.,.,
., ,-,.:r:,;
;7.!,'rr
,
,' '. .,,. . . , : .., . ,,.,, p:,, , 7 r . m ,.,..,,7,.--.,r., .. ' . . ..,,-,v. . ..- r"'r,T;, ?:"T,P
' -' '
r
,>
.::r.
~;b',.,-L'~:
,.'vE,:.\.:,~!,
Database accession Human CD164(ElS) Rat C D l 64(E1-61
EMRLICcnRank AF10651 8 AJ23X574
.Swis.sProt Q04900
References Zanncttino, A. C. ct 31. (1998)Rlood 92, 261.3-2628. Ihrke, G. et al. (2000)Riochcm. J. ,345, 287-296. Masuznwa, Y. ct al. 119921 I. Riochcm. 112,609-615. Watt, S. M. et al. (1998)Rlood 932, 849-866. Watt, S. M. and Chan J. Y.-H. (20001 Lcuk. Lymphoma 37, 1-25. Watt, S. M. et nl. (2000)Rloorl 95, 31 133124.
Family Claudin
Structure Molecular weights Amino acids Polypeptide
21 1
SDS-PAGE rcduccd
22 kDa
11881
Carbohydrate
PPPPP ddddd
a*" PPPPP bidid
N-linkcd sites 0-linked sites
Gene location Gene structure
4 kh
Alternative forms Structure Tho exact topology of the protein has not bccn determined; it has four (possibly threc, scc sencsccncc-associated epithelial membrane protein 1, SEMPl below1 predicted transmembranc domains. No known structural motifs have bccn idcntificd in thc claudin polypeptide sequence. The cytoplasmic tails of all claudins (cxccpt claudin-1 1 ) contain a conserved Tyr-Val sequence at their C-termini. Ry analogy with the Shaker K- and ncurcxin scqucnccs, it is predicted that this is thc intcraction site for binding to intraccllular proteins containing PDZ domains. These include thc thrcc 20 proteins of tight junctions2, which havc previously hccn shown to intcract with occludin [see separate entry).
Ligands It is presumed that claudins intcract hnmophylicallp or hcterophylically with othcr claudins or occludin in thc tight iunction of cpithclium and endothelium. Fihrohlasts transfected with claudin-1, -2, or 3 cxhibit calcium-indcpcndcnt cell adhcsion3.
Function Claudin-1 is a integral memhrane protein of epithelial tight junctions, involved in maintaining epithelial harrier function and hence restricting small molcculc movcmcnt hctwccn cclls of organized ccllular shccts [hence claudin from 'clauderc', to closc). It is associated, and co-purified, with claudin-2 (3H0'0idcntical) and occludin (unrelated amino acid sequence1 (see relevant sections) from a tight iunction membrane fraction from chicken
Iivcr'J. Thc importance of additional tight junction proteins, other than occludin, was shown as a conscqucnce of an in vitro knockout of occludin whcrc the cells continued to form functional tight junctional complexes in its ahscnccj. A human claudin-l homnloguc was also isolatcd as a diffcrcntially cxprcssed sequence in senescing mammary epithelial cells (hence, scncsccncc-associated cpithclial mcmhranc protcin 1, SEMPI). Scqucncc analysis predicted only three transmemhranc domains5.
Distribution Ubiquitous at thc RNA lcvcl, hcing particularly abundant in liver and kidney. Epithelial and endothclial tight Junctionsat protcin lcvcl.
Disease association OMIM 60<371R
Knockout MGI: 1276109
Amino acid sequence of mouse claudin-1
Database accession EMIiLlGcnRank SwissProt
AF115546 095832
References
j
Furuse, M. et al. (1998)J.Cell Biol. 141, 1539-1550. Morita, K. et al.. (1999)Proc. Natl Acad. Sci. 96, 5 11-516. Kuhota, K. ct al. 11999)Curr. Biol. 9, 1035-1038. Furusc, M. et al. (1998)J. Cell Riol. 143,391-401. Swisshclm, K. ct al. (1999)Gcnc 226, 285-295.
Family Claudin
Structure Molecular weights Amino acids Polypeptide
154 18 648
SDS-PAGE reduced
20 kDa
gOo
PPPPP dbbbb
PPPPP bdbbb
Carbohydrate N-linked sites 0-linked sites
Gene location
7qll
Gene structure
1 exon
Alternative forms Structure Claudin-3 is a four membrane spanning domain structure of the claudin family of tight junction proteins shown to have at least 15 members'. Lowaffinity version of the Clostridium perfringens enterotoxin receptor (Clostridium perfringens enterotoxin receptor 1 is the high-affinity form see claudin-4)"3. It was first identified as a hormonally regulated protein in prostate4.
Ligands Clostridium perfringens enterotoxin; the associated tight junction component is yet to be identified. Fibroblasts transfected with claudin-1, -2, or -3 exhibit calcium-independent cell adhesions.
Function Identified as a homologue of Clostridium perfringens enterotoxin receptor 2 in human breast cells. Expression in tight junction implies structural or functional role in epithelial barrier.
Distribution Abundant in intestine, liver and lung by Northern analysis, and widely expressed in other tissues at low levels.
Disease association OMIM 602910
--
Other Molecules ..
~
- .-- .-
---- - -- --
Knockout MGI: 1329044
Amino acid sequence of rat claudin-3
Database accession EMBLIGenRank SwissProt
AF0071R9 015551
References Morita, K. et al. (19991Proc. Natl Acad. Sci. 96, 511-516. Katahira, J. et al. (1997)J. Riol. Chem. 272,26652-26658. V e a c o c k , R. E. et al. (1997)Cenomics 46,443-449. Ho, K.C. et al. (1989)Riochem. 28,6367-6373. 5 Kuhota, K. et al. (1999)Curr. Riol. 9, 1035-1038.
--
--
-- --
Clostridiurn perfringens enterntoxin receptor 1 -
-
-
-
,
Family Claudin
Structure Molecular weights Amino acids Polypeptide
209
SDS-PAGE reduced
PPWP COOH
Carbohydrate N-linked sites 0-linked sites
Gene location
7qll
Gene structure Alternative forms Structure Claudin-4 has four membrane spanning domains. It has no characteristic sequcncc homologies other than to memhers of the claudin gene familyf.
Ligands Clostridium pcrfringens enterotoxin, high-affinity form of receptor.
Function Clostridium perfringens enterotoxin is a protein toxin that elicits diarrhoea by altering intestinal permeability. Rinds to two forms of Clostridium * , ~ low-affinity (see perfringen enterotoxin receptor at high ( c l a ~ d i n - 4 )and claudin-,?\. Component of tight iunctional complex and hence presumed structural or functional role in epithelial harrier integrity.
Distribution Abundant in intestine and kidney by Northern analysis and lower levels in many other tissues. Expressed in tight junctions of crypt enterocytes.
Disease association OMTM 602909
Knockout MGI:1313314
.. .
Other Molecules I
Amino acid sequence of human claudin-4 .. ,, .,
Database accession EMl{L/C;c.nl~nnk SwissProt
NM001,30i 0 1 449.1
References M o r ~ t a K. , ct ;I]. (19901 I'roc. Natl Ac;IL~. SCI.96, 51 1-516. K;~t;lh~r;l, 1. ct ;I]. 119971 1. R~ol.Chem. 272, 266il-2665S.
Family ~~~I;l~lcllll
Structure Molecular ~veiqhts t l r n ~ n o,1c1c1\ I'ol\ pc[7tlelc
?IS
NH
Gene location
7 ~ 1I 11
Gene structure
I cuorl
COOH
Altrrnativr forms
Function C:l:~ucl~n-iI \ ;i m c m l ~ e rc i t the c l ; ~ u r l ~t ;~ lm i l y hcqucncc ;11i;i1\,~1\. ~ n t li \ c c ) n c c ~ i t r ; ~ tIn c ~ t1:lit l lunction\ \ \ . l ~ r * csl,~-cs\crl ~i i r l \ . I / : ( , 111 cpitI1~~11;11 CL~II\. i c i~~ il\ . o l v c 111 ~ l tislit lunctlc)n structure. o r tunction. It i \ ~ r e ~ i ~ ~t oi I>c
Distribution E p ~ t l i c l ~cell\: ; ~ l c s l > r ~ c \ \ ~in o ~;~clult i l u n ~ Ilc;~rt, . sltclct;il ~ l l t ~ \ c l c
Disease associ;~tion
Knockout \1c;l~12761I.!
Other Molec~iles
Amino acid sequence for human claudin-5 ,. . -.
-" --
Database accession EMRL/GcnRank Sw~ssProt
AF0009.59 000.507
References 2
Morlta, K. ct ill. (19991Proc. Natl Acad. Scl. 95, 5 11-5 16. Ho, K.C. ct nl. (1989)Rlochcm. 18,6367-6,773. Pucch, A. ct al, (19971Proc. N;~tlAcad. Sci. 94, 14608-14613. S ~ m t k l nH. , ct al. (1997)Gcnomics 42, 245-251.
>
' -1
- '.*' , ..
.
