A major goal of our research has been the delineation of the role of protein isoprenylation in facilitating Ras and Rhc GTPase-mediated oncogenesis. From these studies, three major themes have emerged. First, the aberrant activation of Ras and Rho GTPase function contributes significantly to many facets of human oncogenesis. Second, while it was initially believed that isoprenoid lipid modification of proteins served simply as hydrophobic, nonspecific membrane-targeting lipid """"""""glues"""""""", we now appreciate that isoprenylation, together with other sequence elements and lipid modifications, dictate a complex spectrum of dynamic membrane interactions that endow otherwise highly related GTPases with strikingly divergent biological roles. Third, since Ras and Rho GTPase membrane association and function are critically dependent on isoprenoid modification, pharmacologic inhibition of protein prenylation may be an effective approach for cancer treatment. Inhibitors of the enzymes that catalyze the isoprenylation of Ras and Rho GTPases have been developed as novel, target-based therapies. In particular, inhibitors (FTIs) of the enzyme farnesyl transferase (FTase) that modifies Ras proteins have shown remarkable anti-tumor activity in preclinical models and are currently under phase II-III clinical evaluation. Surprisingly, it is now accepted that the anti-tumor activity of FTIs is not due to Ras inhibition. Instead, the critical targets of FTIs are thought to be other FTase substrates. Defining these critical FTI targets will be crucial for the successful clinical development of FTIs. We propose four specific aims that extend from these three themes. First, we will define the novel mechanism by which the C-terminal sequences of the Cdc42-related proteins, Wrch-1 and Wrch-2/Chp, dictate membrane association and functional diversity from Cdc42. Unexpectedly, these two Rho GTPases are not substrates for either the FTase or GGTase I enzyme that isoprenylates the other Ras and Rho GTPases. Second, we will determine whether the farnesylated GTPase Rheb, recently implicated in oncogenesis by activation of the mTOR/S6 kinase pathway, is targeted by FTIs. Third, we will determine whether FTI-mediated loss of the farnesylated, Ras-related tumor suppressor proteins NOEY2/ARHI and Rig/Di-Ras define a potentially deleterious consequence of FTI therapy. Finally, we will determine whether the PRL protein tyrosine phosphatases, involved in promoting tumor cell invasion and metastasis, are important targets of FTI antitumor activity. ? ?
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