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J. Biol. Chem., Vol. 282, Issue 43, 31273-31288, October 26, 2007

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Properties, Regulation, and in Vivo Functions of a Novel Protein Kinase D

CAENORHABDITIS ELEGANS DKF-2 LINKS DIACYLGLYCEROL SECOND MESSENGER TO THE REGULATION OF STRESS RESPONSES AND LIFE SPAN^*

From the Department of Molecular Pharmacology, Atran Laboratories, Albert Einstein College of Medicine, Bronx, New York 10461

Protein kinase D (PKD) isoforms are protein kinase C effectors in signaling cascades controlled by diacylglycerol (DAG). All PKDs are regulated by DAG/phorbol 12-myristate 13-acetate-binding C1 domains and an activation loop (A-loop). To understand how PKD isoforms diversify DAG signaling networks, it is essential to determine redundant and novel properties of their regulatory domains, characterize factors controlling PKD gene expression, and discover their in vivo physiological roles. Studies on a novel PKD, Caenorhabditis elegans DKF-2 (D kinase family-2), addressed these topics. The C1b domain mediates phorbol 12-myristate 13-acetate-induced translocation and activation of DKF-2. However, when DAG is elevated, C1a and C1b contribute equally to targeting/activation of DKF-2. DKF-2 C1 domains do not inhibit catalytic activity; they mediate delivery of DKF-2 to a membrane where protein kinase C phosphorylates Ser⁹²⁵ and Ser⁹²⁹ in the A-loop. This potently stimulates DKF-2 catalytic activity. Phosphorylation of Ser⁹²⁵ alone switches on 70% of maximal kinase activity. Persistent phosphorylation of Ser⁹²⁹ tags DKF-2 for proteasomal degradation; Ser(P)⁹²⁵ plays a minor role in DKF-2 degradation. GATA enhancer sequences govern DKF-2 expression in intestine in vivo. Adult life span increases 40% in animals lacking DKF-2. In thermally stressed wild type animals, the DAF-16 transcription factor is segregated from the nuclei of adult intestinal cells. In contrast, DAF-16 enters adult intestinal nuclei of DKF-2-deficient, thermally stressed animals, where it can trigger gene transcription that protects against various insults. The results suggest a mechanism for increased longevity and show that a PKD links DAG signals to regulation of stress responses and life span.

Received for publication, February 21, 2007 , and in revised form, August 16, 2007.

^* 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 Figs. S1–S5 and Tables SI and SII.

¹ To whom correspondence should be addressed: Dept. of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Tel.: 718-430-2505; Fax: 718-430-8922; E-mail: rubin{at}aecom.yu.edu.

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