Integrin Modulation by Lateral Association
2000; Elsevier BV; Volume: 275; Issue: 32 Linguagem: Inglês
10.1074/jbc.r000001200
ISSN1083-351X
Autores Tópico(s)Cellular Mechanics and Interactions
Resumointegrin-associated transmembrane protein Chinese hamster ovary conventional protein kinase C phosphatidylinositol 4-kinase focal adhesion kinase protein kinase C phosphatidylinositol 4,5-bisphosphate Integrins are a major family of cell-matrix and cell-cell receptors. Bidirectional signal transmission between the extracellular matrix or other integrin ligands and the submembranous cytoskeleton and associated adaptor proteins is now being resolved (1Plow E.F. Haas T.A. Zhang L. Loftus J. Smith J.W. J. Biol. Chem. 2000; 275: 21785-21788Abstract Full Text Full Text PDF PubMed Scopus (1125) Google Scholar, 2Calderwood D.A. Shattil S.J. Ginsberg M.H. J. Biol. Chem. 2000; 275: 22607-22610Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar, 3Harris E.S. McIntyre T.M. Prescott S.M. Zimmerman G. J. Biol. Chem. 2000; 275: 23409-23412Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, 4Kolanus W. Seed B. Curr. Opin. Cell Biol. 1997; 9: 725-731Crossref PubMed Scopus (128) Google Scholar, 5Burridge K. Chrzanowska-Wodnicka M. Annu. Rev. Cell Dev. Biol. 1996; 12: 463-518Crossref PubMed Scopus (1662) Google Scholar, 6Schlaepfer D. Hunter T. Trends Cell Biol. 1998; 8: 365-393Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar). This review will concentrate on an emerging area of study: how the type of adhesion and the signaling following integrin ligation may be modulated by lateral interactions with other membrane components. This may occur through direct or indirect interactions. Two major groups of transmembrane proteins will form the focus of this review. One group, the tetraspans or TM4SF proteins (7Maecker H.T. Todd S.C. Levy S. FASEB J. 1997; 11: 428-442Crossref PubMed Scopus (812) Google Scholar, 8Hemler M.E. Mannion B.A. Berditchevski F. Biochim. Biophys. Acta. 1996; 1287: 67-71PubMed Google Scholar, 9Hemler M. Curr. Opin. Cell Biol. 1998; 10: 578-585Crossref PubMed Scopus (321) Google Scholar), is composed of transmembrane proteins implicated in regulation of cell migration and invasion. They can interact directly with the extracellular domain of the α chain of specific integrins. The second group, the syndecans (10Bernfield M. Gotte M. Park P.W. Reizes O. Fitzgerald M.L. Lincecum J. Zako M. Annu. Rev. Biochem. 1999; 68: 729-778Crossref PubMed Scopus (2330) Google Scholar, 11David G. FASEB J. 1993; 7: 1023-1030Crossref PubMed Scopus (374) Google Scholar, 12Carey D.J. Biochem. J. 1997; 327: 1-16Crossref PubMed Scopus (606) Google Scholar, 13Gallagher J.T. Biochem. Soc. Trans. 1997; 25: 1206-1209Crossref PubMed Scopus (57) Google Scholar, 14Woods A. Couchman J.R. Trends Cell Biol. 1998; 8: 189-192Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 15Rapraeger A.C. Ott V.L. Curr. Opin. Cell Biol. 1998; 10: 620-628Crossref PubMed Scopus (101) Google Scholar), has not been shown to bind integrins directly but to bind to separate domains within integrin ligands. These also modify integrin-based adhesion, migration, invasiveness, and matrix assembly. The similarities in integrin modulation will be discussed. Because of space constraints, integrin interactions with other transmembrane proteins will only be briefly mentioned. The first integrin-associated transmembrane protein (IAP,1 CD47) was cloned in 1993 (16Lindberg F.P. Gresham H.D. Schwarz E. Brown E.J. J. Cell Biol. 1993; 123: 485-496Crossref PubMed Scopus (307) Google Scholar). This is a receptor for the cell-binding domain of thrombospondin (17Gao A.