The PlA2 polymorphism of integrin β3 enhances outside-in signaling and adhesive functions

Genetic factors are believed to influence the development of arterial thromboses. Because integrin alpha(IIb)beta(3) plays a crucial role in thrombus formation, we analyzed receptor adhesive properties using Chinese hamster ovary and human kidney embryonal 293 cells overexpressing the Pl(A1) or Pl(A2) polymorphic forms of alpha(IIb)beta(3). Soluble fibrinogen binding was no different between Pl(A1) and Pl(A2) cells, either in a resting state or when alpha(IIb)beta(3) was activated with anti-LIBS6. Pl(A1) and Pl(A2) cells bound equivalently to immobilized fibronectin. In contrast, significantly more Pl(A2) cells bound to immobilized fibrinogen in an alpha(IIb)beta(3)-dependent manner than did Pl(A1) cells. Disruption of the actin cytoskeleton by cytochalasin D abolished the increased binding of Pl(A2) cells. Compared with Pl(A1) cells, Pl(A2) cells exhibited a greater extent of polymerized actin and cell spreading, enhanced tyrosine phosphorylation of pp125(FAK), and greater fibrin clot retraction. These adhesion differences appear to depend on a signaling mechanism sensitive to receptor occupancy. Thus, the Pl(A2) polymorphism altered integrin-mediated functions of adhesion, spreading, actin cytoskeleton rearrangement, and clot retraction.

[1]  M. Furman,et al.  Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists. , 2000, Circulation.

[2]  P. Bray.  Integrin Polymorphisms as Risk Factors for Thrombosis , 1999, Thrombosis and Haemostasis.

[3]  M. Margaglione,et al.  Prothrombotic genetic risk factors in young survivors of myocardial infarction. , 1999, Blood.

[4]  D. Levy,et al.  Increased platelet aggregability associated with platelet GPIIIa PlA2 polymorphism: the Framingham Offspring Study. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[5]  S. Shattil,et al.  RhoA and the Function of Platelet Integrin αIIbβ3 , 1998 .

[6]  B. Coller,et al.  Fibrinogen Coating Density Affects the Conformation of Immobilized Fibrinogen: Implications for Platelet Adhesion and Spreading , 1998, Thrombosis and Haemostasis.

[7]  A. Hall,et al.  Rho GTPases and the actin cytoskeleton. , 1998, Science.

[8]  A. Zeiher,et al.  Platelet glycoprotein Illa polymorphisms and risk of coronary stent thrombosis , 1997, The Lancet.

[9]  A. Carter,et al.  Association of the Platelet PlA Polymorphism of Glycoprotein IIb/IIIa and the Fibrinogen Bβ 448 Polymorphism With Myocardial Infarction and Extent of Coronary Artery Disease , 1997 .

[10]  G. Vilaire,et al.  The PIA2 alloantigen does not alter the affinity of GPIIb-IIIa for fibrinogen or RGD-containing peptides , 1997 .

[11]  D. Arveiler,et al.  The Leu33/Pro Polymorphism (PIA1/PIA2 ) of the Glycoprotein IIIa (GPIIIa) Receptor Is Not Related to Myocardial Infarction in the ECTIM Study , 1997, Thrombosis and Haemostasis.

[12]  P. Ridker,et al.  PIA1/A2 polymorphism of platelet glycoprotein IIIa and risks of myocardial infarction, stroke, and venous thrombosis , 1997, The Lancet.

[13]  A. Carter,et al.  Association of the platelet Pl(A) polymorphism of glycoprotein IIb/IIIa and the fibrinogen Bbeta 448 polymorphism with myocardial infarction and extent of coronary artery disease. , 1997, Circulation.

[14]  Jeffrey W. Smith,et al.  The Ligand Recognition Specificity of Integrins (*) , 1996, The Journal of Biological Chemistry.

[15]  J. Weiss,et al.  A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. , 1996, The New England journal of medicine.

[16]  B. Haimovich,et al.  Protein Kinase C Regulates Tyrosine Phosphorylation of pp125FAK in Platelets Adherent to Fibrinogen , 1996 .

[17]  L. Silengo,et al.  p125FAK tyrosine phosphorylation and focal adhesion assembly: studies with phosphotyrosine phosphatase inhibitors. , 1995, Experimental cell research.

[18]  P. Bray,et al.  A monoclonal antibody (SZ21) specific for platelet GPIIIa distinguishes P1A1 from P1A2. , 1995, Tissue antigens.

[19]  K. Blakemore,et al.  Gene frequencies of the five major human platelet antigens in African American, white, and Korean populations , 1995, Transfusion.

[20]  R. H. Sohn,et al.  Localization of a Binding Site for Phosphatidylinositol 4,5-Bisphosphate on Human Profilin (*) , 1995, The Journal of Biological Chemistry.

[21]  E. Topol,et al.  Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. , 1995, The New England journal of medicine.

[22]  Zingde Sm,et al.  Heat-treated bovine serum albumin is a better blocking reagent for adhesion studies , 1995 .

[23]  S. Zingde,et al.  Heat-treated bovine serum albumin is a better blocking reagent for adhesion studies. , 1995, BioTechniques.

[24]  P. Newman,et al.  Human platelet alloantigens. , 1994, Current opinion in hematology.

[25]  P. Bray,et al.  Quantitation of soluble fibrinogen binding to platelets by fluorescence-activated flow cytometry. , 1994, The Journal of laboratory and clinical medicine.

[26]  V. Quaranta,et al.  Integrin cytoplasmic domains mediate inside-out signal transduction , 1994, The Journal of cell biology.

[27]  M. Ginsberg,et al.  Affinity modulation of the alpha IIb beta 3 integrin (platelet GPIIb-IIIa) is an intrinsic property of the receptor. , 1990, Cell regulation.

[28]  J. George,et al.  Platelet Immunobiology: Molecular and Clinical Aspects , 1989 .

[29]  R. Cook,et al.  Cloning of glycoprotein IIIa cDNA from human erythroleukemia cells and localization of the gene to chromosome 17. , 1988, Blood.

[30]  D. T. Shiu,et al.  Platelet glycoprotein IIb. Chromosomal localization and tissue expression. , 1987, The Journal of clinical investigation.

[31]  J. Northrop,et al.  Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[32]  L. Kedes,et al.  A human beta-actin expression vector system directs high-level accumulation of antisense transcripts. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[33]  O. Leeksma,et al.  Effect of the Binding of Anti‐Zwa Antibodies on Platelet Function , 1984, Vox sanguinis.

[34]  S. Niewiarowski,et al.  Effects of chymotrypsin and adenosine diphosphate on the exposure of fibrinogen receptors on normal human and Glanzmann's thrombasthenic platelets. , 1981, The Journal of biological chemistry.

[35]  T. Edgington,et al.  Interaction of fibrinogen with its platelet receptor as part of a multistep reaction in ADP-induced platelet aggregation. , 1980, The Journal of biological chemistry.

[36]  G. Vilaire,et al.  Exposure of platelet fibrinogen receptors by ADP and epinephrine. , 1979, The Journal of clinical investigation.

[37]  J. Loftus,et al.  Affinity modulation of the allbl33 integrin (platelet GPIlb-lila) is an intrinsic property of the receptor* , 2022 .