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Originally published In Press as doi:10.1074/jbc.M213224200 on March 11, 2003

J. Biol. Chem., Vol. 278, Issue 20, 17969-17976, May 16, 2003
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Tyrosine Phosphorylation of Protein Kinase D in the Pleckstrin Homology Domain Leads to Activation*

Peter StorzDagger , Heike DöpplerDagger , Franz-Josef Johannesdagger §, and Alex TokerDagger

From the Dagger  Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215 and § Fraunhofer Institute for Interfacial Engineering and Biotechnology, 70569 Stuttgart, Germany

Protein kinase D (PKD) is a member of the AGC family of Ser/Thr kinases and is distantly related to protein kinase C (PKC). Formerly known as PKCµ, PKD contains protein domains not found in conventional PKC isoforms. A functional pleckstrin homology (PH) domain is critical for the regulation of PKD activity. Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine phosphorylation sites (Tyr432, Tyr463, and Tyr502), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr463) leads to PKD activation. By using a phospho-specific antibody, we show that Abl directly phosphorylates PKD at Tyr463 in vitro, and in cells phosphorylation of this site is sufficient to mediate full activation of PKD. Mutation of the other two sites, Tyr432 and Tyr502, had no significant influence on PKD activity. These data reveal a tyrosine phosphorylation-dependent activation mechanism for PKD and suggest that this event contributes to the release of the autoinhibitory PKD PH domain leading to kinase activation and downstream responses.

* This work was supported by National Institutes of Health Grant CA 75134 (to A. T.) and by Deutsche Forschungsgemeinschaft Grant STO 439/1-1 (to P. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We dedicate this paper to the memory of Franz-Josef Johannes, a friend, colleague, teacher, and mentor, whose contributions to the PKCµ/PKD field will be greatly missed.

dagger Deceased.

To whom correspondence should be addressed: Dept. of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215. Tel.: 617-667-8535; Fax: 617-667-3616; E-mail: atoker@caregroup.harvard.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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