-G. Lindberg F.P. Finn M.B. Blystone S.D. Brown E.J. Frazier W.A. J. Cell Biol. 1996; 271: 21-24Scopus (332) Google Scholar), and it can regulate vitronectin binding to αvβ3 (16Lindberg F.P. Gresham H.D. Schwarz E. Brown E.J. J. Cell Biol. 1993; 123: 485-496Crossref PubMed Scopus (307) Google Scholar, 18Gao A.-G. Lindberg F.P. Dimitry J.M. Brown E.J. Frazier W.A. J. Cell Biol. 1996; 135: 533-544Crossref PubMed Scopus (186) Google Scholar) and activate αIIbβ3 through thrombospondin binding (19Chung J. Gao A.-G. Frazier W.A. J. Biol. Chem. 1997; 272: 14740-14746Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar). Mice lacking IAP have decreased resistance to bacterial infection probably because of delayed neutrophil migration to the site of infection and defective activation (20Lindberg F.P. Bullard D.C. Caver T.E. Gresham H.D. Beaudet A.L. Brown E.J. Science. 1996; 274: 795-798Crossref PubMed Scopus (303) Google Scholar). IAP may also interact with α2β1 integrin in vascular smooth muscle cells (21Wang X.-Q. Frazier W.A. Mol. Biol. Cell. 1998; 9: 865-874Crossref PubMed Scopus (140) Google Scholar). Second, integrin and growth factor signaling pathways intersect, and a subset of highly phosphorylated platelet-derived growth factor and insulin receptors, together with other downstream signaling components, coprecipitates with αvβ3 after treatment of cells with platelet-derived growth factor or insulin (22Schneller M. Vuori K. Ruoslahti E. EMBO J. 1997; 16: 5600-5607Crossref PubMed Scopus (427) Google Scholar). Third, urokinase plasminogen activator receptor (CD87) co-immunoprecipitates with β1, β2, and β3 integrins (23Wei Y. Mizukami I. Todd R.F. Petty H.R. Cancer Res. 1997; 57: 1682-1689PubMed Google Scholar). Other membrane molecules (reviewed in Ref. 9Hemler M. Curr. Opin. Cell Biol. 1998; 10: 578-585Crossref PubMed Scopus (321) Google Scholar) shown to interact by co-immunoprecipitation are CD98 (with α3β1), which may regulate β1integrin activation (24Fenczik C.A. Sethi T. Ramos J.W. Hughes P.E. Ginsberg M.H. Nature. 1997; 390: 81-85Crossref PubMed Scopus (260) Google Scholar), CD36 (with αIIbβ3), and CD46 (with α3β1). It is not yet clear whether interactions seen by co-immunoprecipitation are direct or due to formation of membrane microdomains containing multiple components, but some cross-linking studies (reviewed in Refs. 7Maecker H.T. Todd S.C. Levy S. FASEB J. 1997; 11: 428-442Crossref PubMed Scopus (812) Google Scholar, 8Hemler M.E. Mannion B.A. Berditchevski F. Biochim. Biophys. Acta. 1996; 1287: 67-71PubMed Google Scholar, 9Hemler M. Curr. Opin. Cell Biol. 1998; 10: 578-585Crossref PubMed Scopus (321) Google Scholar, 10Bernfield M. Gotte M. Park P.W. Reizes O. Fitzgerald M.L. Lincecum J. Zako M. Annu. Rev. Biochem. 1999; 68: 729-778Crossref PubMed Scopus (2330) Google Scholar) indicate direct binding. In addition, EMMPRIN/basigin (CD147), which regulates matrix metalloproteinase production, co-immunoprecipitates and colocalizes with α3β1 and α6β1 integrins (25Berditchevski F. Chang S. Bodorova J. Hemler M.E. J. Biol. Chem. 1997; 272: 29174-29180Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar) and can be cross-linked to these at the cell surface. The dystrophin complex can also associate with β1 integrins, possibly through α and γ sarcoglycan (26Yoshida T. Pan Y. Hanada H. Iwata Y. Shigekawa M. J. Biol. Chem. 1998; 273: 1583-1590Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar). Finally, several studies (Ref. 27Iida J. Meijne A.M.L. Oegema T.R. Yednock T.A. Kovach N.L. Furcht L.T. McCarthy J.B. J. Biol. Chem. 1998; 273: 5955-5961Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar and references therein) demonstrate that α4β1, but not α5β1, integrin-mediated melanoma cell adhesion