Ras oncogenes encode small, membrane-associated, GTP binding proteins that function as signal transducers in pathways that control cell growth, morphology, cell-cell contact, stress response, neoplasia and metastasis. It has been estimated that mutations involving the Ras oncogene contribute to 60-75% of all human neoplasms. Ras proteins are highly conserved in evolution. Homologs have been found all eucaryotes examined to date from yeast to mammals. Molecular studies have focused on three key aspects of Ras regulation: 1) GTP hydrolysis and GDP/GTP exchange, 2) protein-protein interactions through effector binding domains, and 3) post-translational lipid modification (prenylation) and the effect of these modifications on subcellular localization and signaling. Work on Ras prenylation) and the effect of these modifications on subcellular localization and signaling. Work on Ras prenylation has lead to the first rationally designed anti-cancer drug that targets the Ras oncogene. Despite this significant advance, many important questions remain. The long range goal of this project is to use the yeast system to study post-translational regulation of Ras activity with an emphasis on the role of lipid modification in Ras subcellular targeting.
The specific aims are to: 1) Determine how palmitoylation of Ras occurs and how it is regulated, 2) Determine how two newly discovered proteins, Erf2 and Erf4/Shr5, affect the subcellular localization of Ras, and 3) Define the intracellular pathway by which prenylated proteins such as Ras localize to the plasma membrane. This work will aid in the identification of new anti-Ras drug targets as well as improving our understanding of the mechanism of action of drugs currently under development. This work therefore addresses basic cancer research objectives.
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