Platelet Collagen Receptors

Summary

Collagens are important platelet activators in the vascular subendothelium and vessel wall. Since the regulation of platelet activation is a key step in distinguishing normal haemostasis from pathological thrombosis, collagen interactions with platelets are important targets for pharmacological control. Platelets have two major receptors for collagens, the integrin α₂ β₁, with a major role in adhesion and platelet anchoring and the Ig superfamily member, GPVI, principally responsible for signalling and platelet activation. In addition, GPIb-V-IX, can be considered as an indirect collagen receptor acting via von Willebrand factor as bridging molecule and is essential for platelet interactions with collagen at high shear rates. There is some evidence for additional receptors, which may regulate the response to individual collagen types. This review discusses how these receptors work separately with specific agonists and proposes possible mechanisms for how they work together to regulate platelet activation by collagen, which remains controversial and poorly understood.

Key words

Platelet - receptor - collagen - integrin - Ig superfamily

• References

• 1 Staatz WD, Rajpara SM, Wayner EA, Carter WG, Santoro SA. The membrane glycoprotein Ia-IIa (VLA-2) complex mediates the Mg++-dependent adhesion of platelets to collagen. J Cell Biol 1989; 108: 1917-24.
• 2 Springer TA. Folding of the N-terminal, ligand-binding region of integrin α-subunits into a β-propeller domain. Proc Natl Acad Sci USA 1997; 94: 65-72.
• 3 Emsley J, King SL, Bergelson JM, Liddington RC. Crystal structure of the I domain from integrin α₂β₁ . J Biol Chem 1997; 272: 28512-7.
• 4 Emsley J, Knight CG, Farndale RW, Barnes MJ, Liddington RC. Structural basis of collagen recognition by integrin α₂β₁ . Cell 2000; 101: 47-56.
• 5 Knight CG, Morton LF, Peachey AR, Tuckwell DS, Farndale RW, Barnes MJ. The collagen-binding A-domains of integrins α₁β₁ and α₂β₁ recognize the same specific amino acid sequence, GFOGER, in native (triple-helical) collagens. J Biol Chem 2000; 275: 35-40.
• 6 Santoro SA, Walsh JJ, Staatz WD, Baranski KJ. Distinct determinants on collagen support α₂β₁ integrin-mediated platelet adhesion and platelet activation. Cell Regul 1991; 2: 905-13.
• 7 Jung SM, Moroi M. Signal-transducing mechanisms involved in activation of the platelet collagen receptor integrin α₂β₁ . J Biol Chem 2000; 275: 8016-26.
• 8 Kramer RH, Marks N. Identification of integrin collagen receptors on human melanoma cells. J Biol Chem 1989; 264: 4684-8.
• 9 Camper L, Hellman U, Lundgren-Akerlund E. Isolation, cloning, and sequence analysis of the integrin subunit α₁₀, a β₁-associated collagen binding integrin expressed on chondrocytes. J Biol Chem 1998; 273: 20383-9.
• 10 Velling T, Kusche-Gullberg M, Sejersen T, Gullberg D. cDNA cloning and chromosomal localization of human α₁₁ integrin. a collagen-binding, I domain-containing, β₁-associated integrin -chain present in muscle tissues. J Biol Chem 1999; 274: 25735-42.
• 11 Handa M, Watanabe K, Kawai Y, Kamata T, Koyama T, Nagai H, Ikeda Y. Platelet unresponsiveness to collagen: involvement of glycoprotein Ia-IIa (α₂β₁ integrin) deficiency associated with a myeloproliferative disorder. Thromb Haemost 1995; 73: 521-8.
• 12 Nieuwenhuis HK, Akkerman JW, Houdijk WP, Sixma JJ. Human blood platelets showing no response to collagen fail to express surface glycoprotein Ia. Nature 1985; 318: 470-2.
• 13 Kehrel B, Balleisen L, Kokott R, Mesters R, Stenzinger W, Clemetson KJ, van de Loo J. Deficiency of intact thrombospondin and membrane glyco-protein Ia in platelets with defective collagen-induced aggregation and spontaneous loss of disorder. Blood 1988; 71: 1074-8.
