Integrin activation is tightly regulated by intracellular signals, and integrins localize signaling molecules to sites of cell adhesion. These relationships are highly relevant to blood and vascular cells, where integrins regulate growth, differentiation, survival and function. The purpose of this Program Project is to characterize fundamental mechanisms of integrin signaling in blood and vascular cells, with the common goal of identifying general rules of integrin signaling. Project 1 will test the hypothesis that integrin alphaIIbbeta3 utilizes a novel pathway involving protein tyrosine kinases and hematopoietic cell- specific adapter molecules to promote cytoskeletal reorganization in adherent platelets and megakaryocytes. Particular emphasis will be placed on identifying protein-protein interactions that initiate and propagate signal relay form alphaIIbbeta3 to actin. Project 2 will identify and characterize signaling pathways that suppress integrin activation. Special emphasis will be placed on proteins identified in genetic screens to influence integrin activation, including Ras GTPases, MAP kinases, and PEA-15, a death effector, domain-containing protein. Project 3 will test the hypothesis that integrins are components of complex intracellular signaling networks whose spatially and temporally regulated activation governs endothelial cell and monocytic migration. It will determine how these networks regulate localized integrin activity, and how integrins and mechanical forces regulate localized activation of Rac, Cdc42, PAK and ERK kinases to control cell migration. Project 4 will examine relationships between Abl tyrosine kinases and integrin signaling by determining how Abl modulates filopodia formation, cell migration and chemotaxis. It will also determine how integrins stimulate the nuclear export of c-Abl and how they override the inhibition of c-Abl activity by F-actin. These projects will be supported by core units that provide recombinant proteins, cell microinjection and imaging capabilities and administrative coordination. The synergy achieved by this Program will lead to a better understanding of integrin signaling, with implications for hemostasis, vascular biology and blood diseases.
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