STRUCTURE AND FUNCTION OF VASCULAR INTEGRINS

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Platelet-platelet, platelet-matrix, and endothelial-matrix interactions are essential reactions in hemostasis and thrombosis which are mediated by integral membrane proteins on the cell surface. In many cases, these surface proteins have been identified as members of the integrin superfamily, a family of homologous cell surface receptors which have as their ligands adhesive glycoproteins such as fibrinogen, fibronectin, vitronectin, collagen and von Willebrand factor. Known members of the integrin family include glycoproteins IIb (GPIIb) and IIIa (GPIIIa) on the platelet surface and the fibronectin receptor (FnR) and vitronectin receptor (VnR) on the endothelial cell surface. The interaction between integrin receptors and their ligands often involves a tripeptide sequence, -ARG-GLY-ASP-, in the ligand. The overall objective of the Program Project will be to understand at the molecular level the structure and function of vascular integrins. The structural domains of GPIIb and GPIIIa involved in fibrinogen binding and binding to other ligands will be determined and the role of the amino acid sequences flanking these binding domains in the specificity of ligand binding will be examined using synthetic peptides and in vitro mutagenesis. The mechanisms involved in activation of GPIIb/IIIa as a fibrinogen receptor will be determined. The components of the platelet cytoskeleton associated with GPIIb/IIIa and other platelet integrins will be identified. Integrin-deficient endothelial cells and CHO cell variants will be isolated by selection and cloning. These cells will be used for studies of receptor expression and function. The role of integrins in angiogenesis will be examined. The Program Project will also focus on the structure and function of integrin ligands. The domains of one of the GPIIb/IIIa ligands, fibrinogen, involved in binding to GPIIb/IIIa will be, determined in order to distinguish between various models of ligand binding.