• 14 Kunicki TJ, Kritzik M, Annis DS, Nugent DJ. Hereditary variation in platelet integrin α₂β₁ density is associated with two silent polymorphisms in the α₂ gene coding sequence. Blood 1997; 89: 1939-43.
• 15 Coller BS, Beer JH, Scudder LE, Steinberg MH. Collagen-platelet interactions: evidence for a direct interaction of collagen with platelet GPIa/IIa and an indirect interaction with platelet GPIIb/IIIa mediated by adhesive proteins. Blood 1989; 74: 182-92.
• 16 Keely PJ, Parise LV. The α₂β₁ integrin is a necessary co-receptor for collagen-induced activation of Syk and the subsequent phosphorylation of phospholipase Cγ2 in platelets. J Biol Chem 1996; 271: 26668-76.
• 17 Wang R, Kini RM, Chung MC. Rhodocetin, a novel platelet aggregation inhibitor from the venom of Calloselasma rhodostoma (Malayan pit viper): synergistic and noncovalent interaction between its subunits. Biochemistry 1999; 38: 7584-93.
• 18 Marcinkiewicz C, Lobb RR, Marcinkiewicz MM, Daniel JL, Smith JB, Dangelmaier C, Weinreb PH, Beacham DA, Niewiarowski S. Isolation and characterization of EMS16, a C-lectin type protein from Echis multisquamatus venom, a potent and selective inhibitor of the α₂β₁ integrin. Biochemistry 2000; 39: 9859-67.
• 19 Kamiguti AS, Theakston RD, Watson SP, Bon C, Laing GD, Zuzel M. Distinct contributions of glycoprotein VI and α₂β₁ integrin to the induction of platelet protein tyrosine phosphorylation and aggregation. Arch Biochem Biophys 2000; 374: 356-62.
• 20 De Luca M, Ward CM, Ohmori K, Andrews RK, Berndt MC. Jararhagin and jaracetin: novel snake venom inhibitors of the integrin collagen receptor, α₂β₁ . Biochem Biophys Res Commun 1995; 206: 570-6.
• 21 Kamiguti AS, Markland FS, Zhou Q, Laing GD, Theakston RD, Zuzel M. Proteolytic cleavage of the β₁ subunit of platelet α₂β₁ integrin by the metalloproteinase jararhagin compromises collagen-stimulated phosphorylation of pp 72. J Biol Chem 1997; 272: 32599-605.
• 22 Zhou Q, Dangelmaier C, Smith JB. The hemorrhagin catrocollastatin inhibits collagen-induced platelet aggregation by binding to collagen via its disintegrin-like domain. Biochem Biophys Res Commun 1996; 219: 720-6.
• 23 Huang TF, Liu CZ, Yang SH. Aggretin, a novel platelet-aggregation inducer from snake (Calloselasma rhodostoma) venom, activates phospholipase C by acting as a glycoprotein Ia/IIa agonist. Biochem J 1995; 309: 1021-7.
• 24 Chung CH, Au LC, Huang TF. Molecular cloning and sequence analysis of aggretin, a collagen-like platelet aggregation inducer. Biochem Biophys Res Commun 1999; 263: 723-7.
• 25 Shin Y, Morita T. Rhodocytin, a functional novel platelet agonist belonging to the heterodimeric C-type lectin family, induces platelet aggregation independently of glycoprotein Ib. Biochem Biophys Res Commun 1998; 245: 741-5.
• 26 Jung SM, Moroi M. Platelets interact with soluble and insoluble collagens through characteristically different reactions. J Biol Chem 1998; 273: 14827-37.
• 27 Liu S, Calderwood DA, Ginsberg MH. Integrin cytoplasmic domain-binding proteins. J Cell Sci 2000; 113: 3563-71.
• 28 Chen K, Lin Y, Detwiler TC. Protein disulfide isomerase activity is released by activated platelets. Blood 1992; 79: 2226-8.
• 29 Lahav J, Gofer-Dadosh N, Luboshitz J, Hess O, Shaklai M. Protein disulfide isomerase mediates integrin-dependent adhesion. FEBS Lett 2000; 475: 89-92.
• 30 O’Neill S, Robinson A, Deering A, Ryan M, Fitzgerald DJ, Moran N. The platelet integrin α_IIbβ₃ has an endogenous thiol isomerase activity. J Biol Chem 2000; 275: 36984-90.
