STRUCTURE/FUNCTION OF VASCULAR INTEGRINS

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Platelet-platelet, platelet-matrix, and endothelial-matrix interactions mediated by integrins are essential reactions in hemostasis and thrombosis. Hey integrins in the vasculature include glycoproteins IIb/IIIa (alphaIIb/beta3) on the platelet surface and the fibronectin receptor (FnR) and vitronectin receptor (VnR) on the surface of endothelial and other vascular cells. Studies as part of this Program Project and in other laboratories have shown that the interaction between integrin receptors and their ligands not only provides a mechanism for cell adhesion and aggregation, but initiates a variety of cellular signals that are essential for diverse cellular functions such as motility, production of cytokines, and cell division. These signals include activation of kinases, rearrangement of the cellular cytoskeleton, and induction of genes. The overall focus of this renewal Program Project will be identify and characterize the pathways through which these integrin- mediated signals are transduced. The cellular signals involved in activation of alphaIIb/beta3 termed CIB. Cytoplasmic domain sequences involved in the interaction with cytoskeletal proteins, tyrosines kinases, phosphatases, and low molecular weight GTPases will be mapped using in vitro mutagenesis and peptide approaches. The regulation of platelet tyrosine phosphorylation by tyrosine phosphatases will be examined. The role of VASP, a vasodilator-stimulated phosphoprotein, in actin polymerization and activation of alphaIIb/beta3 will be explored. The cooperative effects of integrin-mediated cell anchorage and mitogens on signal generation and regulation of cell cycle traverse will be explored in order to identify the pathways responsible for this cooperativity. The possible transduction of signals from integrins to cyclin-dependent kinases will be examined. These should continue to clarify the role of integrins as signal transduction molecules and the unique effects of these proteins in vascular biology.