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J. Biol. Chem., Vol. 279, Issue 7, 6182-6189, February 13, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/7/6182    most recent M309579200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Barac, A. Articles by Gutkind, J. S. Search for Related Content PubMed PubMed Citation Articles by Barac, A. Articles by Gutkind, J. S. Social Bookmarking                      What's this?

Direct Interaction of p21-Activated Kinase 4 with PDZ-RhoGEF, a G Protein-linked Rho Guanine Exchange Factor^*

Ana Barac, John Basile, José Vázquez-Prado, Yuan Gao¶, Yi Zheng¶, and J. Silvio Gutkind||

From the Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, Department of Pharmacology, Centro De Investigación y De Estudios Avanzados del IPN, CP 07360 México, DF, Mexico, and ^¶Experimental Hematology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229

Rho GTPases regulate a wide variety of cellular processes, ranging from actin cytoskeleton remodeling to cell cycle progression and gene expression. Cell surface receptors act through a complex regulatory molecular network that includes guanine exchange factors (GEFs), GTPase activating proteins, and guanine dissociation inhibitors to achieve the coordinated activation and deactivation of Rho proteins, thereby controlling cell motility and ultimately cell fate. Here we found that a member of the RGL-containing family of Rho guanine exchange factors, PDZ RhoGEF, which, together with LARG and p115RhoGEF, links the G_12/13 family of heterotrimeric G proteins to Rho activation, binds through its C-terminal region to the serine-threonine kinase p21-activated kinase 4 (PAK4), an effector for Cdc42. This interaction results in the phosphorylation of PDZ RhoGEF and abolishes its ability to mediate the accumulation of Rho-GTP by G₁₃. Moreover, when overexpressed, active PAK4 was able to dramatically decrease Rho-GTP loading in vivo and the formation of actin stress fibers in response to serum or LPA stimulation. Together, these results provide evidence that PAK4 can negatively regulate the activation of Rho through a direct protein-protein interaction with G protein-linked Rho GEFs, thus providing a novel potential mechanism for cross-talk among Rho GTPases.

Received for publication, August 28, 2003 , and in revised form, November 16, 2003.

^* 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: Oral and Pharyngeal Cancer Branch, National Institute of Dental Research, National Institutes of Health, 30 Convent Drive, Building 30, Room 212, Bethesda, MD 20892-4330. Tel.: 301-496-6259; Fax: 301-402-0823; E-mail: sg39v{at}nih.gov.

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