-
Family Clauilin gcnc t;lmily An cstcnsivc sene family of nt Ic;lst 20 claiullin proteins [from ' c l n ~ ~ d c r cto' , - ~ . show the s:lmc overall structure hold\ has recently hccn i ~ l c n t i f i c d ~Tllcsc with tour prcrlicterl ~ n c m h r a n csp;lnning segments ant1 n molecular weight in the region 10-25 kna, They show a variahlc tissue distribution hy Northern :~n:llysis:und for some thcrc is in i 7 i t r o s n d electron microscopy evidence tor expression in tight junctions [see entries tor Clnudins-1, -.3-51. Claudin-l 1 ' ~ n i o u s e oligodcnilnlcytc-slwcific protein OSPl is somewllat dist;lntly rel;lted to the other cll;ludins, and is restricted t o myelin sheath intcrlnmcllnr str;lntls ;!nil tight iunctions ( ~ Scrtoli i cells in testis1. It h;ls n vari;lnt cytoplastiiic tail C-tcnninus that sux,qcsts interaction with ;~ltcrnativeintr:iccllul;ir pmteins (scc Claudin-l l. Mutations in paracellin-I, n distant clnuilin homologue, hnvc recently heen shown t o cnusc inherited renal magncslum loss syndrnmc {OMIM 60,Z95915.
Database accession Mouse sequences Clnuilun-7 Cl;tud~n-1.3 Clnuilun 1 1 IOSP\
Human sequences Clni~din-6 C1:ludin-7 Cl;ul~ilin-S Clnudin-9 Clnuilin- 1 0 Claurlin- l l Cl;ludin-l2 Clauilin-14 Cl;~urlin-15 Claudin 16 {P;uraccIlin-ll Claudin- 17 Claudin-1 S Claudin-10
References Furuse, M. ct a]. Il99Xl J. Cell Riol. 141, 15.39-1550. Moritn, K. ct 31. ( I 9 9 9 ~ 1Prrjc. Natl Acad. Sci. 96, 51 1-51 6. Morita, K. ct nl. 1 1 99r)h) 1. Ccll Riol. 145, 579-.iKX. Tsultitn, S. ;mtl Furuse, M. (19991 Trends Cull Riol. 9, 26X-27.1 Simon, R.D. ct al. (19991 Science 2X3, 10.3-106.
Family Short-chain collagcn family
Structure Molecular weights Amino acids Polypcptidc
633 60 104
SDS-PAGE reduced
Carbohydrate N-linked sites 0-linked sites
Gene location
1 Oq22
Gene structure
> 140 kh, >40 exons
Alternative forms
COOH
At least 17 alternate splice forms reported with lengths varying from 516 to 633 amino acids'-5.
Structure Collagen type XI11 is a short-chain, non-fihrillar, transmcmbranc collagcn with three collagenous (COL)domains interspersed by four non-collagenous regions1-'. Collagen type XI11 forms a homotrirner of rrl(XIII] cha1ns5. A potential transmemhrane region of 21 a m ~ n oacids is present in the Ntcrminal NC4 non-collagenous (NC] domain, which results in a predicted type I1 protein oricntation as in collagen Type XVII4
Ligands Interacts with intcgrin a , P l but not a@,'.
Function It is an integral memhrane form of collagen [see collagen X n I ) associated with focal adhesion sites at cell-cell and cell-matrix contacts, but not hemidesmosomesR. If the signal sequence is cleaved, then collagen XI11 would act as a structural matrix protcin.
Distribution Skin, intestine, placenta, honc, cartilagc and striated musclc4.
-
-
.-
Other Molecules
Disease association
0 Knockout Amino acid sequence of human collagen type XI11
Amino ;lcids 1 - 1 1 form
;I
possihlc lncml-rr;~nc; ~ t t a c h l ~ ~site c n t or ;irc clcavcd
ott t o torn1 thc m;~trixvrrsion of thc ~iiolcculc.
Database accession EMRL G c n l h n k TrEMRL
U(30?92 [ m o u ~ c l 07057.5 (rnc~uscl
References
'
"
"
Pihlnianiclni, T . a n d T;irnmii~cn, M. I19001 1. R i o l . Chcm. 26.5, 16921-1 692s. Tilckii, L. ct ;)I. {I99111. Riol. Chcm. 266, 1771.3-17719. J ~ ~ v o n eM n ,. ;lntl Pihli~ianicnii,T. (19921 J. Hic~l.Chcm. 267, ?469.3-2JhYc). . 25700-23707. Ii~voncn,M , c t ;)I. 1 1 V921 J. I3iol. C h c ~ n167, Sncllm;ui, A. ct ;11. 12000)J. I
Family Transmembrane collagen family
Structure Molecular weights Amino acids Polypeptide SDS-PAGE reduced
1497 150 459 180 kDa
NC4 NC5 NC6
---
10
COL4 COL5 COL6 0 COL7 I COLE
0
--
Carbohydrate
NC9 NClO NCll
N-linked sites 0-linked sites
NC12
Gene location
COL3
-
1Oq24.3
NC13NC14
Gene structure
52 kb, 56 exons
Alternative forms
2 mRNA spliced forms have been defined in keratinocytes'.
NC15
-
COL9 COLlO COL12 cOLl COL13
-
COL14
Structure Collagen type XVII is a homotrimcric transmembrane collagen1.2 composed of 15 collagenous (COL) domains varying in size from 15 to 242 amino acids long and 16 non-collagenous domains; the N-terminal noncollagenous (NC)domain, NC16, is large (566 amino acids) and globular'-FS. It has a type I1 membrane protein orientation with a large intracellular segment (NC16I2.The N-terminal part of collagen type XVII is involved in targeting of the protein to the hemidesmosomc. A region adjacent to the transmembrane segment specifies interaction with the epithelial integrin and is proteolytically cleaved to form a 120 kDa soluble form. This is the site of the major epitope recognized by autoantibodies in some forms of acquired blistering skin diseases (hullous pemphigoid, etc.16.
Ligands Rinds a,P, integrin at its extracellular face.
Function It lvas origin;~lly iticntificd ;IS a 180 kD;1 a u t o a n t i ~ c n ' , ;~ssociated ~ with hlisrcrin!: skin disc;~su.Col1;lgcn tvpc XVII is ;I tr;~nsmcmhrancglycoprotcin of epithelial licniidcsniosomcs rrrliicli is csscntial for their structural i n t c ~ r i t v;~ntlhcncc the arllicsic~n of stratifictl epithelium to h a s c n ~ c n t mcmhr;~nclscc also intcxrin tu,.P,, cics~nocollins,dcsmogleins, etc.1.
Distribution Epithelial liemi Jcsmosomcs.
Disease association O M l M 11,381 1 Scvcr;~lmiltations liavc hccn rcportctl in the cxtrncellular part of collagen tvpc XVII. which result in the nl~scnccof prr)tcinv,lo,owing to prcmaturc tcr~ninationot protein translatirm. These result in the relatively hcnign condition of atrophic cpidcr~nolysisI~ullosawhere thc epithelium separates trom the 1~;lscnicntmc~nl>rancat thc Icvcl of the h c m i d c s m o s o n ~ c ~ ~ 'An ~"~. cpitopc on coll:~gcn typc XVII is recognized hy nutoantihotlies in hullous pcmphigoid and hcrpcs xcstntioni.;"".
Knockout Amino acid sequence of human collagen type XVII
Database accession ERIRL CicnHnnk TrEMRL
N 1'0004K5 (j07.56.3 [ ~ r l o u w l
References
Molnar, K. et al. (2000j CIin. Exp. Dermatol. 25, 71-76. Hirako, Y. et al. (19961J. Riot. Chem. 271, 13739-13745. Li, K. et al. (1991)J. Biol. Chem. 266,24064-24069. Hopkinson, S.R. et al. (1995)J. Cell Riol. 130, 1 17-125. Galalica, B. et al. (1997)Am. J. Hum. Genet. 60, 352365. Schumann, H. et al. (2000)Am. J. Pathol. 156,6854595. ' Diaz, L.A. et al. (1990)J. Clin. Invest. 86, 1088-1094. Giudice, G.J. et al. (1993)J. Immunol. 151, 5742-5750. Jonkman, M.F. et al. ( 1996) Arch. Derm. 132, 145-150. In McGrath, J.A. et al. (1995)Nature Genet. 11, 83-86. 2
~ ~ s t r o p h i n - a s s o c i a t eglycoprotein d 1, DAG 1, c~ agrin receptor - -
0 Family Structure Molecular weights Amino acids Polypeptide
SDS-PACE reduced Carbohydrate N-linked sltes 0-linked sites Other
Gene location Gene structure
895 97 580 120-156 kDa (u chain] and 43 kDa (p chain)
3
+ + + (sialatcd)
1-2 glycosoaminoglycan chains predicted 3p2 1
<
COOH
A t e r n a t i v e forms Singlc gcnc gives rise to two glycoproteins, dystroglycan a and P, hy posttranslational cleavage. There are suhstantial tissue-specific differences in n dystroglycan sizc owing to variable glvcosylationl. Structure Post-translational clcavagc of dystroglycan yields two polypeptides. p dystroglycan is a 4,3 kDa type I integral memhrane glycoprotein. cu dystroglycan is membrane-associated, of 120-156 kDa in size depending upon tissue origin, and non-covalently linked to P dvstroglycanI-'. Dvstroglycan is predicted to have two GAG side chains and a mucin-like 0-glvcosylated region in the C-terminal end of a dystroglycans.
