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J. Biol. Chem., Vol. 280, Issue 38, 33055-33065, September 23, 2005

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Transforming Activity of the Rho Family GTPase, Wrch-1, a Wnt-regulated Cdc42 Homolog, Is Dependent on a Novel Carboxyl-terminal Palmitoylation Motif^*

Anastacia C. Berzat1, Janice E. Buss, Emily J. Chenette¶, Carolyn A. Weinbaum||, Adam Shutes¶2, Channing J. Der¶**, Audrey Minden, and Adrienne D. Cox¶**3

From the Curriculum in Genetics and Molecular Biology, the Department of Radiation Oncology and the ^**Department of Pharmacology, ^¶Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, the Department of Biochemistry, Biophysics, and Molecular Biology, Iowa State University, Ames, Iowa 50011, the ^||Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, and the Department of Biological Sciences, Columbia University, New York, New York 10027

Wrch-1 is a Rho family GTPase that shares strong sequence and functional similarity with Cdc42. Like Cdc42, Wrch-1 can promote anchorage-independent growth transformation. We determined that activated Wrch-1 also promoted anchorage-dependent growth transformation of NIH 3T3 fibroblasts. Wrch-1 contains a distinct carboxyl-terminal extension not found in Cdc42, suggesting potential differences in subcellular location and function. Consistent with this, we found that Wrch-1 associated extensively with plasma membrane and endosomes, rather than with cytosol and perinuclear membranes like Cdc42. Like Cdc42, Wrch-1 terminates in a CAAX tetrapeptide (where C is cysteine, A is aliphatic amino acid, and X is any amino acid) motif (CCFV), suggesting that Wrch-1 may be prenylated similarly to Cdc42. Most surprisingly, unlike Cdc42, Wrch-1 did not incorporate isoprenoid moieties, and Wrch-1 membrane localization was not altered by inhibitors of protein prenylation. Instead, we showed that Wrch-1 is modified by the fatty acid palmitate, and pharmacologic inhibition of protein palmitoylation caused mislocalization of Wrch-1. Most interestingly, mutation of the second cysteine of the CCFV motif (CCFV > CSFV), but not the first, abrogated both Wrch-1 membrane localization and transformation. These results suggest that Wrch-1 membrane association, subcellular localization, and biological activity are mediated by a novel membrane-targeting mechanism distinct from that of Cdc42 and other isoprenylated Rho family GTPases.

Received for publication, October 4, 2004 , and in revised form, July 7, 2005.

^* This work was supported in part by National Institutes of Health Grants CA63071, CA67771, CA109550 (to A. D. C.), CA51890 (to J. E. B.), GM46372 (to C. A. W.), CA63071, and CA67771 (to C. J. D.). 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.

¹ Supported by National Institutes of Health Predoctoral Fellowship CA103143.

² Supported by a Susan G. Komen fellowship.

³ To whom correspondence should be addressed: Dept. of Radiation Oncology, 101 Manning Dr., 1050 NCCCC, CB 7512, University of North Carolina, Chapel Hill, NC 27599-7512. Tel.: 919-966-7713 (ext. 305); Fax: 919-966-7681; E-mail: adricox{at}med.unc.edu.

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