requires a transmembrane chondroitin sulfate proteoglycan (MCSP in human, NG2 in rat). A sequence in the α4integrin subunit can bind directly to chondroitin sulfate glycosaminoglycan and, when used as an antagonist, can block α4β1-mediated melanoma cell adhesion (27Iida J. Meijne A.M.L. Oegema T.R. Yednock T.A. Kovach N.L. Furcht L.T. McCarthy J.B. J. Biol. Chem. 1998; 273: 5955-5961Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). Tetraspans/TM4SFs are a large family of transmembrane proteins, which have four transmembrane domains, short N- and C-terminal cytoplasmic tails, and two extracellular loops (reviewed in Refs.7Maecker H.T. Todd S.C. Levy S. FASEB J. 1997; 11: 428-442Crossref PubMed Scopus (812) Google Scholar, 8Hemler M.E. Mannion B.A. Berditchevski F. Biochim. Biophys. Acta. 1996; 1287: 67-71PubMed Google Scholar, 9Hemler M. Curr. Opin. Cell Biol. 1998; 10: 578-585Crossref PubMed Scopus (321) Google Scholar). The transmembrane domains are the most highly conserved between family members, particularly the inclusion of polar amino acids, and the sequences of hydrophobic residues. There are also 2–3 conserved charged residues in the 4-amino acid cytoplasmic loop between transmembrane domains 2 and 3, including a glutamic acid residue. These, together with a PXSC motif and the conserved placement of 3 cysteines in the large extracellular domain form the structural basis for the family classification (7Maecker H.T. Todd S.C. Levy S. FASEB J. 1997; 11: 428-442Crossref PubMed Scopus (812) Google Scholar, 8Hemler M.E. Mannion B.A. Berditchevski F. Biochim. Biophys. Acta. 1996; 1287: 67-71PubMed Google Scholar, 9Hemler M. Curr. Opin. Cell Biol. 1998; 10: 578-585Crossref PubMed Scopus (321) Google Scholar). The extracellular domains of tetraspans/TM4SFs are otherwise divergent between each family member and, except for some conservation of glycosylation sites, are ≈80% identical between species. An exception to this is the tetraspan/TM4SF (NAG-2), which is 90% conserved between mouse and human (27Iida J. Meijne A.M.L. Oegema T.R. Yednock T.A. Kovach N.L. Furcht L.T. McCarthy J.B. J. Biol. Chem. 1998; 273: 5955-5961Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). Tetraspans/TM4SFs are very widely expressed and can interact with themselves, other tetraspans/TM4SFs, and a range of other cell surface components. Because of the multicomponent complexes they participate in, they have been termed "adaptor" or "facilitator" molecules (7Maecker H.T. Todd S.C. Levy S. FASEB J. 1997; 11: 428-442Crossref PubMed Scopus (812) Google Scholar, 8Hemler M.E. Mannion B.A. Berditchevski F. Biochim. Biophys. Acta. 1996; 1287: 67-71PubMed Google Scholar). Some are nearly ubiquitously expressed (e.g. CD9, CD63, and CD81), whereas others are limited to platelets, immune cells, or neuronal cells (reviewed in Refs. 7Maecker H.T. Todd S.C. Levy S. FASEB J. 1997; 11: 428-442Crossref PubMed Scopus (812) Google Scholar, 8Hemler M.E. Mannion B.A. Berditchevski F. Biochim. Biophys. Acta. 1996; 1287: 67-71PubMed Google Scholar, 9Hemler M. Curr. Opin. Cell Biol. 1998; 10: 578-585Crossref PubMed Scopus (321) Google Scholar). Many were originally identified as tumor-associated proteins and implicated in changes in adhesion, motility, metastatic potential, or proliferation (7Maecker H.T. Todd S.C. Levy S. FASEB J. 1997; 11: 428-442Crossref PubMed Scopus (812) Google Scholar, 8Hemler M.E. Mannion B.A. Berditchevski F. Biochim. Biophys. Acta. 1996; 1287: 67-71PubMed Google Scholar, 9Hemler M. Curr. Opin. Cell Biol. 1998; 10: 578-585Crossref PubMed Scopus (321) Google Scholar). For example, CD9 transfection into carcinoma cells reduced motility and metastasis, and reduced CD9 expression