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J. Biol. Chem., Vol. 279, Issue 33, 34361-34372, August 13, 2004

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G Protein-coupled Receptor-mediated Phosphorylation of the Activation Loop of Protein Kinase D

DEPENDENCE ON PLASMA MEMBRANE TRANSLOCATION AND PROTEIN KINASE C^*

Osvaldo Rey, Joseph R. Reeve, Jr., Elena Zhukova, James Sinnett-Smith, and Enrique Rozengurt

From the Unit of Signal Transduction and Gastrointestinal Cancer, Division of Digestive Diseases, Department of Medicine, UCLA-CURE Digestive Diseases Research Center and Molecular Biology Institute, David Geffen School of Medicine, UCLA, Los Angeles, California 90095

Protein kinase D (PKD) is a serine/threonine protein kinase activated by G protein-coupled receptor (GPCR) agonists through an incompletely characterized mechanism that includes its reversible plasma membrane translocation and activation loop phosphorylation via a protein kinase C (PKC)-dependent pathway. To gain a better understanding of the mechanism regulating the activation of PKD in response to GPCR stimulation, we investigated the role of its rapid plasma membrane translocation on its activation loop phosphorylation and identified the endogenous PKC isozyme that mediates that event in vivo. We had found that the activation loop of a PKD mutant, with reduced affinity for diacylglycerol and phorbol esters, was only phosphorylated upon its plasma membrane association. We also found that the activation loop phosphorylation and rapid plasma membrane dissociation of PKD were inhibited either by preventing the plasma membrane translocation of PKC, through abolition of its interaction with receptor for activated C kinase, or by suppressing the expression of PKC via specific small interfering RNAs. Thus, this study demonstrates that the plasma membrane translocation of PKD, in response to GPCR stimulation, is necessary for the PKC-mediated phosphorylation of the activation loop of PKD and that this event requires the translocation of both kinases to the plasma membrane. Based on these and previous results, we propose a model of GPCR-mediated PKD regulation that integrates its changes in distribution, catalytic activity, and multisite phosphorylation.

Received for publication, March 24, 2004 , and in revised form, May 28, 2004.

^* This work was supported by National Institutes of Health Grants DK 55003, DK 56930, and NCI P50 CA090388 (to E. R.) and Grant DK33580 (to J. R. R., Jr.), by CURE Digestive Diseases Research Center Grant DK-41301 (to E. R.), and by the Department of Veterans Affairs Research Service. 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.

Recipient of National Cancer Institute Mentored Career Development Award K01CA097956.

Ronald S. Hirshberg Professor of Translational Pancreatic Cancer Research. To whom correspondence should be addressed: 900 Veteran Ave., Warren Hall Rm. 11-124, Dept. of Medicine, School of Medicine, UCLA, Los Angeles, CA 90095-1786. Tel.: 310-794-6610; Fax: 310-267-2399; E-mail: erozengurt{at}mednet.ucla.edu.

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