• 31 Zucker MB, Masiello NC. Platelet aggregation caused by dithiothreitol. Thromb Haemost 1984; 51: 119-24.
• 32 Peerschke EI. Regulation of platelet aggregation by post-fibrinogen binding events. Insights provided by dithiothreitol-treated platelets. Thromb Haemost 1995; 73: 862-7.
• 33 Gofer-Dadosh N, Klepfish A, Schmilowitz H, Shaklai M, Lahav J. Affinity modulation in platelet α₂β₁ following ligand binding. Biochem Biophys Res Commun 1997; 232: 724-7.
• 34 Essex DW, Li M. Protein disulphide isomerase mediates platelet aggregation and secretion. Br J Haematol 1999; 104: 448-54.
• 35 Kritzik M, Savage B, Nugent DJ, Santoso S, Ruggeri ZM, Kunicki TJ. Nucleotide polymorphisms in the α₂ gene define multiple alleles that are associated with differences in platelet α₂β₁ density. Blood 1998; 92: 2382-8.
• 36 Moshfegh K, Wuillemin WA, Redondo M, Lammle B, Beer JH, LiechtiGallati S, Meyer BJ. Association of two silent polymorphisms of platelet glycoprotein Ia/IIa receptor with risk of myocardial infarction: a case-control study. Lancet 1999; 353: 351-4.
• 37 Carlsson LE, Santoso S, Spitzer C, Kessler C, Greinacher A. The α₂ gene coding sequence T807/A873 of the platelet collagen receptor integrin α₂β₁ might be a genetic risk factor for the development of stroke in younger patients. Blood 1999; 93: 3583-6.
• 38 Reiner AP, Kumar PN, Schwartz SM, Longstreth Jr WT, Pearce RM, Rosendaal FR, Psaty BM, Siscovick DS. Genetic variants of platelet glyco-protein receptors and risk of stroke in young women. Stroke 2000; 31: 1628-33.
• 39 von Beckerath N, Koch W, Mehilli J, Bottiger C, Schomig A, Kastrati A. Glycoprotein Ia gene C807T polymorphism and risk for major adverse cardiac events within the first 30 days after coronary artery stenting. Blood 2000; 95: 3297-301.
• 40 Matsubara Y, Murata M, Maruyama T, Handa M, Yamagata N, Watanabe G, Saruta T, Ikeda Y. Association between diabetic retinopathy and genetic variations in α₂β₁ integrin, a platelet receptor for collagen. Blood 2000; 95: 1560-4.
• 41 Roest M, Banga JD, Grobbee DE, de Groot PG, Sixma JJ, Tempelman MJ, van Der Schouw YT. Homozygosity for 807 T polymorphism in alpha(2) subunit of platelet α₂β₁ is associated with increased risk of cardiovascular mortality in high-risk women. Circulation 2000; 102: 1645-50.
• 42 Di Paola J, Federici AB, Mannucci PM, Canciani MT, Kritzik M, Kunicki TJ, Nugent D. Low platelet α₂β₁ levels in type I von Willebrand disease correlate with impaired platelet function in a high shear stress system. Blood 1999; 93: 3578-82.
• 43 Roest M, Sixma JJ, Wu YP, Ijsseldijk MJ, Tempelman M, Slootweg PJ, de Groot PG, van Zanten GH. Platelet adhesion to collagen in healthy volunteers is influenced by variation of both α₂β₁ density and von Wille-brand factor. Blood 2000; 96: 1433-7.
• 44 Clemetson KJ, McGregor JL, James E, Dechavanne M, Luscher EF. Characterization of the platelet membrane glycoprotein abnormalities in Bernard-Soulier syndrome and comparison with normal by surface-labeling techniques and high-resolution two-dimensional gel electrophoresis. J Clin Invest 1982; 70: 304-11.
• 45 Sugiyama T, Okuma M, Ushikubi F, Sensaki S, Kanaji K, Uchino H. A novel platelet aggregating factor found in a patient with defective collagen-induced platelet aggregation and autoimmune thrombocytopenia. Blood 1987; 69: 1712-20.
• 46 Moroi M, Jung SM, Okuma M, Shinmyozu K. A patient with platelets deficient in glycoprotein VI that lack both collagen-induced aggregation and adhesion. J Clin Invest 1989; 84: 1440-5.
