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J. Biol. Chem., Vol. 279, Issue 8, 7346-7352, February 20, 2004

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Carboxyl Methylation of Ras Regulates Membrane Targeting and Effector Engagement^*

Vi K. Chiu, Joseph Silletti, Victoria Dinsell¶, Heidi Wiener, Kristina Loukeris, Guoming Ou¶, Mark R. Philips||, and Michael H. Pillinger¶||**

From the Departments of Medicine, Cell Biology, and ^||Pharmacology, New York University School of Medicine, New York, New York 10016, ^¶The Hospital for Joint Diseases, New York, New York 10003, and ^**the Department of Medicine of the New York Harbor Healthcare System of Veterans Affairs, New York, New York 10010

Post-translational modification of Ras proteins includes prenylcysteine-directed carboxyl methylation. Because Ras participates in Erk activation by epidermal growth factor (EGF), we tested whether Ras methylation regulates Erk activation. EGF stimulation of Erk was inhibited by AFC (N-acetyl-S-farnesyl-L-cysteine), an inhibitor of methylation, but not AGC (N-acetyl-S-geranyl-L-cysteine), an inactive analog of AFC. AFC inhibited Ras methylation as well as the activation of pathway enzymes between Ras and Erk but did not inhibit EGF receptor phosphorylation, confirming action at the level of Ras. Transient transfection of human prenylcysteine-directed carboxyl methyltransferase increased EGF-stimulated Erk activation. AFC but not AGC inhibited movement of transiently transfected green fluorescent protein-Ras from the cytosol to the plasma membrane of COS-1 cells and depleted green fluorescent protein-Ras from the plasma membrane in stably transfected Madin-Darby canine kidney cells, suggesting that methylation regulates Erk by ensuring proper membrane localization of Ras. However, when COS-1 cells were transfected with Ras complexed to CD8, plasma membrane localization of Ras was unaffected by AFC, yet EGF-stimulated Erk activation was inhibited by AFC. Thus, Ras methylation appears to regulate Erk activation both through the localization of Ras as well as the propagation of Ras-dependent signals.

Received for publication, October 22, 2003 , and in revised form, December 1, 2003.

^* This work was supported by Arthritis Foundation, New York Chapter, Young Scholar and Research Grants (to M. H. P.), by National Institutes of Health Grants AI36224 and GM55279 (to M. R. P.), the Burroughs Wellcome Foundation (to M. R. P), and National Institutes of Health General Clinical Research Center Grant NCRR M01RR00096. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Div. of Rheumatology, Dept. of Medicine 630-111J, New York Harbor Healthcare System, 423 E. 23rd St., New York, NY 10010. Tel.: 212-951-3328; Fax: 212-951-3329; E-mail: michael.pillinger{at}med.nyu.edu.

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