Ligands In skeletal muscle cu dystroglycan [IS6 kDa form) binds the basement memhrane component, laminin-2'. Dystroglycan and laminin together act as a receptor for M!~cnhncteriuml e p r n ~in Schwann cells9 and may be involved in the pathogenesis of the associated ncuropathy. a dystroglycan acts as a receptor for lvmphocytic choriomcningitis and Lassa fever viruses10. a dystroglycan also functions as a receptor for agrin, an heparan sulphate proteoglycan, which cross-links laminin and dystroglycan at neuromuscular i~nctions~ and ~ J is~ thus involved in post-synaptic membrane organization and the localization of acetvlcholinesterase reccptorsI".
Function The dystroglycan complex is involved in early embryonic development, morphogcncsis of musclc, and scvcral othcr functions in 3 variety of tissues.
Dystroglycan forms part of the dystrophin-associated pmtcin complex involved in the linkage of hasement memhrane extracellular matrix t o the cellular actin cytoskeleton of skeletal and cardiac r n u ~ c l e ~ ~ The 'J~. cytoplasmic protein, dystrophin, cross-links actin to the cytoplasmic tail of p dystroglycan, which in turn hinds u dystroglycan and its matrix ligand, laminin-2. P dystroglycan is also associated with at least five other proteins in the ccll membrane (four sarcoglycans and sarcospan). The molecular assembly is somewhat different in neuromuscular junctions, where a different protein, utrophin, acts as the actin linkcr. The finding that dystroglycan is rnorc widely expressed than initially reported has led to the demonstration that it comhines with other memhrane and cytoplasmic proteins in a tissue-specific manner. Thus, dystroglycan is highly expressed in the hemidesmosome of stratified epithelia, hut it is not associated with sarcoglycans or sarcospan as in muscle. Here it seems to associate with different memhrane molecules, and does not utilize standard dystrophin or utrophin to hind it to the actin c y t ~ s k c l c t o n ~ ~ .
Distribution Dystroglycan is found in the majority of fetal and adult tissues. There is increasing evidence that cxprcssion of dystroglycan in skclctal and cardiac muscle, central and peripheral nervous systems, epithelial hemidesmosomes and placental (Reichcrt'sl membranes is functionally important' (see helowl.
Disease association OMIM 128239
The involvement of dystroglycan in thc pathogcncsis of muscular dystrophy is complcx.Thc 156 kDa a dystroglycan protcin is dramatically reduced in Duchcnne type muscular dystrophy but is not mutatedl"th. Mutations in other components of the dystrophin complex, such as dystmphin, laminin-2 and sarcoglycans, however, have heen shown to he c a u s a t i ~ e ~ ; ~ ~ .
Knockout MGI:lOlRh4 TIlc Gcnc Knockout FactsR~ok'~, p253 The mouse homologue of dystroglycan, Dag 1, was deletedm and resulted in an early embryonic lethal phenotype at 6.5 days owing to the loss of structural integrity of Rcichcrt's membrane, a spccializcd extra-embryonic basement membrane. Owing to the early lethality, no link to muscular dystrophy pathogencsis could he made.
Amino acid sequence of human dystroglycan 1 6l 12 1 191 24 1
MRMSVGLSLL ..,;:.." .,;-rr),7 . , PLPTDVG7,'l!'i ACA?sDEP','T'.' Fb!.'GPG?!?L'I'
LPLWGRTFLL LLSVVMAOSF T,':?SE?SSrl::!P D;'!EE?QLF.IAS?~ 7?7L,.. . m -.-q - -. . ,. . ' . . - . . ., . .iS.S GTIT TK?'SI;AG RE:ILPS!*?L'-l'/J TS'.'SA?W,C?, ?!GC?II'QTST: 7.'FSIF'.'YFFD HSDLOSilR?:\ LT'.'ILDADLT ?!~!TI'?~?I3!. Li!FI*?PS?SF3,.' ELW?!P!KL!IP '."'?,Oi 3 0 1 I:YYPP:,P"P'.' PDr3TH:jT?-? "?\:CFP"T-i TOFPPS?TVP TPTSPATAPP 1
-..-.-
F!S?rLSDLUE4 DSOSHT1,EGL SPDPGPT.'VSS
L'NP!RLFDk!S?< GY PVStC:,JHIA TETMAPP'b'3D
Dystroglycan is clcsvcd into a and P (transmcmhrancl pcptides at amino acid GAS.< (holdl.
Database accession EMRL/GcnRank SwissProt
L 197 1 1 Q14118
References Ihragli~~nov-Rcskrovnava, 0. ct 81. (19931 Hum. Molcc. Gcnct. 2, 16511657. Ihragh~mov-Rcskrovnaya,0. et al. (1992) N a t t ~ r c,355, 696-702. ? Rrancacc~o, A. ct al. (19951Matrlx Riol. 14, 681 -685. * Yotsumotn, S. et al. (19961Hum. Mol. Genet. 5, 1259-1267. Tinslcy, 1.M. ct al. (1994)Proc. Natl Acad. Sci. 91, 8307-8313. * Hcmlcr, M.E. j 19991 Cc11 97, 54,3-546. Durbeei, M. et al. (19981Curr. Opin. Cell Riol. 10, 594-601. C h ~ h a A. , ct al. (1997) 1. Riol. Chcm. 272, 2156-2162. Ramhukkana, A. et al. (19981 Sctence 282, 2076-2078. ' V a o , W. ct al. (19981Scicncc 282, 2079-2081. l 1 Gee, S.H. ct al. (1994) Cell 77, 675-686. Ma, J. ct al. 1199.31 J. Riol. Chem. 268, 25108-25 117. Campancll~,J.T. ct 81. 119941 Ccll 77, 663.674. Henry, M.D. and Camphcll, K.P. (1998)Ccll 95, 859-970. I5 Matsumura, K. ct al. (19921Naturc ,359, 320-322. Matsumura, K. et al. j 199.7) J. Clln. Invest. 92, 866-871. I' Camphcll, K.P. (19951Ccll 80, 675-679. In Strauh, V et al. (19971 Curr. Opin. Neurol. 10, 168-175. I V Mak, T.W. 119981Tht. Gcnc Knockout FactsBook. Academic Pruss, London. 20 Wllhamson, R.A. ct al. (19971 Hum.Molcc. Gcnct. (1, 831-841. f J
Family Ly-6 (mouse)family
Structure Molecular weights Amino acids Polypeptide
128 13286
SDS-PAGE reduced
20 kDn
Carbohydrate N-linkcd sites 0-linked sites Other
Gene location
8q24qtr
Gene structure
3 exons
Alternative forms Structure E48 is the human homologue of the mouse ThB antigen. It is a member of the Ly-6 gene family (containing the Ly-6/UPAR domain) and is GPI-linked to the memhrane12.
Ligands Unknown.
Function E48 is involved in keratinocyte cell-cell adhesiod", and regulation of kcratinocyte activation and functinnI.2.
Distribution Outer layer of transitional epithelia and keratinocytes of stratified squamous epithelia. Human lymphocytes do not express E48, unlike the mouse homolop~e, ThR, which is found on both lymphocytes and epithelium'.
Disease association There is recent evidence that E48 expression may he involved in tumour progression and m e t a s t a s i ~ ~ ~ .
1Knockout
-
-
Other Molecules -
Amino acid sequence of human E48 : ~TALLL-. .. .. . , . .. . ,... . . . .. .. .. ....-... ..
LAVATG~ALT :m ; . . .. . .. .
, ..
.
"r.
.. . . ... ... .... ,
'I.
,, ' ,-r'
.
. )
.,.. . 7 , ---I ::
-, .
.
.
r
... ..:,.
,7?u; (.:..:.:.:,: , .,.:,:. -L-*... ,..
.. .:..:.-.
: . -
:
-.... . , . .,,.... .. . . ...,. - . .:(."( . :. (::
'
The scquenccs underlined and in italics arc clcavcd off t o form mature E48 and a GPI anchnr is added.
Database accession EMRL/CenRank SwlssProt
X8269.Z Q14210
References Rmkenhoff, R.H. et al. 119951 1. Ccll R~ol.129, 1677-1689. Rrakenhoff, R.H. ct al. (19971J. Immunol. 159, 4879-4886. Schnivcrs, A.H. et al. (1991)Exp. Ccll Rcs. 196, 264-269. W ~ t z I.P. , (1999)1. Cell. Riochem. Suppl. 34, 61-66. Eshel, R. et al. (200011. Riol. Chem. 275, 1283,1-12840.