• 47 Arai M, Yamamoto N, Moroi M, Akamatsu N, Fukutake K, Tanoue K. Platelets with 10% of the normal amount of glycoprotein VI have an impaired response to collagen that results in a mild bleeding tendency. Br J Haematol 1995; 89: 124-30.
• 48 Clemetson JM, Polgar J, Magnenat E, Wells TN, Clemetson KJ. The platelet collagen receptor glycoprotein VI is a member of the immunoglobulin superfamily closely related to Fc R and the natural killer receptors. J Biol Chem 1999; 274: 29019-24.
• 49 Miura Y, Ohnuma M, Jung SM, Moroi M. Cloning and expression of the platelet-specific collagen receptor glycoprotein VI. Thromb Res 2000; 98: 301-9.
• 50 Jandrot-Perrus M, Busfield S, Lagrue AH, Xiong X, Debili N, Chickering T, Couedic JP, Goodearl A, Dussault B, Fraser C, Vainchenker W, Villeval JL. Cloning, characterization, and functional studies of human and mouse glycoprotein VI: a platelet-specific collagen receptor from the immunoglobulin superfamily. Blood 2000; 96: 1798-807.
• 51 Ezumi Y, Uchiyama T, Takayama H. Molecular cloning, genomic structure, chromosomal localization, and alternative splice forms of the platelet collagen receptor glycoprotein VI. Biochem Biophys Res Commun 2000; 277: 27-36.
• 52 Tsuji M, Ezumi Y, Arai M, Takayama H. A novel association of Fc receptor γ-chain with glycoprotein VI and their co-expression as a collagen receptor in human platelets. J Biol Chem 1997; 272: 23528-31.
• 53 Nieswandt B, Bergmeier W, Schulte V, Rackebrandt K, Gessner JE, Zirngibl H. Expression and function of the mouse collagen receptor glycoprotein VI is strictly dependent on its association with the FcRγ chain. J Biol Chem 2000; 275: 23998-4002.
• 54 Nieswandt B, Schulte V, Bergmeier W, Mokhtari-Nejad R, Rackebrandt K, Cazenave JP, Ohlmann P, Gachet C, Zirngibl H. Long-term antithrombotic protection by in vivo depletion of platelet glycoprotein VI in mice. J Exp Med 2001; 193: 459-69.
• 55 Gibbins JM, Okuma M, Farndale R, Barnes M, Watson SP. Glycoprotein VI is the collagen receptor in platelets which underlies tyrosine phosphorylation of the Fc receptor γ-chain. FEBS Lett 1997; 413: 255-9.
• 56 Polgar J, Clemetson JM, Kehrel BE, Wiedemann M, Magnenat EM, Wells TNC, Clemetson KJ. Platelet activation and signal transduction by convulxin, a C-type lectin from Crotalus durissus terrificus (tropical rattlesnake) venom via the p62/GPVI collagen receptor. J Biol Chem 1997; 272: 13576-83.
• 57 Niedergang F, Alcover A, Knight CG, Farndale RW, Barnes MJ, Francischetti IM, Bon C, Leduc M. Convulxin binding to platelet receptor GPVI: competition with collagen related peptides. Biochem Biophys Res Commun 2000; 273: 246-50.
• 58 Kehrel B, Wierwille S, Clemetson KJ, Anders O, Steiner M, Knight CG, Farndale RW, Okuma M, Barnes MJ. Glycoprotein VI is a major collagen receptor for platelet activation: it recognizes the platelet-activating quaternary structure of collagen, whereas CD36, glycoprotein IIb/IIIa, and von Willebrand factor do not. Blood 1998; 91: 491-9.
• 59 Morton HC, van den Herik-Oudijk IE, Vossebeld P, Snijders A, Verhoeven AJ, Capel PJ, van de Winkel JG. Functional association between the human myeloid immunoglobulin A Fc receptor (CD89) and FcR γ-chain. Molecular basis for CD89/FcR γ-chain association. J Biol Chem 1995; 270: 29781-7.
• 60 Maeda A, Kurosaki M, Kurosaki T. Paired immunoglobulin-like receptor (PIR)-A is involved in activating mast cells through its association with Fc receptor γ-chain. J Exp Med 1998; 188: 991-5.