accompanies poor prognosis in breast carcinoma (29Miyake M. Nakano K. Itoi S.I. Koh T. Taki T. Cancer Res. 1996; 56: 1244-1249PubMed Google Scholar). They also may play role(s) in development. For example, the Drosophila lbl gene is needed for normal formation of neuromuscular junctions, CD9 is transiently expressed during neuronal development, and the complement of tetraspans/TM4SFs expressed by T and B cells differs with the developmental stage (reviewed in Refs. 7Maecker H.T. Todd S.C. Levy S. FASEB J. 1997; 11: 428-442Crossref PubMed Scopus (812) Google Scholar, 8Hemler M.E. Mannion B.A. Berditchevski F. Biochim. Biophys. Acta. 1996; 1287: 67-71PubMed Google Scholar, 9Hemler M. Curr. Opin. Cell Biol. 1998; 10: 578-585Crossref PubMed Scopus (321) Google Scholar). Recently (30Berditchevski F. Bazzoni G. Hemler M.E. J. Biol. Chem. 1995; 270: 17784-17790Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar) tetraspans/TM4SFs were found to interact with integrins. The association is constitutive, e.g. in resting platelets (31Indig F.E. Diaz-Gonzalez R. Ginsberg M.H. Biochem. J. 1997; 327: 291-298Crossref PubMed Scopus (72) Google Scholar), and independent of adhesion because it occurs in cells in suspension (32Berditchevski F. Tolias K.F. Wong K. Carpenter C.L. Hemler M.E. J. Biol. Chem. 1997; 272: 2595-2598Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar). Most studies have used co-immunoprecipitation under low stringency conditions and surface cross-linking and have identified integrin-tetraspan/TM4SF interactions with α4β1, α3β1, α6β1, and αIIbβ3 with cell type-specific or contradictory reports for α2β1, α5β1, or αLβ2(reviewed in Refs. 7Maecker H.T. Todd S.C. Levy S. FASEB J. 1997; 11: 428-442Crossref PubMed Scopus (812) Google Scholar, 8Hemler M.E. Mannion B.A. Berditchevski F. Biochim. Biophys. Acta. 1996; 1287: 67-71PubMed Google Scholar, 9Hemler M. Curr. Opin. Cell Biol. 1998; 10: 578-585Crossref PubMed Scopus (321) Google Scholar). Although deletion/chimeric transfection studies indicate tetraspans/TM4SFs interact through the extracellular domain of the α subunit (32Berditchevski F. Tolias K.F. Wong K. Carpenter C.L. Hemler M.E. J. Biol. Chem. 1997; 272: 2595-2598Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, 33Yauch R.L. Berditchevski F. Hemler M.E. Mol. Cell. Biol. 1998; 9: 2751-2765Crossref Scopus (269) Google Scholar), hydrophobic interactions may play some role (31Indig F.E. Diaz-Gonzalez R. Ginsberg M.H. Biochem. J. 1997; 327: 291-298Crossref PubMed Scopus (72) Google Scholar), and the β subunit may also contribute because, although α6β1 does interact, α6β4 does not (30Berditchevski F. Bazzoni G. Hemler M.E. J. Biol. Chem. 1995; 270: 17784-17790Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 34Berditchevski F. Zutter M.M. Hemler M.E. Mol. Biol. Cell. 1996; 7: 193-207Crossref PubMed Scopus (251) Google Scholar). Integrins and tetraspans/TM4SFs co-localize in clusters, particularly at leading lamellae of cells or in "footprints" left after cell detachment (28Tachibana I. Bodorova J. Berditchevski F. Zutter M.M. Hemler M.E. J. Biol. Chem. 1997; 272: 29181-29189Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 30Berditchevski F. Bazzoni G. Hemler M.E. J. Biol. Chem. 1995; 270: 17784-17790Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 31Indig F.E. Diaz-Gonzalez R. Ginsberg M.H. Biochem. J. 1997; 327: 291-298Crossref PubMed Scopus (72) Google Scholar, 32Berditchevski F. Tolias K.F. Wong K. Carpenter C.L. Hemler M.E. J. Biol. Chem. 1997; 272: 2595-2598Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, 34Berditchevski F. Zutter M.M. Hemler M.E. Mol. Biol. Cell. 1996; 7: 193-207Crossref PubMed Scopus (251) Google