. --
E-selectin li and, Golgi sialoglycoprotein MG-160, cysteine-ric 1 FGFreceptor -
P
0 Family Structure Molecular weights
Gln-rich regton
Amino acids Polypeptide
1175 133 733
SDS-PAGE reduced
150 kDa (130 kDa unreduced)
Carbohydrate N-linked sites 0-linked sites
5
Gene location
16q22-q23
$ A
10 more cysteine-rich repeats A
Gene structure Alternative forms Structure
I
!
rii~ 1111
1111 1111
COOH
ESL-1 is a type I membrane sialoglycoprotein consisting of a glutamine-rich N-terminal region followed by 16 repeats of a 50-60 amino a c ~ dlong cyteine-rich motif. Aside from the N-terminal part of ESL-1, the sequence is highly homologous to the human cysteine-rich FGF receptor, which may be a splice variant of 'human ESL-l'l, and to the Golgi protein MG-1602.
Ligands E-selectin (CD62E) is hound hy the isoform of ESL-1 found on myeloid cells1. Other variants hind basic FCF (as 'cysteine-rich FGF receptort3)and are distinct from the signal transducing forms of FGF receptors.
Function The ubiquitous expression of ESL-1 in the Golgi apparatus of most cells from early stages of embryogenesis to adult life suggests that it might he involved in Golgi functionz, although this is not proven. In vitro studies have demonstrated that ESL-1 is a major ligand for myeloid E-selectin (CD62E) and is presumably involved in selective leucocyte endothelial transmigration1.
I
Distribution
I
Ubiquitous cellufar di~trihution'.~. The carbohydrate variant that binds to E-selectin (CDb2EJis only found in myeloid cells'.
I
Disease association OMTM 600753
--
-
--
-
Other Molecules -
Knockout MGI: 104967
Amino acid sequence of mouse ESL-1
Database accession EMRLIGcnRank Swis5Prot
X840<37(mouse\ QA 1543
References Stcegma~cr,M. ct al. (1995) Naturc 373, 615420. Gonatas, 1.0.ct al. (1989)J. Bin]. Chem. 264, 646-653. Rurrus, L.W.c t al. (19921Mol. Ccll Riol. 12, 5600-5609. Gonatas, 1.0.ct al. (1995)J. Cell Sci. 108, 457-467.
~ a c - 2 , ~ - 2 9CBP-30135,IgE hinding protein, galactoside binding protein, .etc. -
Family C-terminal lectin domain belongs to galaptinls-lectin family
Structure Molecular weights Amino acids Polypeptide
250 26 057
SDS-PAGE reduced
31 kDa (35,67 and 80 kDa]
PGAYPG repeats
[Multimer]
Carbohydrate N-l~nkcdsltes 0-linked sites
0
Gene location
14q21-q22
IIII~IIII~ I I I1I I I I I I
Gene structure Alternative forms Exists as monomeric, dimeric and trimeric forms.
Structure The C-terminal domain belongs to the galaptinls-lectin family14. Towards the ProlGly-rich N-terminal end of galectin 3, there arc eight nine-aminoacid-long tandem repeats of Y-P-G-xxx-P-G-A. Galectin 3 exists as a mixture of multimers through its N-terminal domains-'. Serinc phophoryalated (Serh and 121. No signal or transmembrane sequences, and the surface expression of galectin 3 is pmbabry due to secretion and association with cells via carbohydrate binding to other membrane molecules through its lectin domain6.'.
Ligands Galectin 3 binds P galactosides on laminin and IRE via the C-terminal lectin domains.? It also hinds to FccRl (high-affinity IRE receptor) and the secreted glycoprotein, Mac-2 hinding protein, which belongs to the scavenger receptor family7.
Function It is a membrane and secreted protein of inflammatory macrophages, which binds galactose-containing ligands. It also mediates macrophage adhesion to laminin when cross-linked by transglutaminase. T h e intracellular distribution of galectin 3/Mac-2 t o the apical peripheral membrane of polarized colonic epithelia cells suggests an additional role in targeted cellular protein secretion. A separate intracellular role is postulated due to its localization in the n u c l e u ~ " ~Recent . evidence
Other Molecules
suggests that galcctin ,Z is involvc~l in turnour proliferation and apoptosisv. I t inturacts with thc neural adllcsion molcculc, L 1 , and promotcs ncuritc outgrnwth").
Distribution Activated macrophagcs, hast~philsand mast cells, scncnry n c u r o n ~ ~ . 2nd '~~, colonic cp1th~Iii11~1 and colon canccrssl.
Disease association OMIM 15d619
0 Knockout Amino acid sequence of human galectin-3
. . !
Database accession EMRL/GenRank Sw issProt
M577 10 PI 79.3 1
References Chcrayil, R.1. ct sl. (1990)Proc. Natl Acad. Sci. USA 87, 7324-7328. Rohcrtson, M.W. ct al. (19901 Riochem. 29, 8093-8100. Oda, Y. ct al. (19911 Gcnc 99, 279-18.3. Raz, A. (1991JCanccrRcs.51, 217.1-2178. Liu, F.-T. 1199.31Immunol. Totlav 14, 486-490. Rarondes, S.H. ct al. (19941 j. Riol. Chcm. 269, 20807-20810. Hughes, R.C. (1991)Glvcohiology 4, 5-12. Lotz, M.M. ct al. (199.31 Proc. Natl Acad. Sci. USA 90, LZ46(1-,Z470. Kim, H.R. ct al. i 19991 Canccr Rcs. 59, 4148-41 54. I n Pcshcva, P. ct a]. (19981 J. Ncurosci. Rcs. 54, hZ9-654. i r Ho, M.-K. and Springer, T.A. (1982J1. Immunol. 128, 1221-1227. ' W u f l c i t , M.E. ct al. 119971 1. Riol. Chcm. 272, 14294-1430
Glycosylation-dependent cell SGPSO Proteose-Peptone component 3 (PP3) -
Family
Structure Molecular weights Amino acids Polypeptide
146 amino acids
SDS-PAGE reduccd
50 kDa [SOkDa unreducedl
15 440
Carbohydrate N-linked sites 0-linked sites
1 Abundant + + +
Gene location
Mouse chromosome 15
Gene structure
2.5 kh
R ? COOH
Alternative forms Structure Sulphated secreted mucoprotein1-I with two extracellular serinelthreonine rich regions, which are heavily 0 - g l y ~ o s y l a t e d ~ ~ ~ .
Ligands Carbohydrate-dependent hinding to L-selectin (CDh2L) on the luminal surface of high cndothelial venules of peripheral lymph nodes, involving Olinked carbohydrates, including sulphated forms of sialyated Lewisx carbohydrate sequence.
Function GlyCAM-1 is involved in lcucocytc adhesion via L-selectin (CDh2LJ and hence migration through high endothelium during inflammations (see Lselectin entry). Being a secreted molecule it is speculated that GlyCAM-1 reassociatcs with the cell surface and acts to downreplate L-selectinmediated adhesionh. The soluhle form of GlyCAM-1 may he involved in regulating T cell activation.
Distribution Peripheral and mesentcric lymph node high venular endothelium6, lactating mammary glandRand lung9. Detectahle in blood and milk as secreted form9; the milk form does not hind L-selectin. Increased plasma levels of GlvCAM-1 are obscrvcd following exposure to inflammatory stimuliJ0.
Disease association
Pm
Other Molecules
Knockout MGT:95759
Amino acid sequence of rat GlyCAM-1
Database accession EMRL/GcnRank SwissProt
LO8 100 [rat] Q04807 [rat]
References
.I
In
Laskv, L.A ct al. (19921Ccll69, 927-9,38. Dowhenko, D. et al. (1993al J. R~ol.Chem. 268, 4525-4529. Dowbcnko, D. ct 81. (1993bl J. Blol. Chcm. 268, 14,399-14403. Hemmer~ch,S. et al. (199511. R~ol.Chem. 270,12035-12047. Johnson-Lcgcr,C. ct nl. (20001J. Cell Scl. 1I,?, 921-933. lirustc~n,hl. et nl. (19921 J. Exp. Med. 176, 1415-1419. . 97, 54-64. Onrust, S.V. ct al. (19961J. C l ~ nInvest. Nlsh~mura,T. ct al. (1993)1. Riochcm. 114, 567-569. Lasky, L.A (199il Annu. Rev. R~ochem.64, 1 13-139 Sugur~,T. ct al. 119961 I. Lcukoc. Riol. 60, 593-597.
--
I
-
Heat stable antigen, CD24, BA-1, (mouse) Ly-52 --
-
----
- --
Family Structure Molecular weights Amino acids Polypcptidc
80 8 083
SDS-PAGE reduced
35-45 kDa
P~PP~PPPP bbbb bbbb
Carbohydrate N-linked sites 0-linked sites
2 prohahl y + + +
Gene location
6q2 1
Gene structure
2 exons
Alternative forms Multiple HSA/CD24 gencs have heen idcntificd in human and mouse1-' as have RNA splice variants.
Structure HSA is a sialoglycoprotein that is GPI-linked to the membrane. The mature protein is prudicted to be of 33 amino acidsz&. Its high content of threonine and scrinc implies cxtcnsivc 0-glycosylation.
Ligands HSA is a ligand for P-selectin (CDh2P)'J.
