CONVERGENCE OF INTEGRIN AND RHO SIGNALING PATHWAYS

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Signaling through integrins (extracellular matrix protein receptors) and the small molecular weight GTP-binding protein, Rho, modify the cytoskeleton and regulate cell adhesion and motility. Alteration of the signaling processes that control these functions can transform normal cells to metastatic malignant cells. Integrin activation localizes the protein tyrosine kinase, pp125FAK, to focal adhesion complexes where it interacts with cytoskeletal and signal transducing proteins influencing cell attachment and migration. Rho-mediated alterations in the cytoskeleton are less well characterized. We recently identified a novel GTPase activating protein for Rho (Graf), which specifically interacts with ppl25FAK, and colocalizes with the actin cytoskeleton. We hypothesize that Graf is involved in the convergence of integrin and small molecular weight G protein signal transduction. The role of Graf will be investigated by the following specific aims: 1) Determine the Graf expression pattern and clone the remainder of the 5' translated region and 2) Characterize Graf's involvement in Rho and integrin- mediated signal transduction in vivo. Elucidation of the convergence of these signaling pathways will significantly improve our knowledge of important biological phenomena such as aberrant cell migration associated with cancer metastasis.