Scholar) or at intercellular contact sites (35Yanez-Mo M. Alfranca A. Cabanas C. Marazuela M. Tejedor R. Ursa M.A. Ashman L.K. de Landazuri M.O. Sanchez-Madrid F. J. Cell Biol. 1998; 141: 791-804Crossref PubMed Scopus (239) Google Scholar). However, tetraspans/TM4SFs seem to be excluded from focal adhesions (28Tachibana I. Bodorova J. Berditchevski F. Zutter M.M. Hemler M.E. J. Biol. Chem. 1997; 272: 29181-29189Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 30Berditchevski F. Bazzoni G. Hemler M.E. J. Biol. Chem. 1995; 270: 17784-17790Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 31Indig F.E. Diaz-Gonzalez R. Ginsberg M.H. Biochem. J. 1997; 327: 291-298Crossref PubMed Scopus (72) Google Scholar, 32Berditchevski F. Tolias K.F. Wong K. Carpenter C.L. Hemler M.E. J. Biol. Chem. 1997; 272: 2595-2598Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, 34Berditchevski F. Zutter M.M. Hemler M.E. Mol. Biol. Cell. 1996; 7: 193-207Crossref PubMed Scopus (251) Google Scholar, 36Berditchevski F. Odintsova E. J. Cell Biol. 1999; 146: 477-492Crossref PubMed Scopus (258) Google Scholar). Indeed, in CHO co-transfection experiments, CD9 colocalized with αIIbβ3 integrin only in clusters at the leading edge of lamellae, whereas αIIbβ3 was additionally present in focal adhesions in cells seeded on fibrinogen (31Indig F.E. Diaz-Gonzalez R. Ginsberg M.H. Biochem. J. 1997; 327: 291-298Crossref PubMed Scopus (72) Google Scholar). Furthermore, CD9 transfection of CHO cells did not alter focal adhesion formation (31Indig F.E. Diaz-Gonzalez R. Ginsberg M.H. Biochem. J. 1997; 327: 291-298Crossref PubMed Scopus (72) Google Scholar). However, transfection with CD9 did alter actin cytoskeleton organization in HT1080 cells (36Berditchevski F. Odintsova E. J. Cell Biol. 1999; 146: 477-492Crossref PubMed Scopus (258) Google Scholar), and the effect varied with substrate. Most studies point to a role for tetraspans/TM4SFs and their associated integrins (e.g. α3β1and α6β1) in migration rather than adhesionper se (8Hemler M.E. Mannion B.A. Berditchevski F. Biochim. Biophys. Acta. 1996; 1287: 67-71PubMed Google Scholar, 35Yanez-Mo M. Alfranca A. Cabanas C. Marazuela M. Tejedor R. Ursa M.A. Ashman L.K. de Landazuri M.O. Sanchez-Madrid F. J. Cell Biol. 1998; 141: 791-804Crossref PubMed Scopus (239) Google Scholar, 37Skubitz K.M. Campbell K.D. Iida J. Skubitz A.P.N. J. Immunol. 1996; 157: 3617-3626PubMed Google Scholar). This is highlighted by one study (33Yauch R.L. Berditchevski F. Hemler M.E. Mol. Cell. Biol. 1998; 9: 2751-2765Crossref Scopus (269) Google Scholar) that confirmed a stable, specific interaction of one tetraspan/TM4SF (CD151) with integrin α3β1 by co-immunoprecipitation under stringent conditions. Unlike previous studies, where only subsets of tetraspan/TM4SF or integrin molecules interacted, most (70–90%) of α3β1associated with CD151 and no additional cell surface components were co-immunoprecipitated. Antibodies against either CD151 or α3β1 dramatically reduced neutrophil migration, confirmed in a separate study (35Yanez-Mo M. Alfranca A. Cabanas C. Marazuela M. Tejedor R. Ursa M.A. Ashman L.K. de Landazuri M.O. Sanchez-Madrid F. J. Cell Biol. 1998; 141: 791-804Crossref PubMed Scopus (239) Google Scholar). Anti-α3β1 (but not anti-α6β1) or anti-CD151 (but not anti-CD9) specifically inhibited neurite outgrowth, with no effect on adhesion. It remains to be seen whether the association of α3β1 with CD151 is responsible for the previously observed association of α3β1with CD9, CD63, CD81, and NAG-2 (33Yauch R.L. Berditchevski F. Hemler M.E. Mol. Cell. Biol. 1998; 9: 2751-2765Crossref Scopus (269) Google Scholar). Tetraspan/TM4SF interaction with integrins may provide indirect association of integrins, which do not have intrinsic enzymatic activity, with enzymes or other signaling molecules. Src family tyrosine kinase and lesser amounts of serine/threonine kinase activities associate with CD63-β2 integrin complexes (37Skubitz K.M. Campbell K.D. Iida J. Skubitz A.P.N. J. Immunol. 