Function Possible functional involvement in R cell proliferation and differentiationv. HSA/P-selectin interaction may play an ancillary role to the maior selectin (CD62) ligands in leucocyte interactions or endothelial transitlR. HSA mediates tumour cell binding to endothelium under static conditionsR. Signal transduction via HSA may modify integrin a$, (CD49dbmediated adhesive interactionslO.HSA, decorated with the CD57 epitope (see entry), interacts with L1 in the brain".
Distribution Activated, but not late (antibody forming cells), R lymphocytes and granulocytes, hut not T cells and monocytes, express HSA5.6Jzl'. Tissue distribution differs in the mouse being expressed by thymocytes, erythrocytes, dcvcloping epithelium and central nervous ~ y s t e m ' ~ . 'High ~. expression by small cell lung carcinoma6.
---
---
-
-- -
Other Molecules
Disease association OMIM 600074
Knockout MG1:88323 HSA knockout micc havc alterations in numhcrs of immaturc honc marrow R-cclls1hnd erythrocyte abnormalities.
Amino acid sequence of human HSA :
M G W A R L G LGLLLLALLL PTQIYSf'::':'': , . -. , . . ;. . . . , - - ,.. . ;:. .. -., . . ,. . . . . . .-..- .. . . .
': :':l':'::::?;,': :-.?::.:C: ,:..?::
-.. .... .:....'....-. . .. .,. ,.
,
,
8
?,,.
>
The sequences underlined and in itnlics are cleaved off to form mature HSA and n GPT anchor is added.
Database accession EMRL/GenRank SwissProt
M58664 P250h;i
References Wcngcr, R.H. ct al. (1991)Eur. j. Immunol. 21, 1039-1046. Wcnger, R.H. et al. (1993)1. Riol. Chem. 268, 23345-23353. .'Hough, M. R. ct 81. (1994)Gcnomics 22, 154-161. * Kay, R. ct al. (1990)1. Immunol. 145, 1952-1959. Kay, R. ct al. (1991)1. Immunol. 147, 1412-1416. " Jackson, D. ct al. (19921Cancer Res. 52, 5264-5270. ' Sammar, M. ct al. (1994)Int. Immunol. 6 , 1027-1036. Aigncr, S. ct al. (1997)Blood 899, ,3.385-cZ.395. Kadmon, G. ct al. (1992)J. Cell Riol. 118, 1245-1258. l R Hahnc, M. ct 81. (19941J. Exp. Mcd. 179, 1391-1395. Sammar, M. ct al. (1997)Riochcm. Riophys. Data 13.37, 287-294. I2 Kcmshcnd, J.T. ct nl. I19821 Hvbridoma 1, 109-12<3. Hsu, S.-M. and Jaffc, E.S. (1984)Am. J. Pathol. 114, ,387-395. IJ Takci, F. ct al. (19811 Immunology 42, .?71-,378. I5 Enk, A.H. and Katz, 5.1. (1994)J. Immunol. 152, 3264-3270. Wenger, R.H. et 81. (1995) Transgenic Rcs. 4, 173-1 83. I' Niclscn, P.J. ct al. (1997)Rlond S9, 1058-1067,
Family Hyaluronan receptor
Structure Molecular weights Amino acids Polypeptide
322 35 158
SDS-PAGE reduced
60 kDa
C
Carbohydrate N-linked sites 0-linked sites
2
Gene location
1 lq15
Gene sttuctute
+
6 exons, approximately 1 l kh
2
COOH
Alternative forms Structure Thc N-terminus of L W E - 1 contains an extended link domain generating the presumptive hyaluronan binding site1.
Ligands L W E - 1 is a cell surface receptor for the glycosaminoglycan, h yaluronanf.
extracellular
matrix
Function L W E - 1 has a putative function in sequestering hyaluronan on lymph vessel wall and/or supporting hyaluronan-mediated rolling of leucocytes in the lymph fluid.
Distribution L W E - 1 cxhibits a restricted pattern of expression being mostly confined to lymphatic endothelial cellsf.
0 Disease association
0 Knockout
.
.
. .
Other Molecules
Amino acid sequence of human LYVE-1 :
MARCFSLVLL LTS1WTTRL.L VQGS:.:. :-!'!:: 7:,.:'.':'i':
. .. - . . , ;. . , , . .. .,,.__ . i; ' ,.,. .. . .. .. . ~ * - ... . .--.- .-......... . . . ,, , , , ,.. . - . . . ! ,.,. :,- ...r.7un:.: . . .,* . . .,.,,.\ .. . : , > .,, -..,.;:, r r . .:. .r. , .. . . .. ,. . , .,. .. .. . .. . -
1
.
, , - .
:.; . ,..... -. .., ..,.,- .
, , , ....--r.,;,: , ,
(.,,.-
,
..
,
,
,
..:..,,... . . ,
.r,.:.-.. ;._r . .,. . .
I,,:-...
,.7;:-l."r .,
:"': :T : '.'::r'7;.I:ij i;~':r-r-r'r:. : . . ..... ....... , .. * , . ...,. . . .-. . . . ... . '.... .,'. r ;.. r: ,. .,., ,,-. . . . . . ... . ,>-- P :, . . .... . .
-.,----; ,,
.
..
;..-r /1_1. -..--9.-
. ..
_ r-.-
Database accession EMRLIGenRank TrEMRL
..-
.I
....-, (~,.7..,,.7i~,7 -. -.,-.. . . . .. . ..
* !,
AF 1 18 108 Q9Y5YJ
References Ranerii, S. et al. (19991 1. Cell Riol. 144, 789-801.
..
-
7bTV...~,7VT!~..., ..
8 .
-- .?.,.
r..-.k.r - .>.,.,.
,..Trp::.': ,
;:.,L
.-;,r-
r.;.-
Family
n I I
ELL/occludin family
Structure Molecular weights Amino acids Polypeptide
522 59 143
SDS-PAGE reduced
60 kDa
IIIII IIIII
IIIII IIIII COOH
Carbohydrate N-linked sites 0-linked sites
0 0
Gene location Gene structure Alternative forms Structure Occludln is an integral membrane protein of epithelial tight i u n c t i o n ~ ~The .~. first occludin sequence cloned was from the kangeroo rat and was predicted to have four transmemhrane domains with both N- and C-termini oriented cytoplasmically. Howcvcr, thosc occludins that have been cloned subsequently from other species (including human] have been found to have five predicted memhrane spanning domains and hence would have a different configuration with their N-tcrmmus extraccllular (as illustrated]. The first extracellular domain, which may he functional in intercellular adhesion, contains a high proportion of tyrosinc and glycinc amino acid rcsidues. The C-terminal part of the molecule interacts with TJPl/ZO-1 (OMIM 601009), a PDZ domain7containing protein of tight iunction plaques.
Ligands Probably interacts with occludin or claudins on opposing cclls within the tight iunction. It has been shown recently that occludin interacts directly with the gap junction component, Cx32,in polariscd hepatocytcs4.
Function Occludin is involved in the formation and function of cell-ccll tight iunctional interactions in epithelial and endothelial c e I l ~ 1 ,Tight ~ ~ . junction structure, component proteins and function havc been extcnsivcly reviewed recently"14. In vitro deletion of o ~ c l u d i nfailed ~ ~ to abrogate tight junctional transccllular rcsistancc suggesting the involvement of other key molecules (see claudins). Occludin is presumed t o either play a secondary role in tight junction formation, or to be involved in functional gating of m o l e c ~ ~ l e s passing through cpithclial or cndothclial harriers.
Other Molecules
Distribution Tight junctions of epithelium and cndothelium in a wide rangc of tissues.
Disease association OMIM 602876
Knockout MG1: 1 06 18.3 111 vrtro knockoutf5 in embryonic stem cells showed that tight junctions formed in the absence of occludin upon epithelial differentiation. This led to thc rliscr~vury of the claudin family of prcltcins as bcing ussuntial components for the structural integrity of epithelial junctions.
Amino acid sequence of human occludin r,-"
<
. -'
i.
'
r
1
"
.(
' 1
,.
'
.
' ,
.- . . , .
I
...
^
1
* . l o
SVGYPYGGSG -'" '1" MLMAAFCFI AALVIFVTSV I VI IVSA
ILGIMVFIAT I W I M -IAIVL FMIIVAFALI IFFAV 1
..I,
'
ILSH LIIVMCIAIF ACVAST
. .
-
.-
r
'
-,
-
' "YGTSLLGG
"'
- -I . ' * - "
..'
. - -
8"
.-
T .
F.1
-, - T
-
rn
?,,h
fJ
?
- -
[
,- ' 'rr * I F
?
?
... . .
