α_IIbβ₃ and Its Antagonism at the New Millennium

Summary

Because of its major role in regulating platelet functions and its prominence on the cell surface, integrin α_IIbβ₃ has been the subject of intensive investigations. Such studies have provided substantial insights into its structure-function relationships and have led to the development of anti-thrombotic drugs that target the receptor. Nevertheless, recent findings have indicated that our understanding of the structure and function of α_IIbβ₃ remains inadequate. This article addresses two aspects of still evolving α_IIbβ₃ function: 1) the interface between α_IIbβ₃ and the blood coagulation system, resulting from interaction of prothrombin with the receptor; and 2) the molecular basis for recognition of the RGD and the fibrinogen γ-chain peptide ligands by α_IIbβ₃. As illustrated by these two examples, there is still much to be learned about α_IIbβ₃ if we are to fully appreciate its functions and its potential as a therapeutic target.

Key words

Anti-thrombotic therapy - integrin α_IIbβ₃ - adhesive proteins - blood coagulation proteins

• References

• 1 Topol EJ, Byzova TV, Plow EF. Platelet GPIIb-IIIa blockers. Lancet 1999; 353: 227-31.
• 2 Chew DP, Bhatt DL, Sapp S, Topol EJ. Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists – A meta-analysis of phase III multi-center randomized trials. Circulation 2001; 103: 201-6.
• 3 GUSTO-IV ACS Trial.. Presented at the 22nd Congress of the European Society of Cardiology. 2000 (abstr.).
• 4 Marguerie GA, Plow EF. The fibrinogen dependent pathway of platelet aggregation. Ann N Y Acad Sci 1983; 408: 556-67.
• 5 Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 1992; 69: 11-25.
• 6 Plow EF, Haas TA, Zhang L, Loftus J, Smith JW. Ligand binding to integrins. J Biol Chem 2000; 275: 21785-8.
• 7 Bennett JS, Vilaire G. Exposure of platelet fibrinogen receptors by ADP and epinephrine. J Clin Invest 1979; 64: 1393-401.
• 8 Marguerie GA, Plow EF, Edgington TS. Human platelets possess an inducible and saturable receptor specific for fibrinogen. J Biol Chem 1979; 254: 5357-63.
• 9 Fujimoto T, Hawiger J. Adenosine diphosphate induces binding of von Willebrand factor to human platelets. Nature 1982; 297: 154-6.
• 10 Ruggeri ZM, Bader R, DeMarco L. Glanzmann thrombasthenia. Deficient binding of von Willebrand factor to thrombin-stimulated platelets. Proc Natl Acad Sci USA 1982; 79: 6038-41.
• 11 Plow EF, Ginsberg MH. Specific and saturable binding of plasma fibronectin to thrombin-stimulated human platelets. J Biol Chem 1981; 256: 9477-82.
• 12 Savage B, Almus-Jacobs F, Ruggeri ZM. Specific synergy of multiple substrate-receptor interactions in platelet thrombus formation under flow. Cell 1998; 94: 657-66.
• 13 Kulkarni S, Dopheide SM, Yap CL, Ravanat C, Freund M, Mangin P, Heel KA, Street A, Harper IS, Lanza F, Jackson SP. A revised model of platelet aggregation. J Clin Invest 2000; 105: 783-91.
• 14 Ni H, Denis CV, Subbarao S, Degen JL, Sato TN, Hynes RO, Wagner DD. Persistence of platelet thrombus formation in arterioles of mice lacking both Willebrand factor and fibrinogen. J Clin Invest 2000; 106: 385-92.
• 15 Jedsadayanmata A, Chen CC, Kireeva ML, Lau LF, Lam SC. Activation-dependent adhesion of human platelets to Cyr61 and Fisp12/mouse connective tissue growth factor is mediated through integrin α_IIbβ₃ . J Biol Chem 1999; 274: 24321-7.
