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J. Biol. Chem., Vol. 282, Issue 6, 3624-3631, February 9, 2007

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Glycogen Synthase Kinase-3 Phosphorylates CdGAP at a Consensus ERK 1 Regulatory Site^*

From the Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 2B2, Canada

Rho GTPases regulate a multitude of cellular processes from cytoskeletal reorganization to gene transcription and are negatively regulated by GTPase-activating proteins (GAPs). Cdc42 GTPase-activating protein (CdGAP) is a ubiquitously expressed GAP for Rac1 and Cdc42. In this study, we set out to identify CdGAP-binding partners and, using a yeast two-hybrid approach, glycogen synthase kinase 3 (GSK-3) was identified as a partner for CdGAP. GSK-3 exists in two isoforms, and , and is involved in regulating many cellular functions from insulin response to tumorigenesis. We show that GSK-3 and - interact with CdGAP in mammalian cells. We also demonstrate that GSK-3 phosphorylates CdGAP both in vitro and in vivo on Thr-776, which we have previously shown to be an ERK 1/2 phosphorylation site involved in CdGAP regulation. We report that the mRNA and protein levels of CdGAP are increased upon serum stimulation and that GSK-3 activity is necessary for the up-regulation of the protein levels of CdGAP but not for the increase in mRNA. We conclude that GSK-3 is an important regulator of CdGAP and that regulation of CdGAP protein levels by serum presents a novel mechanism for cells to control Cdc42/Rac1 GTPase signaling pathways.

Received for publication, October 27, 2006 , and in revised form, December 7, 2006.

^* This work was supported by the Canadian Cancer Society through the National Cancer Institute of Canada. 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 Recipient of a Canada Graduate Scholarship administered by the Canadian Institutes of Health Research (CIHR).

² Present address: Dept. of Cell Biology and Program in Neuroscience, Harvard Medical School, Boston, MA 02115.

³ Recipient of a Postdoctoral Fellowship Award from the CIHR.

⁴ The recipient of a CIHR New Investigator Award. To whom correspondence should be addressed: Dept. of Anatomy and Cell Biology, McGill University, 3640 University St., Montreal, QC H3A 2B2, Canada. Tel.: 514-398-1784; Fax: 514-398-5047; E-mail: nathalie.lamarche{at}mcgill.ca.

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