title: The Pl(A2) polymorphism of integrin beta(3) enhances outside-in signaling and adhesive functions.
abstract: 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.
authors.affiliation: Department of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: K V
authors.initials: KV
authors.lastname: Vijayan
authors.forename: P J
authors.initials: PJ
authors.lastname: Goldschmidt-Clermont
authors.forename: C
authors.initials: C
authors.lastname: Roos
authors.forename: P F
authors.initials: PF
authors.lastname: Bray
mesh_terms: D000199:Actins / Q000378:metabolism; D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D016824:Antigens, Human Platelet / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D001704:Biopolymers; D016466:CHO Cells; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D048429:Cell Size; D003018:Clot Retraction; D003327:Coronary Disease / Q000453:epidemiology / Q000235:genetics*; D006224:Cricetinae; D003412:Cricetulus; D015638:Cytochalasin D / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020022:Genetic Predisposition to Disease; D006801:Humans; D007668:Kidney; D008297:Male; D010766:Phosphorylation; D010974:Platelet Aggregation / Q000235:genetics; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D011110:Polymorphism, Genetic; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000199:Actins; D016824:Antigens, Human Platelet; D001704:Biopolymers; D015815:Cell Adhesion Molecules; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D020033:Protein Isoforms; C083451:human platelet antigen 1b; D015638:Cytochalasin D; D005340:Fibrinogen; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human