1-
Database accession EMRLlGenRank SwlssProt
U49 184 Q 16625
References Furuse, M. et al. (199<3)1. Cell Riol. 123, 1777-1 788. Ando-Akatsuka, Y. et al. (19961 I. Ccll Riol. 1.3.3, 4*347. Cravcn, S.E and Rredt, D.S. 119981 Ccll 9.3, 495-498. * Koii~na,T. et al. (19'191Riocllem. Riophys. Res. Comm. 266, 222-229. Fumsc, M. ct al. (1994)1. Ccll Riol. 117, 1617-1626. McCarthy, K.M. et al. (1996)1. Cell Sci. 109, 2287-2298. Tsukita, S a n d Furusc, M. (1999)Trends Cell Riol. 9, 168-27,3. Ruhin, L.L.and Staddon, 1.M. (19991 Annu. Rev. Ncurosci, 22, 11-38. Stcvcnson, R.R. and Kcon, R.H. (19981 Annu. Rev. Cell Dev. Riol. 14, 89-1 09. lo Citi, S. and Cordenonsi, M. (1998)Riochem. Riophys. Acta 1448, 1-1 1. Matter, K. and Balda, M.S. (19991 Int. Rcv. Cytol. 186, 117-146. Madara, 1.L. (19981 Annu. Rev. Physiol. 60, 143-159. I.? Mitic, L.L. and Anderson, 1.M. (1998)Annu. Rev. Phvsiol. 60, 12.1-142. IJ Denken, R.M. and Nigam, S.K. (19981 Am. 1. Physiol. 274, Fl-9. IFSaitou, M. et al. (199S11. Ccll Riol. 141, 397-408.
Podocalyxin-likeprotein, Ly 102
-
-
-
Family Sialomucin
Structure Molecular weights Amino acids Polypeptide
528 55 561
SDS-PAGE reduced
160-165 kDa
Carbohydrate N-linked sites 0-linked sites GAG
5
4 potcntial GAG attachment sites
Gene location
7q32-7q33
+++
Gene structure Alternative forms Structure
COOH
The sequencc of podocalyxin-likc protcin (PCLP) together with the discrepancy between predicted and actual molecular weight indicates extensive 0-linked glycosylation hetween the N-terminus and Thr 300. This suggests that PCLP would have an extended filamentous conformation. Carbohydrate analysis demonstrates that the net negative charge derives from both sulphate and sialic acid residues1.2. In addition, in the extracellular domain there are four potential GAG attachment sites and four membrane proximal cysteine residues for potential disulphide bond formation? The cytoplasmic domain is highly acidic with a numher of potential phosphorylation sites.
Ligands PCLP is a ligand for L-selectin4.
Function The expression of PCLP in high endothelial venules and the demonstration that it can hind L-selectin, and mediate the tethering and rolling of lymphocytes under physiological flow conditions, indicates a function in the recruitment of lymphocytcs to secondary lymphoid organs. The similar structure and expression patterns of PCLP and CD34 suggest that they may have redundant or overlapping physiological roles4. It is not known whether PCLP has an adhesive function in the podocytes or whether it has a structural role maintaining the integrity of the filtration slits by contributing to the anionic glycocalyxf. Like all mucins, PCLP may also have a cytoprotective and/or antiadhesive function.
-
--
-
--
Other Molecules
Distribution
-
PCLP is localized to the apical surface of renal glomcrular cpithclial (podocvtel foot processes, vascular endothelial cells and high endothelial v c n u l e ~ In ~ .addition PCLPl is a marker for hacmangiohlasts that give rise to long-term repopulating hacmatopoietic stem cells'.
Disease association OMIM 602632 Reduced sialylation of PCLP is found in aminonucleoside nephrosisn. Urinary levcls of PCLP is an indicator of glomcnilar cpithclial cell injuryv.
0 Knockout Amino acid sequence of human podocalyxin-like protein LLLLSTppLL p - 7 : 7 ;.-"-!
MRC-LSAL
r:#:','':',711T-'
-?r;"'.-. .'
--.
i.
. . . . . .. ., .
r- '- r , . " b ? ' -
:"f-:r,-r,.zTT . . . .... ., , - . . . . . . . ........ . . . . .... :.'.. . -.. .,__ . . r, !- - .,- - .,;,, ?,Z . ---,-. .. .I. ...---. .- ""'.,,' . . . . ". ,"". . . -. .... . "'-" . . , . ,. .., . --. . . . . ;., -?:'"" . . . I:.'.,-- -. . # ". . . ..'';,,EF!L. - - r::r_,pr . - r. .r ,.,r,-.. . .. .. . ..-: :..,!. ..,--" . . , -., - - .- . . . . . -,--. . ... .--..-r -.- r,7..T-T; 7,-" . - - . ,--, -,:--.-: . --.---7-. 7,r".,r ,--r-., ;,,--- .. -., -.,T .. *. . .. . ., . .?. : >r . .., . . . ' , . . . . . . .... .". . . . , . . . . . . . . . . . ."r,.' " . . --,? .,...... . . .. . .. . .:. . . .. . ., , . . . . ., . . . . .. .. - - - _ . :.: ..,-. - . . .,.-, . .n . .:. . .,... .c:-. . . -,-. ., . .. r :?. F::? 'C-" :-.,-:T7: ; r..7':cr->-.... ..------. ......>'. .:r:y y - >-..--r-,;.<:.r-;.. ~~..&.:,?>~,,;~ .-... . r,. ..... .......,~.<,- .... . ,.,.. .. .,.... r:<.;.t:r,:,. .! .:-": . . . ., ,;.: .,;; . . ... . . ....,L . . .qO'. ;-,n. - * . .. . ,,-. - . .<.-..
-
L_,
\:
I. .I..?
!
-
7
.
>.l-
.I
!
.I;.
p.,
,
.?.
-8
...... I - ..,, ,. . . . .. . . . ,. .. . . . . . . .. . , . . . .. . . . ., A .
,
. 8
- L .
,,..>.
,.-.,. . .,.,.
.
......
--:,--
.......I
..
Database accession EMRL/GtnRank TrEMRL
U975 19 000592
References
.5
Keriaschki, D. et al. (19841j. Rid. Chcm. 98, 1591-1596. Dckan, G, ct al. (19911 Proc. Natl Acad. Sci. USA 88, 5,398-5402. Kershaw, D.R. et al. (19971J. Riol. Chcm. 272, 15708-15714. Sassctti, C. ct al. (199811. Exp. Mcd. 187, 1965-1975. Horvat, R. et al. 119861 1. Ccll Rid. 102, 484491. Kcrshaw, D.R. ct 81. 11995) 1. Riol. Chcm. 270, 29439-29446. Hara, T. et al. (1999)Immunity 11, 567-578. Keriaschki, D. et al. ( 1985) Am. J. Pathol. 118,.34.3-.390. Hara, M. ct al. (1995)Ncphron 69,397-403.
P-selectin ligand, CD162
--
--
1
Family Sialomucin
Structure Molecular weights Amino acids Polypeptide
412 41 301 120 kDa (250, 160 kDa (neutrophils)](220 kDa in HLhO cells1
SDS-PAGE reduced Carbohydrate N-linked sites O-linked sites
3 Abundant + + +
Gene location
12q24
Gene structure
9 kb, 1 cxon, gcne structure resembling that of CD43 and CD42h (gpIha)
3 '.I
tyrosine sulfation sites
COOH
COOH
Alternative forms Two variants {short and long forms, prohahly hy post-translational proteolytic cleavage rather than splice variation as PSGL-1 is encoded hy a single exon).
Structure Disulphide-bonded homodimeric type I transmcmhranc mucin-like g l y ~ o p r o t c i n ~An , ~ .N-terminal 23 amino acid propeptide sequence is cleaved at a consensus dihasic site (RxRR) hy 'PACE' (paired hasic amino acidconverting cnzyme17. This is followed by a sulphatcd region containing three tyrosines. A region containing a series of 16 repeats of 10 amino acids is present in its extracellular part in most leucocytcs (or 15 in HL60 and other These are heavily 0-glycosylated cell lines; and only 10 in murine PSGL-I forming a mucin-like structurei. 0-glycan stnlcture has hecn determined", a subset containing 'core-2', sialylated and fucosylated structures being required for functional integrity of PSGL-1 and hinding to all three selectins. N-terminal tyrosine sulphation is also required for recognition of P-selectin (CD62Pl and L-selectin (CD62LlXn. Rinding to E-selctin (CDh2El occurs at lower affinity and docs not rcquirc tyrosinc s~1Iphation2,J~.
Ligands Rinds to P-, L- and E-selectins (CDGZP, CDh2L and CDG2E, r e s p e ~ t i v e l y l ~ J J - ~ ~ .
Function High-affinity counter-receptor for P-selectin (CD62P) (hence, PSGL-I, Pselcctin glycoprotein ligandl on mycloid cells and activated T lymphocytcs2.J5. PSGL-1 mediates rolling of leucocytcs (neutrophils)on activated endothelium under conditons of physiological blood flow"JJ.J"J', lcucocytc hinding to platclcts and Ieucocyte interactions (neutrophils, T lymphocytes) at sites of inflammation via their interaction with P- and L-selectins.
Distribution Most peripheral T cells, some B cells, ncutrophils, monocytcs and p]ate~ets2.11.1i.JRr0
Disease association OMIM 6007.18
Knockout MGI: l 06689 PSGL-I -1- mice are viahle and fertile hut leukocyte infiltration into inflammatory sites is significantly delayed suggesting that PSGL-1 is the predominant neutrophil P-selectin ligand hut is not required as a counterreceptor for E-sclectin in r ? i ~ o ~ ~ .
