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Vol. 16, Issue 4, 1606-1616, April 2005
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¶
* Department of Medicine, Cell Biology, and Pharmacology, New York University School of Medicine, New York, NY 10016;
Gladstone Institute of Cardiovascular Disease, Cardiovascular Research Institute, and Department of Medicine, University of California, San Francisco, San Francisco, CA 94158
Submitted November 3, 2004;
Accepted January 4, 2005
Monitoring Editor: Sandra Schmid
The CAAX motif at the C terminus of most monomeric GTPases is required for membrane targeting because it signals for a series of three posttranslational modifications that include isoprenylation, endoproteolytic release of the C-terminal– AAX amino acids, and carboxyl methylation of the newly exposed isoprenylcysteine. The individual contributions of these modifications to protein trafficking and function are unknown. To address this issue, we performed a series of experiments with mouse embryonic fibroblasts (MEFs) lacking Rce1 (responsible for removal of the –AAX sequence) or Icmt (responsible for carboxyl methylation of the isoprenylcysteine). In MEFs lacking Rce1 or Icmt, farnesylated Ras proteins were mislocalized. In contrast, the intracellular localizations of geranylgeranylated Rho GTPases were not perturbed. Consistent with the latter finding, RhoGDI binding and actin remodeling were normal in Rce1- and Icmt-deficient cells. Swapping geranylgeranylation for farnesylation on Ras proteins or vice versa on Rho proteins reversed the differential sensitivities to Rce1 and Icmt deficiency. These results suggest that postprenylation CAAX processing is required for proper localization of farnesylated Ras but not geranygeranylated Rho proteins.
Present address: University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390
Present address: Sahlgrenska University Hospital, Institute of Laboratory Medicine, Sahlgrenska Sjukhuset, S-413 45 Göteborg, Sweden
|| Present address: Brigham and Woman's Hospital, 75 Francis St., Boston MA 02115
¶ Present address: David Geffen School of Medicine at UCLA, Los Angeles, CA 90095
Address correspondence to: Mark Philips (philim01{at}med.nyu.edu).
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