1996; 157: 3617-3626PubMed Google Scholar), and CD53 binds an unknown tyrosine phosphatase (38Carmo A.M. Wright M.D. Eur. J. Immunol. 1995; 25: 2090-2095Crossref PubMed Scopus (44) Google Scholar). Conventional protein kinase C (cPKC) isotypes can associate with CD81 and CD151 (9Hemler M. Curr. Opin. Cell Biol. 1998; 10: 578-585Crossref PubMed Scopus (321) Google Scholar) after activation. Phosphatidylinositol 4-kinase (PI4-K; probably type II) associates constitutively with a multicomponent complex containing the tetraspans/TM4SFs CD63, CD81, and α3β1(32Berditchevski F. Tolias K.F. Wong K. Carpenter C.L. Hemler M.E. J. Biol. Chem. 1997; 272: 2595-2598Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar) and with the CD151-α3β1 complex (33Yauch R.L. Berditchevski F. Hemler M.E. Mol. Cell. Biol. 1998; 9: 2751-2765Crossref Scopus (269) Google Scholar). Indeed, 95% of PI4-K activity was associated with α3β1 through CD151 with only minor amounts through CD63 and CD81. The enzyme associates with the tetraspan/TM4SF protein rather than α3β1 (32Berditchevski F. Tolias K.F. Wong K. Carpenter C.L. Hemler M.E. J. Biol. Chem. 1997; 272: 2595-2598Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, 33Yauch R.L. Berditchevski F. Hemler M.E. Mol. Cell. Biol. 1998; 9: 2751-2765Crossref Scopus (269) Google Scholar). Interestingly, clustering the α3β1-CD63-CD81 complex with antibodies to either tetraspan/TM4SF protein did not induce tyrosine phosphorylation of FAK or pp130cas, whereas clustering with anti-integrin did. HT1080 cells containing CD9 do, however, differ in FAK phosphorylation from wild type, and again this depends on which substrate is used for adhesion (36Berditchevski F. Odintsova E. J. Cell Biol. 1999; 146: 477-492Crossref PubMed Scopus (258) Google Scholar). Furthermore, antibodies against CD63, CD82, or CD151 all potentiated FAK phosphorylation when present as a mixed substrate with collagen (36Berditchevski F. Odintsova E. J. Cell Biol. 1999; 146: 477-492Crossref PubMed Scopus (258) Google Scholar), but adhesion to these antibodies alone reduced the level of FAK phosphorylation below even that seen in suspended cells. Thus, signaling through the tetraspans/TM4SF proteins appears complex. This recent study also demonstrated that tetraspan/TM4SF proteins are only weakly associated with the actin cytoskeleton (36Berditchevski F. Odintsova E. J. Cell Biol. 1999; 146: 477-492Crossref PubMed Scopus (258) Google Scholar). Thus, interactions of tetraspan/TM4SF proteins with their ligands has been suggested as an alternate signaling pathway leading to weak or transient cell-matrix-cytoskeleton interactions suitable for lamellipodial extension and retraction. CD9, CD63, CD81, CD82, and CD151 colocalize at punctate structures at the cell periphery, rather than focal adhesions, and although some colocalization of talin and FAK occurs, they do not appear to colocalize with vinculin- or paxillin-containing structures (36Berditchevski F. Odintsova E. J. Cell Biol. 1999; 146: 477-492Crossref PubMed Scopus (258) Google Scholar). Integrins are inserted at the leading edge of cells (reviewed in Ref. 39Lauffenburger D.A. Horwitz A.F. Cell. 1996; 84: 359-369Abstract Full Text Full Text PDF PubMed Scopus (3287) Google Scholar), PI4-K is implicated in vesicular transport (40Wiedemann C. Schäfer T. Burger M.M. EMBO J. 1996; 15: 2094-2101Crossref PubMed Scopus (170) Google