I
Amino acid sequence of human PSGL-1 1 MPLQLLLLLI LLQPGNSLQL iiTDTl+'A3EAE.K ALGPLL-APDP .RQSTEYEYLD YD'?LPETEPP
7':".'?i:(:y..'.'7' AQYTSLTATE IF!] AO?TOPTGI,F AOTTAP.Z.AYF. AOTT.A?AAM- AOTT?PAA!,!E 24 1 AOTTOPTATC ACTTPLAAI-!E AI,STETSI:.TE !?.LSM?PTTb'B 3 0 1 SP!LSVPJYPV3 APD!l:S1.'YQr LLAI LIL?..L'm.' ATIFFVCT'!"' 361 E M V C I S S L L P xGEGPSATF, IlCCL.St:.Ai-S? C : L T P ? P P 3 ?
6 1 EMIA:;I?:STDTT PLrT!;I":;'?P!<S
1 2 1 TOTTOPAATE >.QTTQP'dPTE AQ7TPLA.L.T:
?LTTEL'I?I!CG AQTTPL->ATE .AOTTOTTA!.!E GI,F T PFS'JSS LAVFLSPTGH
TILSTDSAAME AQTTPPAATE AOTTAPSATE 'JTHKGI P!.!AA MVP1!PE:YSPT
PFGD3LTLHSF LP
The propeptide (amino acids 19-41) cleaved by 'PACE' enzyme is underlined and italicized.
Database accession EMRLlGenRank SwissProt
U25956 Q 14242
References Sako, D. et al. (1993)Cell 75, 1179-1 186. McEver, R.P. et al. (1995)J. Biol. Chem. 270, 11025-1 1028. Li, F. et al. (19963)J. Riol. Chem. 271, 6342-6348. Veldman, G.M. et al. (1995)J. Riol. Chem. 270, 16470-16475. Moore, K.L. et al. (1994)J. Riol. Chem. 269, 23318-23327. Wilkins, P.P. et al. (1995)J. Riol. Chem. 270, 22677-22680. ' Sako, D. et al. (1995)Cell 83,323431. Pouyani, T. and Seed, R. (1995)Cell 83,333-343. Wilkins, P.P. et al. (1995)J. Riol. Chem. 270, 22677-22680. lo Li, F. ct al. (1996b)J. Biol. Chcm. 271,3255-326s. Spertini, 0. et al. (1996)J. Cell Riol. 135, 523-531. l2 Rosen, S.D. and Rertozzi, C.R. (1996)Curr. Riol. 6, 261-264. Tu, L. et al. (1996)J. Immunol. 157,3995-4004. 14 Walcheck, B. et al. (1996)J. Clin. Invest. 98, 1081-1087. 15 Vachino, G.et al. (1995)J. Biol. Chem. 270, 2196621974. l6 Alon, R. ct al. (1994)J. Cell Biol. 127, 1485-1495. Norman, K.E. et al. (1995)Blood 86,4417-4421. lR Laszik, 2. et al. (1996)Blood 88,30104021. f q Frenettc, P.S. ct al. (2000)J. Exp. Mcd. 191, 1413-1422. Yang, J. et al. (1999)J. Exp. Med. 190, 1769-1782.
-
- -
Vascular adhesion protein-1 -
-
n Family Coppcr/topaquinonc oxldase family
Structure Molecular weights
COOH
Amino acids Polypeptide
763 84 568
SDS-PAGE reduced
1 10 kDa
Carbohydrate N-linked sites 0-linked sites
6
+
Gene location Gene structure
14.4 kh, 4 exons in mouse1
Alternative forms Cell-specific isoforms have been descrihedz
NH2 NH2
Structure Unusually for an adhesion rcccptor, VAP-1 is a type I1 transmembrane protein with its N-terminus intracellularly. The extracellular domain contains sites for hoth N-and 0-linked glycosylation and enzyme treatment demonstrates that VAP-1 is a sialoglycoprotein. Strikingly, sequence analysis of VAP- 1 revealed significant identity to the copper-containing amine oxidase family. Moreover, VAP-1 was shown to have a quinone cofactor and monoamine oxidase activity. Western hlot analysis demonstrates that VAP-1 is expressed at the cell surface as a 170-190 kDa homodimerhs.
Ligands VAP-1 ligand(s) have not been identified. However, it is known that VAP-1 mediates lymphocyte binding to peripheral lymph nodes in a selectinindependent mannep.
Function Endothclial VAP-1 initiates the contact of a subset of lymphocytes to the peripheral lymph nodc high cndothelial v e n u l e ~ ~ . The ~ . ~ . relationship hetween the copper-dependent monoamine oxidase enzyme activity" and the role of VAP-1 as an adhesion receptor is not clear. lt is possihle that different functions arc mediated in diffcrcnt VAP- 1 expressing tissuesJ.
Distribution VAP-1 is cxprcsscd mainly in thc high cndothclial vcnulcs of peripheral lymph node lymphatic tissue and is upregulated in chronic i n f l a m r n a t i ~ n ~ . ~ . Expression is also dctcctcd in hepatic cndotlielial cclls, smooth muscle and dcndritic cclls.
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References Rono, P. et al. (1998)J. Immunol. 161, 2953-2960. Salml, M. and Jalkancn, S. (1995)Eur. 1. Immunol. 25, 2803-2812. Rono, P. ct al. (1998)J. Immunol. 160, 5563-5571. Smith, D.J. ut al. (1998)J. Exp. Med. 188, 17-27. Zhang, X. and McIntirc, W.S. (1996)Gcnc 179, 279-286. Salmi, M. et al. (19971J. Exp. Med. 186, 589-600. ' Salmi, M. and Jalkanun, S. (1996)J. Exp. Mcd. 183, 569-579. Salmi, M. and Jalkanen, S. (1992)Science 257, 1407-1409. Salmi, M. ct al. (1993)J. Exp. Mcd. 178, 2255-2260.
Adherens junctions, 12 Adhesion molecules criteria for selection, 2-3 ALCAM, 89 a agrin receptor. See Dystroglycan Amino acid codes, 6 AMOG, 235 Amphiglycan. See Syndecan-4 apCAM See NCAM Axonin- 1. See TAG-1 B lymphocyte cell adhesion molecule. See CD22 BA- 1. See HSA Basigin. See CD 147 BEN. See ALCAM pp. See Integrin.p, Blast-2. See CD23 BL-CAM. See CD22 BP180. See Collagen type XVII (a1 chain) BPAG2. See Collagen type XVII (a1 chain) Brain cadherin. See Br-cadherin Bullous pemphigoid antigen 2. See Collagen type XVII (a1 chain) Cadherin- 1. See E-Cadherin Cadherin-2. See N-Cadherin Cadherin-3. See P-Cadherin Cadherin-4. See R-Cadherin Cadherin-5. See VE-Cadherin Cadherin-6. See K-Cadherin Cadherin-8, 57 Cadherin- 11. See OB-Cadherin Cadherin- 12. See Br-Cadherin Cadherin-13. See H-Cadherin Cadherin- 14, 65 Cadherin- 15. See M-Cadherin Cadherin- 16. See Ksp-Cadherin Cadherin-17. See LI-Cadherin Br-Cadherin, 61 E-Cadherin, 43 H-Cadherin, 63 K-Cadherin, 55 Ksp-Cadherin, 69 LI-Cadherin, 71 M-Cadherin, 67 N-Cadherin,46
N-Cadherin 2. See Br-Cadherin OB-Cadherin, 59 P-Cadherin, 49 R-Cadherin, 5 1 T-Cadherin. See H-Cadherin VE-Cadherin, 53 Cadherins, 7-13,41-72 classic cadherins, 7-10 desmosomal cadherins, 8, 10 function, 12-13 ligands and regulation of ligand binding, 11 protocadherins, 10-1 1 signal transduction, 11-12 structure, 7-1 1 Carcinoembryonic antigen cell adhesion family. See CEACAM family CBP-30135. See Galectin 3 C-CAM family. See CEACAM family CD6, 237 CD 11a. See Integrin a, CD 11b. See Integrin a, CD 11c. See Integrin a, CD 11d. See Integrin a, CDl8. See Integrin .P, CD22, 91 CD23,239 CD24. See HSA CD29. See Integrin .P, CD31,94 CD33, 97 CD34,241 CD36, 244 CD36 family, 28 CD39, 247 CD41. See Integrin a,,, CD42a, 249 CD42b, 25 1 CD42c, 254 CD42d, 256 CD43,258 CD44,261 CD49a. See Integrin a, CD49b. See Integrin a, CD49c. See Integrin a,3 CD49d. See Integrin a, CD49e. See Integrin a, CD49f. See Integrin a,
CD50. See ICAM-3 CD5 1. See Integrin a, CD54. See ICAM-1 CD56. See NCAM CD57,264 CD61. See Integrin P, CD62E. See E-selectin CD62L. See L-selectin CD62P. See P-selectin CD66 family. See CEACAM family CD96,99 CD98,266 CD 102. See ICAM-2 CD103. See Integrin a, CD104. See Integrin P, CD 106. See VCAM-1 CD138. See Syndecan-1 CD144. See VE-cadherin CD146. See MUC18 CD147, 101 CD 162. See PSGL-1 CD164,268 CD166. See ALCAM CD169. See Sialoadhesin CD171. See L1 CD242. See ICAM-4 CEACAM family, 104 Cell adhesion molecule web resources, 34 Claudin-1, 271 Claudin-3, 273 Claudin-4, 275 Claudin-5, 277 Claudins database accessions, 279 family, 279 Clostridium perfringens enteroxin receptor 1. See Claudin-4 enteroxin receptor 2. See Claudin-3 Collagen type XI11 (a1 chain), 280 Collagen type XVII ( a 1chain),282 Complement receptor 4. See Integrin a x
