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J. Biol. Chem., Vol. 279, Issue 18, 18392-18400, April 30, 2004

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p21-activated Kinase 1 Phosphorylates and Regulates 14-3-3 Binding to GEF-H1, a Microtubule-localized Rho Exchange Factor^*

Frank T. Zenke, Mira Krendel¶, Celine DerMardirossian, Charles C. King||, Benjamin P. Bohl, and Gary M. Bokoch**

From the Departments of Immunology and Cell Biology, The Scripps Research Institute, La Jolla, California 92037

GEF-H1 is a guanine nucleotide exchange factor for Rho whose activity is regulated through a cycle of microtubule binding and release. Here we identify a region in the carboxyl terminus of GEF-H1 that is important for suppression of its guanine nucleotide exchange activity by microtubules. This portion of the protein includes a coiled-coil motif, a proline-rich motif that may interact with Src homology 3 domain-containing proteins, and a potential binding site for 14-3-3 proteins. We identify GEF-H1 as a binding target and substrate for p21-activated kinase 1 (PAK1), an effector of Rac and Cdc42 GTPases, using an affinity-based screen and localize a PAK1 phosphorylation site to the inhibitory carboxylterminal region of GEF-H1. We show that phosphorylation of GEF-H1 at Ser⁸⁸⁵ by PAK1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules. Phosphorylation of GEF-H1 by PAK may be involved in regulation of GEF-H1 activity and may serve to coordinate Rho-, Rac-, and Cdc42-mediated signaling pathways.

Received for publication, January 6, 2004 , and in revised form, February 7, 2004.

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Fig. 1.

Both authors contributed equally to this work.

Present address: Merck KgaA, Oncology Research Darmstadt, Frankfurter Strasse 250, 64293 Darmstadt, Germany.

^¶ Present address: Dept. of Molecular, Cellular, and Developmental Biology, KBT-342, Yale University, 266 Whitney Ave., New Haven, CT 06520.

^|| Present address: Dept. of Pharmacology, University of California, 9500 Gilman Dr., San Diego, CA 92093.

^** To whom correspondence should be addressed: Depts. of Immunology and Cell Biology, The Scripps Research Inst., IMM14, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-874-8217; Fax: 858-784-8218; E-mail: bokoch{at}scripps.edu.

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