Scholar), and CD63 has an internalization motif (41Hotta H. Ross A.H. Huebner K. Isobe M. Wendeborn S. Chao M.V. Ricciardi R.P. Tsujimoto Y. Croce C.M. Koprowski H. Cancer Res. 1988; 48: 2955-2962PubMed Google Scholar), which allows for lamellipodial colocalization of integrin/CD63 and rapid re-internalization of α3β1 if complexes are not stabilized. Cell surface proteoglycans can modify cell adhesion and migration, similar to the tetraspans/TM4SFs (reviewed in Refs. 10Bernfield M. Gotte M. Park P.W. Reizes O. Fitzgerald M.L. Lincecum J. Zako M. Annu. Rev. Biochem. 1999; 68: 729-778Crossref PubMed Scopus (2330) Google Scholar, 11David G. FASEB J. 1993; 7: 1023-1030Crossref PubMed Scopus (374) Google Scholar, 12Carey D.J. Biochem. J. 1997; 327: 1-16Crossref PubMed Scopus (606) Google Scholar, 13Gallagher J.T. Biochem. Soc. Trans. 1997; 25: 1206-1209Crossref PubMed Scopus (57) Google Scholar, 14Woods A. Couchman J.R. Trends Cell Biol. 1998; 8: 189-192Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 15Rapraeger A.C. Ott V.L. Curr. Opin. Cell Biol. 1998; 10: 620-628Crossref PubMed Scopus (101) Google Scholar). Several early studies indicated a need for interaction of both heparin binding and "cell" binding motifs for the development of stress fibers and focal adhesions in a variety of anchorage-dependent cells (reviewed in Ref. 14Woods A. Couchman J.R. Trends Cell Biol. 1998; 8: 189-192Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar). This has been confirmed recently (42Bloom L. Ingham K.C. Hynes R.O. Mol. Biol. Cell. 1999; 10: 1521-1536Crossref PubMed Scopus (124) Google Scholar, 43Saoncella S. Echtenmeyer F. Denhez F. Nowlen J.K. Mosher D.F. Robinson S.D. Hynes R.O. Goetinck P.F. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 2805-2810Crossref PubMed Scopus (337) Google Scholar). Cell attachment and spreading appears to be integrin-mediated, whereas later cytoskeletal organization appears to be heparan sulfate proteoglycan-mediated (14Woods A. Couchman J.R. Trends Cell Biol. 1998; 8: 189-192Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar), with concomitant activation of PKC (44Woods A. Couchman J.R. J. Cell Sci. 1992; 101: 277-290Crossref PubMed Google Scholar). A study monitoring CHO responses through transfected αIIbβ3 to fibrinogen substrates (45Defilippi P. Venturino M. Gulino D. Duperray A. Boquet P. Fiorentini C. Volpe G. Palmier M. Silengo L. Tarone G. J. Biol. Chem. 1997; 272: 21726-21734Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar) showed that antibody-coated substrates, whether integrin-activating or not, induced only limited spreading; full spreading required additional activation of PKC, and stress fiber formation followed Rho activation. The roles of the G proteins Rac, Rho, and Cdc42 in cell spreading and stress fiber/focal adhesion formation have been recently reviewed (46Mackay D.J.G. Hall A. J. Biol. Chem. 1998; 273: 20685-20688Abstract Full Text Full Text PDF PubMed Scopus (569) Google Scholar). Thus, there appear to be three sets of signaling involved in focal adhesion assembly: tyrosine phosphorylation events associated with integrin ligation, PKC activation associated with cell surface proteoglycan interactions, and Rho-GTP signaling. There is one report of a syndecan being coimmunoprecipitated with CD9 tetraspanin/TM4SF, which also associates with integrin β1 (47Jones P.H. Bishop L.A. Watt F.M. Cell Adhes. Commun. 1996; 4: 297-305Crossref PubMed Scopus (89) Google Scholar). Direct interactions of syndecans with integrins have not been reported, but co-immunoprecipitation under low stringency such as used for tetraspan/TM4SF-integrin interactions has not been described. Syndecans have a single transmembrane domain, a short cytoplasmic domain, and a larger extracellular domain that bears 3–5 glycosaminoglycan chains, mostly heparan sulfate (10Bernfield M. Gotte M. Park P.W. Reizes O. Fitzgerald M.L. Lincecum J. Zako M. Annu. Rev. Biochem. 