Contactin-1, 108 CR3. See Integrin a, Cysteine-rich FGF receptor. See ESL-1 DAG 1. See Dystroglycan Database accession, 6
Desmocollin 1, 73 Desmocollin 2, 76 Desmocollin 3, 78 Desmoglein 1, 80 Desmoglein 2, 83 Desmoglein 3, 85 Desmosomes, 1, 2 Disease association, 5 DM-GRASP. See ALCAM Dystroglycan, 285 Dystrophin-associated glycoprotein 1. See Dystroglycan E48,288 Ecto-apyrase (EC 3.6.1.5). See CD39 ELAM- 1. See E-selectin EMMPRIN. See CD147 Endolyn. See CD164 Endothelial leucocyte adhesion molecule-1 . See E-selectin Epithelial cadherin. See E-Cadherin ESL-1, 290 EST databases, 34 4F2 (mouse)lymphocyte activation antigen. See CD98 Fascilin I1 (Drosophila).See NCAM FccRII. See CD23 Fibroglycan. See Syndecan-2 Fibronectin receptor. See Integrin a, Galactoprotein P3. See Integrin a, Galactoside binding protein. See Galectin 3 Galectin 3, 292 GenBank, 33 Gene knockout resources, 34 GlyCAM- 1, 294 Glycocalicin. See CD42b Glycosaminoglycans (GAG),4 Glycosylation, 4 Glycosylation analysis, 35 Glycosylation-dependent cell adhesion molecule 1. See GlyCAM- 1 GMP-140. See P-selectin Golgi sialoglycoprotein MG-160. See ESL- 1 gpIba. See CD42b gpIbp. See CD42c
gpIV or gpIIIb. See CD36 gpV. See CD42d gpIX. See CD42a gp67. See CD33 HDGC. See Desmoglein 2 Heart cadherin. See H-cadherin Heat stable antigen. See HSA Heparan sulphate proteoglycan. See Syndecan-2 Hermes-3. See CD44 HML-1. See Integrin a, HNK1. See CD57 HSA, 296 HSPG. See Syndecan-2 Human genetic diseases, 34 Human gp135 (chick F11, mouse F3). See Contactin-1 ICAM-1, 111 ICAM-2, 114 ICAM-3, 116 ICAM-4, 118 ICAM-5, 120 Icons used for protein domains and repeats, ix IgE binding protein. See Galectin 3 Immunoglobulin superfamily, 13-15 ligands, 15 neural IgSF members, 14-15 siglecs, 14 signal transduction, 15 structure, 13-14 subfamilies, 14 Integrin a,, 159 Integrin a,, 161 Integrin a,, 164 Integrin a,, 167 Integrin a,, 170 Integrin a,, 173 Integrin a,, 176 Integrin a,, 178 Integrin a,, 180 Integrin a,,, 182 Integrin a,,,, 184 Integrin a,, 157 Integrin a,, 190 Integrin a,, 149 Integrin a,, 152
Integrin a,, 187 Integrin a,, 155 Integrin P,, 192 Integrin P,, 195 Integrin P,, 198 Integrin P,, 20 1 Integrin P,, 204 Integrin P,, 206 Integrin P,, 208 Integrin P,, 210 Integrins, 16-2 1 alternative forms, 19 associated proteins, 20-1 cell adhesion molecules of focal adhesion contacts, 16 clinical use of antagonists, 21 ligand specificity, 19-20 peptides recognition motifs, 21 structure, 16-18 subunit structures, 17 three-dimensional models, 18-1 9 Intercellular adhesion molecule- 1. See ICAM-1 Intercellular adhesion molecule-2. See ICAM-2 Intercellular adhesion molecule-3. See ICAM-3 Intercellular adhesion molecule-4. See ICAM-4 Intercellular adhesion molecule-5. See ICAM-5 JAM, 122 Junctional adhesion molecule. See JAM KG-CAM. See ALCAM Kidney cadherin. See K-cadherin Kidney-specific cadherin. See Ksp-cadherin L1, 124 L-29. See Galectin 3 LAM-1. See L-selectin Landsteiner-Wiener blood group antigen. See ICAM-4 LECAM-1. See L-selectin Leu-7. See CD57 Leu-14. See CD22
Leucine-rich repeat (LLR]molecules, 28 Leucocyte antigen p150/95. See Integrin a, Leukosialin. See CD43 LFA-1. See Integrin a, Liverlintestine cadherin. See LIcadherin LPAM-1. See Integrin P, LW. See ICAM-4 Ly-6 family. See E48 Ly-52. See HSA LWE-1, 298 Mac- 1. See Integrin a, Mac-2. See Galectin 3 MAdCAM- 1, 127 MAG, 129 MCAM. See MUC 18 MEL-14. See L-selectin Mel-CAM. See MUC 18 MGC-24. See CD164 MGC-24v. See CD164 MGI (Mouse Genome Informatics), 5 Milk fat globule membrane protein. See CD36 Molecular biology databases, 35 Mouse Genomic Informatics (MGI) database, 37 Mouse knockout databases, 36-7 MPZ. See P(0) MUC18, 131 Mucosal addressin cell adhesion molecule 1. See MAdCAM- 1 Muscle cadherin. See M-cadherin Myelin-associated glycoprotein. See MAG Myelin protein zero. See P(0) Na,K-ATPase .2 polypeptide. See AMOG NCAM, 133 NCAM L1. See L1 Neural cadherin. See N-cadherin Neural cell adhesion molecule. See NCAM Neural IgsF members, 14 Neurolin. See ALCAM NILE. See L1
Nucleotide and protein analysis databases, 35 Occludin, 300 OMIM (Online Mendelian Inheritance in Man], 5, 36 Osteoblast cadherin. See OB-cadherin OX-47[rat]. See CD147 P(O),136 P-zero. See P(O] PADGEM. See P-selectin PAS IV. See CD36 PCLP1,302 PECAM- 1. See CD3 1 Pemphigus vulgaris antigen. See Desmoglein 3 Pgp-1. See CD44 Placental cadherin. See P-cadherin Platelet endothelial cell adhesion molecule-1 . See CD3 1 Platelet glycoprotein gpIIb. See Integrin a,,, Platelet glycoprotein gpIIIa. See Integrin P, Platelet gpIa. See Integrin a, Platelet gpIc. See Integrin P,; Integrin a, Platelet gpIIa. See Integrin P, Podocalyxin-like protein. See PCLPl Protein modelling databases, 35 Protocadherins, 10-1 1 PSGL-1, 305 PVA. See Desmoglein 3 Quick sequence searches, 34 Retinal cadherin. See R-cadherin Ryudocan. See Syndecan-4 SC 1. See ALCAM E-Selectin, 215 E-Selectin ligand. See ESL-1 L-Selectin, 218 P-Selectin, 220 P-Selectin ligand. See PSGL-1 Selectins, 22-7 function, 23-5 ligands and regulation of ligand
binding, 22-3 oligosaccharide ligands, 24 structure, 22 SEMP1. See Claudin-1 Senescence-associated epithelial membrane protein 1. See Claudin-1 SGP50. See GlyCAM-1 Sgp90. See CD34 Sialoadhesin, 138 Sialomucin. See CD164 Siglecs, 14 Siglec-1. See Sialoadhesin Siglec-2. See CD22 Siglec-3. See CD33 Siglec-4a. See MAG SwissProt database, 36 N-Syndecan. See Syndecan-3 Syndecan-1, 225 Syndecan-2, 227 Syndecan-3,229 Syndecan-4,231 Syndecans, 25-7 T12. See CD6 T cell activation increased late expression/TACTILE. See CD96 TAG-1, 141 TAX- 1. See TAG-1 TBASE database, 36 Telencephalin. See ICAM-5
Tissue distribution, 5 Tp120. See CD6 Transiently expressed axonal glycoprotein. See TAG-1 Truncated cadherin. See H-cadherin TSP-180. See Integrin P, Uvomorulin. See E-cadherin VAP- 1, 307 Vascular adhesion protein- 1. See VAP- 1 Vascular ATP diphosphohydrolase. See CD39 Vascular cell adhesion molecule 1. See VCAM- 1 Vascular endothelial cadherin. See VE-cadherin VCAM-1, 143 Ventral prostate 1 homologue. See Claudin-3 Vitronectin receptor. See Integrin a, VLA1. See Integrin a, VLA2. See Integrin a, VLA3. See Integrin a, VLA4. See Integrin a, VLA5. See Integrin a, VLA6. See Integrin a, World Wide Web (WWW)databases, 33
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