• 61 Taylor LS, McVicar DW. Functional association of FcεRIγ with arginine(632) of paired immunoglobulin-like receptor (PIR)-A3 in murine macrophages. Blood 1999; 94: 1790-6.
• 62 Zheng Y-M, Liu C, Chen H, Locke D, Ryan JC, Kahn ML. Expression of the platelet receptor GPVI confers signaling via the Fc receptor γ-chain in response to the snake venom convulxin but not to collagen. J Biol Chem 2001; 276: in press.
• 63 Moroi M, Jung SM, Shinmyozu K, Tomiyama Y, Ordinas A, Diaz-Ricart M. Analysis of platelet adhesion to a collagen-coated surface under flow conditions: the involvement of glycoprotein VI in the platelet adhesion. Blood 1996; 88: 2081-92.
• 64 Morton LF, Hargreaves PG, Farndale RW, Young RD, Barnes MJ. Integrin α₂β₁-independent activation of platelets by simple collagen-like peptides: collagen tertiary (triple-helical) and quaternary (polymeric) structures are sufficient alone for α₂β₁-independent platelet reactivity. Biochem J 1995; 306: 337-44.
• 65 Jandrot-Perrus M, Lagrue AH, Okuma M, Bon C. Adhesion and activation of human platelets induced by convulxin involve glycoprotein VI and inte-grin α₂β₁ . J Biol Chem 1997; 272: 27035-41.
• 66 Asselin J, Gibbins JM, Achison M, Lee YH, Morton LF, Farndale RW, Barnes MJ, Watson SP. A collagen-like peptide stimulates tyrosine phosphorylation of syk and phospholipase C γ2 in platelets independent of the integrin α₂β₁ . Blood 1997; 89: 1235-42.
• 67 Ichinohe T, Takayama H, Ezumi Y, Arai M, Yamamoto N, Takahashi H, Okuma M. Collagen-stimulated activation of Syk but not c-Src is severely compromised in human platelets lacking membrane glycoprotein VI. J Biol Chem 1997; 272: 63-8.
• 68 Marlas G, Joseph D, Huet C. I-isolation and electron microscope studies of a potent platelet-aggregating glycoprotein from the venom of Crotalus durissus cascavella . Biochimie 1983; 65: 405-16.
• 69 Xu Y, Gurusiddappa S, Rich RL, Owens RT, Keene DR, Mayne R, Hook A, Hook M. Multiple binding sites in collagen type I for the integrins α₁β₁ and α₂β₁ . J Biol Chem 2000; 275: 38981-9.
• 70 Ruan CG, Du XP, Xi XD, Castaldi PA, Berndt MC. A murine antiglyco-protein Ib complex monoclonal antibody, SZ 2, inhibits platelet aggregation induced by both ristocetin and collagen. Blood 1987; 69: 570-7.
• 71 Depraetere H, Kerekes A, Deckmyn H. The collagen-binding leech products rLAPP and calin prevent both von Willebrand factor and α₂β₁ (GPIa/IIa)-I-domain binding to collagen in a different manner. Thromb Haemost 1999; 82: 1160-3.
• 72 Zaffran Y, Meyer SC, Negrescu E, Reddy KB, Fox JE. Signaling across the platelet adhesion receptor glycoprotein Ib-IX induces α_IIbβ₃ activation both in platelets and a transfected Chinese hamster ovary cell system. J Biol Chem 2000; 275: 16779-87.
• 73 Yap CL, Hughan SC, Cranmer SL, Nesbitt WS, Rooney MM, Giuliano S, Kulkarni S, Dopheide SM, Yuan Y, Salem HH, Jackson SP. Synergistic adhesive interactions and signaling mechanisms operating between platelet glycoprotein Ib/IX and integrin α_IIbβ₃: studies in human platelets and transfected Chinese hamster ovary cells. J Biol Chem 2000; 275: 41377-88.
• 74 Phillips DR, Agin PP. Platelet plasma membrane glycoproteins. Identification of a proteolytic substrate for thrombin. Biochem Biophys Res Commun 1977; 75: 940-7.
