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Oklahoma City, MA, United States

Chenette E.J.,Nature Publishing Group Cambridge | Der C.J.,University of North Carolina at Chapel Hill
Enzymes | Year: 2011

The activity of Ras-related GTPases supports a myriad of physiological and pathophysiological cellular events. Ras-mediated signaling is regulated by guanine nucleotide binding and hydrolysis, which governs binding to and activation of downstream effector proteins. However, the subcellular localization of active Ras proteins-and hence the identity of nearby effector and regulatory proteins-can determine the biological outcome of these signaling events. Most Ras superfamily members associate with cellular membranes, and precise subcellular localization is determined by residues at the C-terminus of the protein (and modification of these residues) that increase the affinity for membranes; these can include palmitoylation of cysteines, stretches of basic residues, and prenylation of the extreme C-terminal cysteine residue. In this chapter, we discuss the process, regulation, and biological consequence of lipidmodification of Ras superfamily smallGTPases, with a focus on the role of isoprenoid modification of Rho and Rab family members. For each subfamily, we describe the responsible prenyltransferases and the effects of prenylation on protein localization and activity. Finally, we chronicle the development of prenylation inhibitors as potential anticancer therapeutics. From the literature reviewed in this chapter, prenylation emerges as one mechanism that imparts unique localization and function to these otherwise highly conserved small GTPases. © 2011 Elsevier Inc. Source

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