Specific members of the Rho branch of the human Ras superfamily of proteins (RhoA, Rac1 and CDC42) have attracted considerable attention over the past five years for four primary reasons. First, it is now well established that Rho family proteins are regulators of extracellular stimuli-mediated signaling pathways that control actin cytoskeletal soranization, gene expression and cell cycle progression. Consequently, Rho family proteins can regulate cell growth and differentiation, cell motility, and cell-cell and cell-substratum interactions. Second, it has been shown that aberrant expression of Rho family proteins causes tumorigenic, invasive and metastatic transformation of fibroblast, hematopoietic, and epithelial cells. Third, oncogenic Ras signaling and transformation have been demostrated to require toe function of specific Rho family proteins. Finally, there is strong evidence that Dbl family oncogene proteins cause transformation and promote invasion by activation of Rho family proteins. Taken together, these properties of Rho family proteins have implicated them as important regulators of cellular processes that may contribute to the uncontrolled growth and invasive properties of human tumor cells. However, the mechanisms by which Rho family proteins promote cellular transformation, and how Rho family proteins contribute to the transforming actions of oncogenic Ras and other oncoproteins, remain to be established. They have proposed four specific aims to delineate the signaling pathways and components that promote the transforming actions of Rho family proteins and their activators (Dbl family oncogene proteins).
Specific Aim 1 will determine the signaling pathways important for Rac1 and RhoA transforming activity, and consequently, define what Rac1 and RhoA functions contribute to Ras transformation.
Specific Aim 2 will be to determine if other Rho family proteins (RhoG, TTF and TC10) can also promote cellular transformation and whether they are essential for Ras transformation.
Specific Aim 3 will determine if the Dbl homology (DH) domains of SOS1 and RasGRF (known GEFs and activators of Ras) are also activators of Rho family proteins and can cause cellular transforming. If so, this would establish SOS1 and RasGRF as bifunctional activators of Ras and Rho. Finally, Specific Aim 4 will determine the contribution of the pleckstrin homology (PH) domain to Dbl family protein (Vav) signaling and transformation. These studies will determine if the PH domain is a regulator of DH domain function by regulating Vav subcellular location and membrane association. Taken together, these studies will elucidate the mechanisms by which Rho and Dbl family proteins may promote malignant transformation.
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