• 75 Kahn ML, Diacovo TG, Bainton DF, Lanza F, Trejo J, Coughlin SR. Glycoprotein V-deficient platelets have undiminished thrombin responsiveness and do not exhibit a Bernard-Soulier phenotype. Blood 1999; 94: 4112-21.
• 76 Ramakrishnan V, DeGuzman F, Bao M, Hall SW, Leung LL, Phillips DR. A thrombin receptor function for platelet glycoprotein Ib-IX unmasked by cleavage of glycoprotein V. Proc Natl Acad Sci USA 2001; 98: 1823-8.
• 77 Ni H, Ramakrishnan V, Papalia JM, Phillips DR, Wagner DD. Increased thrombogenesis and embolus formation in mice lacking glycoprotein V. Blood 2000; 96: 812a (abstr).
• 78 Lanza F, Moog S, Morales M, Ravanat C, Schuhler S, Freund M, Strassel C, Nieswandt B, Gachet C, Cazenave J-P. Recent evidence for a role of glycoprotein V in platelet adhesion and aggregation. Platelets 2001; 12: in press.
• 79 Diaz-Ricart M, Tandon NN, Carretero M, Ordinas A, Bastida E, Jamieson GA. Platelets lacking functional CD36 (glycoprotein IV) show reduced adhesion to collagen in flowing whole blood. Blood 1993; 82: 491-6.
• 80 Asch AS, Liu I, Briccetti FM, Barnwell JW, Kwakye-Berko F, Dokun A, Goldberger J, Pernambuco M. Analysis of CD36 binding domains: Ligand specificity controlled by dephosphorylation of an ectodomain. Science 1993; 262: 1436-40.
• 81 Endemann G, Stanton LW, Madden KS, Bryant CM, White RT, Protter AA. CD36 is a receptor for oxidized low density lipoprotein. J Biol Chem 1993; 268: 11811-6.
• 82 Coburn CT, Knapp Jr FF, Febbraio M, Beets AL, Silverstein RL, Abumrad NA. Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. J Biol Chem 2000; 275: 32523-9.
• 83 Kehrel B, Kronenberg A, Rauterberg J, Niesing-Bresch D, Niehues U, Kardoeus J, Schwippert B, Tschöpe D, Van de Loo J, Clemetson KJ. Platelets deficient in glycoprotein IIIb aggregate normally to collagens type I and III but not to collagen type V. Blood 1993; 82: 3364-70.
• 84 Daniel JL, Dangelmaier C, Strouse R, Smith JB. Collagen induces normal signal transduction in platelets deficient in CD36 (platelet glycoprotein IV). Thromb Haemost 1994; 71: 353-6.
• 85 Kashiwagi H, Tomiyama Y, Honda S, Kosugi S, Shiraga M, Nagao N, Sekiguchi S, Kanayama Y, Kurata Y, Matsuzawa Y. Molecular basis of CD36 deficiency. Evidence that a 478C T substitution (proline90 serine) in CD36 cDNA accounts for CD36 deficiency. J Clin Invest 1995; 95: 1040-6.
• 86 Newman PJ, Berndt MC, Gorski J, White GCI, Lyman S, Paddock C, Muller WA. PECAM-1 (CD31) Cloning and relation to adhesion molecules of the immunoglobulin gene superfamily. Science 1990; 247: 1219-22.
• 87 Cicmil M, Thomas JM, Sage T, Barry FA, Gibbins JM. PECAM-1: A negative regulator of platelet activation?. Blood 2000; 245a (abstr).
• 88 Chiang TM, Rinaldy A, Kang AH. Cloning, characterization, and functional studies of a nonintegrin platelet receptor for type I collagen. J Clin Invest 1997; 100: 514-21.
• 89 Chiang TM, Kang AH. A synthetic peptide derived from the sequence of a type I collagen receptor inhibits type I collagen-mediated platelet aggregation. J Clin Invest 1997; 100: 2079-84.
• 90 Chiang TM, Wang YB, Kang ES. Role of the recombinant protein of the platelet receptor for type I collagen in the release of nitric oxide during platelet aggregation. Thromb Res 2000; 100: 427-32.
• 91 Monnet E, Fauvel-Lafeve F. A new platelet receptor specific to type III collagen. Type III collagen-binding protein. J Biol Chem 2000; 275: 10912-7.