• 16 Felding-Habermann B, Silletti S, Mei F, Siu C-H, Yip PM, Brooks P, Cheresh DA, O’Toole TE, Ginsberg MH, Montgomery AM. A single immunoglobulin-like domain of the human neural cell adhesion molecule L1 supports adhesion by multiple vascular and platelet integrins. J Cell Biol 1997; 139: 1567-81.
• 17 Byzova TV, Plow EF. Networking in the hemostatic system. Integrin α_IIbβ₃ binds prothrombin and influences its activation. J Biol Chem 1997; 272: 27183-8.
• 18 Vijayalakshmi J, Padmanabhan KP, Mann KG, Tulinsky A. The isomorphous structures of prethrombin2, hirugen-, and PPACK-thrombin: changes accompanying activation and exosite binding to thrombin. Protein Sci 1994; 3: 2254-71.
• 19 Stubbs MT, Bode W. A player of many parts: the spotlight falls on thrombin structure. Thromb Res 1993; 69: 1-58.
• 20 Reverter JC, Beguin S, Kessels H, Kumar R, Hemker HC, Coller BS. Inhibition of platelet-mediated, tissue factor-induced thrombin generation by the mouse/human chimeric 7E3 antibody: potential implications for the effect of c7E3 Fab treatment on acute thrombosis and “clinical retenosis”. J Clin Invest 1996; 98: 863-74.
• 21 Weiss HJ, Lages B. Platelet prothrombinase activity and intracellular calcium responses in patients with storage pool deficiency, glycoprotein IIb-IIIa deficiency, or impaired platelet coagulant activity – a comparison with Scott syndrome. Blood 1997; 89: 1599-611.
• 22 Bovill EG, Tracy RP, Hayes TE, Jenny RJ, Bhushan FH, Mann KG. Evidence that meizothrombin is an intermediate product in the clotting of whole blood. Arterioscler Thromb Vasc Biol 1995; 15: 754-8.
• 23 Byzova TV, Kim WE, Plow EF. Acceleration of prothrombin activation by its interaction with α_IIbβ₃ . Thromb Haemost. 1999 78 (suppl 1): #1301 (abstr.).
• 24 Clemetson KJ, Clemetson JM. Platelet GPIb-V-IX complex. Structure, function, physiology, and pathology. Semin Thromb Hemost 1995; 21: 130-6.
• 25 Jamieson GA, Okumura T. Reduced thrombin binding and aggregation in Bernard-Soulier platelets. J Clin Invest 1978; 61: 861-4.
• 26 Mazzucatto M, Marco LD, Masotti A, Pradella P, Bahou WF, Ruggeri ZM. Characterization of the initial alpha-thrombin interaction with glycoprotein Ib in relation to platelet activation. J Biol Chem 1998; 273: 1880-7.
• 27 Mann KG, Elion J, Butkowski RJ, Downing M, Nesheim ME. Prothrombin. Methods Enzymol 1981; 80: 286-302.
• 28 Moliterno DJ, Califf RM, Aguirre FV. et al. Effect of platelet glycoprotein IIb/IIIa integrin blockade on activated clotting time during percutaneous transluminal coronary angioplasty or directional atherectomy (the EPIC trial). Am J Cardiol 1995; 75: 559-62.
• 29 Furman MI, Krueger LA, Frelinger III AL, Barnard MR, Mascelli MA, Nakada MT, Michelson AD. GPIIb-IIIa antagonist-induced reduction in platelet surface factor V/Va binding and phosphatidylserine expression in whole blood. Thromb Haemost 2000; 84: 492-8.
• 30 Kloczewiak M, Timmons S, Hawiger J. Localization of a site interacting with human platelet receptor on carboxy-terminal segment of human fibrinogen gamma chain. Biochem Biophys Res Commun 1982; 107: 181-7.
• 31 Gartner TK, Bennett JS. The tetrapeptide analogue of the cell attachment site of fibronectin inhibits platelet aggregation and fibrinogen binding to activated platelets. J Biol Chem 1985; 260: 11891-4.
• 32 Plow EF, Pierschbacher MD, Ruoslahti E, Marguerie GA, Ginsberg MH. The effect of Arg-Gly-Asp-containing peptides on fibrinogen and von Willebrand factor binding to platelets. Proc Natl Acad Sci USA 1985; 82: 8057-61.
