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J. Biol. Chem., Vol. 281, Issue 26, 17801-17814, June 30, 2006

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Characterization of a Novel Protein Kinase D

CAENORHABDITIS ELEGANS DKF-1 IS ACTIVATED BY TRANSLOCATION-PHOSPHORYLATION AND REGULATES MOVEMENT AND GROWTH IN VIVO^*

Hui Feng¹, Min Ren¹, Shi-Lan Wu, David H. Hall, and Charles S. Rubin²

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

Protein kinase D (PKD) isoforms are protein kinase C (PKC) effectors in diacylglycerol (DAG)-regulated signaling pathways. Key physiological processes are placed under DAG control by the distinctive substrate specificity and intracellular distribution of PKDs. Comprehension of the roles of PKDs in homeostasis and signal transduction requires further knowledge of regulatory interplay among PKD and PKC isoforms, analysis of PKC-independent PKD activation, and characterization of functions controlled by PKDs in vivo. Caenorhabditis elegans and mammals share conserved signaling mechanisms, molecules, and pathways Thus, characterization of the C. elegans PKDs could yield insights into regulation and functions that apply to all eukaryotic PKDs. C. elegans DKF-1 (D kinase family-1) contains tandem DAG binding (C1) modules, a PH (pleckstrin homology) domain, and a Ser/Thr protein kinase segment, which are homologous with domains in classical PKDs. DKF-1 and PKDs have similar substrate specificities. Phorbol 12-myristate 13-acetate (PMA) switches on DKF-1 catalytic activity in situ by promoting phosphorylation of a single amino acid Thr⁵⁸⁸ in the activation loop. DKF-1 phosphorylation and activation are unaffected when PKC activity is eliminated by inhibitors. Both phosphorylation and kinase activity of DKF-1 are extinguished by substituting Ala for Thr⁵⁸⁸ or Gln for Lys⁴⁵⁵ ("kinase dead") or incubating with protein phosphatase 2C. Thus, DKF-1 is a PMA-activated, PKC-independent D kinase. In vivo, dkf-1 gene promoter activity is evident in neurons. Both dkf-1 gene disruption (null phenotype) and RNA interference-mediated depletion of DKF-1 protein cause lower body paralysis. Targeted DKF-1 expression corrected this locomotory defect in dkf-1 null animals. Supraphysiological expression of DKF-1 limited C. elegans growth to 60% of normal length.

Received for publication, November 4, 2005 , and in revised form, April 5, 2006.

^* 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 These authors made equal contributions to this work.

² 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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