The Rho family GTPases Rac, Rho and Cdc42 are central coordinators of the signal transduction pathways that regulate the actin cytoskeleton, cell migration, gene expression and cell proliferation. Our past work demonstrated that integrins, which are the major receptors for extracellular matrix proteins, regulate Rho family GTPases in two ways. First, integrins controls GTP loading (i.e., activation). There is a separate level of regulation in which integrins control membrane targeting of the activated GTPases. Both steps, activation and membrane targeting, are essential for GTPases to activate downstream effectors. In the current grant application, we propose to pursue two projects to elucidate these two mechanisms. First, we will study a new nucleotide exchange factor for Cdc42 that we have recently cloned. It's protein binding partners, mode of regulation and roles in signal transduction will be investigated. Second, we will investigate the mechanism by which integrins control the membrane targeting of active Rac. The project will be based on preliminary data suggesting that effects of integrins on lipid rafts and/or caveolae mediate this effect. Thus, the regulation of lipid rafts/caveolae by integrins and their role in Rac signal transduction will be investigated. These studies will contribute to our fundamental understanding of how integrins regulate Rho family GTPases. These regulatory events are central to cell migration, growth and function in normal physiology and human diseases.
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