• 33 Andrieux A, Hudry-Clergeon G, Ryckwaert J-J, Chapel A, Ginsberg MH, Plow EF, Marguerie G. Amino acid sequences in fibrinogen mediating its interaction with its platelet receptor, GPIIb-IIIa. J Biol Chem 1989; 264: 9258-65.
• 34 Farrell DH, Thiagarajan P, Chung DW, Davie EW. Role of fibrinogen alpha and gamma chain sites in platelet aggregation. Proc Natl Acad Sci USA 1992; 89: 10729-32.
• 35 Hettasch JM, Bolyard MG, Lord ST. The residues AGDV of recombinant gamma chains of human fibrinogen must be carboxy-terminal to support human platelet aggregation. Thromb Haemost 1992; 68: 701-6.
• 36 Rooney MM, Parise LV, Lord ST. Dissecting clot retraction and platelet aggregation. J Biol Chem 1996; 271: 8553-5.
• 37 Lam SCT, Plow EF, Smith MA, Andrieux A, Ryckwaert J-J, Marguerie G, Ginsberg MH. Evidence that arginine-glycine-aspartic acid and fibrinogen gamma chain peptides share a common binding site on platelets. J Biol Chem 1987; 262: 947-50.
• 38 Plow EF, Marguerie GA, Ginsberg M. Fibrinogen, fibrinogen receptors and the peptides that inhibit these interactions. Biochem Pharmacol 1987; 36: 4035-40.
• 39 Cierniewski CS, Byzova T, Papierak M, Haas TA, Niewiarowska J, Zhang L, Cieslak M, Plow EF. Peptide ligands can bind to distinct sites in integrin α_IIbβ₃ and elicit different functional responses. J Biol Chem 1999; 274: 16923-32.
• 40 Suehiro K, Smith JW, Plow EF. The ligand recognition specificity of β₃ integrins. J Biol Chem 1996; 271: 10365-71.
• 41 D’Souza SE, Ginsberg MH, Burke TA, Lam SCT, Plow EF. Localization of an Arg-Gly-Asp recognition site within an integrin adhesion receptor. Science 1988; 242: 91-3.
• 42 Andrieux A, Rabiet M-J, Chapel A, Concord E, Marguerie G. A highly conserved sequence of the Arg-Gly-Asp-binding domain of the integrin beta-3 subunit is sensitive to stimulation. J Biol Chem 1991; 266: 14202-7.
• 43 Takada Y, Puzon W. Identification of a regulatory region of integrin β₁ subunit using activating and inhibiting antibodies. J Biol Chem 1993; 268: 17597-601.
• 44 Alemany M, Concord E, Garin J, Vinçon M, Giles A, Marguerie G, Gulino D. Sequence 274-368 in the β₃-subunit of the integrin α_IIbβ₃ provides a ligand recognition and binding domain for the gamma-chain of fibrinogen that is independent of platelet activation. Blood 1996; 87: 592-601.
• 45 Loftus JC, Liddington RC. Perspectives Series: cell adhesion in vascular biology. New insights into integrin-ligand interaction. J Clin Invest 1997; 99: 2302-6.
• 46 Huang C, Zang Q, Takagi J, Springer TA. Structural and functional studies with antibodies to the integrin α₂ subunit. A model for the I-like domain. J Biol Chem 2000; 275: 21514-24.
• 47 Rahman S, Kakkar VV, Authi KS. The integrin α_IIbβ₃ contains distinct and interacting binding sites for snake-venom RGD (Arg-Gly-Asp) proteins. Evidence that the receptor-binding characteristics of snake-venom RGD proteins are related to the amino acid environment flanking the sequence RGD. Biochem J 1995; 312: 223-32.
• 48 Hu DD, Barbas III CF, Smith JW. An allosteric Ca²⁺ binding site on the β₃-integrins that regulates the dissociation rate for RGD ligands. J Biol Chem 1996; 271: 21745-51.
• 49 Emsley J, Knight CG, Farndale RW, Barnes MJ, Liddington RC. Structural basis of collagen recognition by integrin α₂β₁ . Cell 2000; 101: 47-56.