Abundant data supports a prominent role for Vascular Endothelial Growth Factor (VEGF) in the growth and metastasis of multiple tumor types, including many of the most highly vascularized such as glioblastoma, renal cell carcinoma, angiosarcoma, and Kaposi's sarcoma. Our long-range objective is a comprehensive understanding of signal transduction initiated by VEGF and the relationship of these signals to the angiogenic phenotype. VEGF and other proangiogenic growth factors likely share many signal transduction pathways, particularly downstream from """"""""integrators"""""""" of signal transduction such as Ras and FAK. Our initial funded studies identified Ras activation as both necessary and sufficient for the angiogenic phenotype and mapped the relationship between VEGF signaling events and biological actions. Focal Adhesion Kinase (FAK), like Ras, integrates inputs from multiple extracellular stimuli including growth factor receptors, G-protein-coupled receptors, mechanical stimuli, and integrin/matrix interactions. While many studies have correlated changes in FAK phosphorylation with changes in endothelial cell function, few studies have directly investigated the role of FAK signaling. Our preliminary data demonstrate FAK signaling is essential for cell proliferation in response to VEGF. FAK has been implicated in controlling cell proliferation in other cell types through the regulation of ERK (fibroblasts) or JNK (smooth muscle cells). Our data demonstrates activation of these cascades by VEGF is not affected by disrupting FAK signal transduction. Rather, FAK appears to control cell cycle progression through a novel induction of a cyclin-dependent kinase inhibitor. Based on these data, as well as our previous results with Ras/MAPK signaling, our hypothesis is that the regulation of FAK signal transduction and associated changes in cell phenotype will have unique and endothelial cell specific components that could ultimately be exploited to modulate the angiogenic response. Our objective in this proposal is to directly investigate the role of FAK signal transduction in integrating the biological response to VEGF, determine the mechanistic basis for the observed regulation, and to investigate the role of FAK and Ras signal transduction in modulating the angiogenic response in vivo.
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