Download PDF
Thromb Haemost 2001; 86(01): 34-40
DOI: 10.1055/s-0037-1616198
Research Article
Schattauer GmbH

αIIbβ3 and Its Antagonism at the New Millennium

Edward F. Plow
1   Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, Cleveland Clinic Foundation, Cleveland, OH, USA
,
Czeslaw S. Cierniewski
2   Department of Biophysics, Medical University in Lodz, Lodz, Poland
,
Zihui Xiao
1   Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, Cleveland Clinic Foundation, Cleveland, OH, USA
,
Thomas A. Haas
1   Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, Cleveland Clinic Foundation, Cleveland, OH, USA
,
Tatiana V. Byzova
1   Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, Cleveland Clinic Foundation, Cleveland, OH, USA
› Author Affiliations
Further Information

Publication History

Publication Date:
12 December 2017 (online)

    Permissions and Reprints

Summary

Because of its major role in regulating platelet functions and its prominence on the cell surface, integrin αIIbβ3 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 αIIbβ3 remains inadequate. This article addresses two aspects of still evolving αIIbβ3 function: 1) the interface between αIIbβ3 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 αIIbβ3. As illustrated by these two examples, there is still much to be learned about αIIbβ3 if we are to fully appreciate its functions and its potential as a therapeutic target.

Key words

Anti-thrombotic therapy - integrin αIIbβ3 - adhesive proteins - blood coagulation proteins
 

  • References

  • 1 Topol EJ, Byzova TV, Plow EF. Platelet GPIIb-IIIa blockers. Lancet 1999; 353: 227-31.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 3 GUSTO-IV ACS Trial.. Presented at the 22nd Congress of the European Society of Cardiology. 2000 (abstr.).
    PubMedGoogle Scholar
  • 4 Marguerie GA, Plow EF. The fibrinogen dependent pathway of platelet aggregation. Ann N Y Acad Sci 1983; 408: 556-67.
    CrossrefPubMedGoogle Scholar
  • 5 Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 1992; 69: 11-25.
    CrossrefPubMedGoogle Scholar
  • 6 Plow EF, Haas TA, Zhang L, Loftus J, Smith JW. Ligand binding to integrins. J Biol Chem 2000; 275: 21785-8.
    CrossrefPubMedGoogle Scholar
  • 7 Bennett JS, Vilaire G. Exposure of platelet fibrinogen receptors by ADP and epinephrine. J Clin Invest 1979; 64: 1393-401.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 9 Fujimoto T, Hawiger J. Adenosine diphosphate induces binding of von Willebrand factor to human platelets. Nature 1982; 297: 154-6.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 11 Plow EF, Ginsberg MH. Specific and saturable binding of plasma fibronectin to thrombin-stimulated human platelets. J Biol Chem 1981; 256: 9477-82.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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 αIIbβ3 . J Biol Chem 1999; 274: 24321-7.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 17 Byzova TV, Plow EF. Networking in the hemostatic system. Integrin αIIbβ3 binds prothrombin and influences its activation. J Biol Chem 1997; 272: 27183-8.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 19 Stubbs MT, Bode W. A player of many parts: the spotlight falls on thrombin structure. Thromb Res 1993; 69: 1-58.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 23 Byzova TV, Kim WE, Plow EF. Acceleration of prothrombin activation by its interaction with αIIbβ3 . Thromb Haemost. 1999 78 (suppl 1): #1301 (abstr.).
    PubMedGoogle Scholar
  • 24 Clemetson KJ, Clemetson JM. Platelet GPIb-V-IX complex. Structure, function, physiology, and pathology. Semin Thromb Hemost 1995; 21: 130-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Jamieson GA, Okumura T. Reduced thrombin binding and aggregation in Bernard-Soulier platelets. J Clin Invest 1978; 61: 861-4.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 27 Mann KG, Elion J, Butkowski RJ, Downing M, Nesheim ME. Prothrombin. Methods Enzymol 1981; 80: 286-302.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Rooney MM, Parise LV, Lord ST. Dissecting clot retraction and platelet aggregation. J Biol Chem 1996; 271: 8553-5.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 38 Plow EF, Marguerie GA, Ginsberg M. Fibrinogen, fibrinogen receptors and the peptides that inhibit these interactions. Biochem Pharmacol 1987; 36: 4035-40.
    CrossrefPubMedGoogle Scholar
  • 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 αIIbβ3 and elicit different functional responses. J Biol Chem 1999; 274: 16923-32.
    CrossrefPubMedGoogle Scholar
  • 40 Suehiro K, Smith JW, Plow EF. The ligand recognition specificity of β3 integrins. J Biol Chem 1996; 271: 10365-71.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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 αIIbβ3 provides a ligand recognition and binding domain for the gamma-chain of fibrinogen that is independent of platelet activation. Blood 1996; 87: 592-601.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 47 Rahman S, Kakkar VV, Authi KS. The integrin αIIbβ3 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 49 Emsley J, Knight CG, Farndale RW, Barnes MJ, Liddington RC. Structural basis of collagen recognition by integrin α2β1 . Cell 2000; 101: 47-56.
    CrossrefPubMedGoogle Scholar