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J. Biol. Chem., Vol. 281, Issue 32, 23218-23226, August 11, 2006

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Protein Kinase C (PKC)-Annexin V Interaction

A REQUIRED STEP IN PKC TRANSLOCATION AND FUNCTION^*

From the Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, California 94305

Protein kinase C (PKC) plays a critical role in diseases such as cancer, stroke, and cardiac ischemia, and participates in a variety of signal transduction pathways such as apoptosis, cell proliferation, and tumor suppression. Though much is known about PKC downstream signaling events, the mechanisms of regulation of PKC activation and subsequent translocation have not been elucidated. Protein-protein interactions regulate and determine the specificity of many cellular signaling events. Such a specific protein-protein interaction is described here between PKC and annexin V. We demonstrate, at physiologically relevant conditions, that a transient interaction between annexin V and PKC occurs in cells after PKC stimulation, but before PKC translocates to the particulate fraction. Evidence of PKC-annexin V binding is provided also by FRET and by in vitro binding studies. Dissociation of the PKC-annexin V complex requires ATP and microtubule integrity. Furthermore, depletion of endogenous annexin V, but not annexin IV, with siRNA inhibits PKC translocation following PKC stimulation. A rationally designed eight amino acid peptide, corresponding to the interaction site for PKC on annexin V, inhibits PKC translocation and PKC-mediated function as evidenced by its protective effect in a model of myocardial infarction. Our data indicate that translocation of PKC is not simply a diffusion-driven process, but is instead a multi-step event regulated by protein-protein interactions. We show that following cell activation, PKC-annexin V binding is a transient and an essential step in the function of PKC, thus identifying a new role for annexin V in PKC signaling and a new step in PKC activation.

Received for publication, March 6, 2006 , and in revised form, May 17, 2006.

^* This research was supported by National Institutes of Health Grant HL52141. 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 To whom correspondence should be addressed: Dept. of Molecular Pharmacology, Stanford University School of Medicine, CCSR, Rm. 3145A, 269 Campus Dr., Stanford, CA 94305-5174. Tel.: 650-725-7720; Fax: 650-723-2253; E-mail: mochly{at}stanford.edu.

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