1999; 68: 729-778Crossref PubMed Scopus (2330) Google Scholar, 11David G. FASEB J. 1993; 7: 1023-1030Crossref PubMed Scopus (374) Google Scholar, 12Carey D.J. Biochem. J. 1997; 327: 1-16Crossref PubMed Scopus (606) Google Scholar, 13Gallagher J.T. Biochem. Soc. Trans. 1997; 25: 1206-1209Crossref PubMed Scopus (57) Google Scholar, 14Woods A. Couchman J.R. Trends Cell Biol. 1998; 8: 189-192Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 15Rapraeger A.C. Ott V.L. Curr. Opin. Cell Biol. 1998; 10: 620-628Crossref PubMed Scopus (101) Google Scholar). The four mammalian syndecans have cell and developmental expression specificity (48Kim C.W. Goldberger O.A. Gallo R.L. Bernfield M. Mol. Biol. Cell. 1994; 5: 797-805Crossref PubMed Scopus (352) Google Scholar). Briefly, syndecan-1, -2, and -3 are the major syndecans of epithelial, fibroblastic, and neuronal cells, respectively, whereas syndecan-4 is unusual, appearing as a minor component of most cells. Syndecan core proteins range in size from ∼20 kDa (syndecan-4) to ∼45 kDa (syndecan-1) as deduced from sequencing, which is not unlike that of tetraspans/TM4SFs (Table I). Like the tetraspans/TM4SFs, syndecan core proteins have high homology in the transmembrane domain. In addition, however, syndecans have two cytoplasmic regions, proximal and distal to the membrane, that are also highly conserved. We have termed these C1 and C2, respectively (14Woods A. Couchman J.R. Trends Cell Biol. 1998; 8: 189-192Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar). In between these constant regions is a small cytoplasmic sequence (denoted V) unique to each syndecan but conserved between species. This has led to suggestions of syndecans having common and unique functions (14Woods A. Couchman J.R. Trends Cell Biol. 1998; 8: 189-192Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar,15Rapraeger A.C. Ott V.L. Curr. Opin. Cell Biol. 1998; 10: 620-628Crossref PubMed Scopus (101) Google Scholar). The extracellular domains are highly divergent except for the glycosaminoglycan attachment sites (10Bernfield M. Gotte M. Park P.W. Reizes O. Fitzgerald M.L. Lincecum J. Zako M. Annu. Rev. Biochem. 1999; 68: 729-778Crossref PubMed Scopus (2330) Google Scholar, 11David G. FASEB J. 1993; 7: 1023-1030Crossref PubMed Scopus (374) Google Scholar, 12Carey D.J. Biochem. J. 1997; 327: 1-16Crossref PubMed Scopus (606) Google Scholar, 13Gallagher J.T. Biochem. Soc. Trans. 1997; 25: 1206-1209Crossref PubMed Scopus (57) Google Scholar, 14Woods A. Couchman J.R. Trends Cell Biol. 1998; 8: 189-192Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 15Rapraeger A.C. Ott V.L. Curr. Opin. Cell Biol. 1998; 10: 620-628Crossref PubMed Scopus (101) Google Scholar), even for the same syndecan of different species.Table ISimilarities and properties of tetraspans and syndecansTetraspansSyndecansLow ectodomain sequence conservation except glycosylation sitesYesYesHighly conserved transmembrane sequencesYes (4)Yes (1)Homotypic interactionsYesYesHeterotypic interactions between family membersYesNoInducible interactions with cPKCCD81, CD151 Syndecan-4Interactions with integrinsYes?Interactions with extracellular matrix moleculesNoYes Open table in a new tab Syndecans can bind a wide range of extracellular matrix molecules, growth factors, lipoproteins, and enzymes through their heparan sulfate chains (10Bernfield M. Gotte M. Park P.W. Reizes O. Fitzgerald M.L. Lincec
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