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J. Biol. Chem., Vol. 281, Issue 8, 5149-5157, February 24, 2006

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The Nuclear Import of Protein Kinase D3 Requires Its Catalytic Activity^*

Osvaldo Rey¹, Romeo Papazyan, Richard T. Waldron, Steven H. Young, Jennifer Lippincott-Schwartz, Rodrigo Jacamo, and Enrique Rozengurt²

From the Unit of Signal Transduction and Gastrointestinal Cancer, Division of Digestive Diseases, Department of Medicine, CURE Digestive Diseases Research Center and Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, California 90095 and the National Institute of Child Health and Human Development, Cell Biology and Metabolism Branch, National Institutes of Health, Bethesda, Maryland 20892

The protein kinase D (PKD) family consists of three serine/threonine protein kinases termed PKD, PKD2, and PKD3, which are similar in overall structure and primary amino acid sequence. However, each isozyme displays a distinctive intracellular localization. Taking advantage of the structural homology and opposite nuclear localization of PKD2 and PKD3, we generated an extensive set of chimeric proteins between both isozymes to determine which PKD3 domain(s) mediates its nuclear localization. We found that the C-terminal region of PKD3, which contains its catalytic domain, is necessary but not sufficient for its nuclear localization. Real time imaging of a photoactivatable green fluorescent protein fused to PKD3 revealed that point mutations that render PKD3 catalytically inactive completely prevented its nuclear import despite its interaction with importin and . We also found that activation loop phosphorylation of PKD3 did not require its nuclear localization, and it was not sufficient to promote the nuclear import of PKD3. These results identify a novel function for the kinase activity of PKD3 in promoting its nuclear entry and suggest that the catalytic activity of PKD3 may regulate its nuclear import through autophosphorylation and/or interaction with another protein(s).

Received for publication, July 22, 2005 , and in revised form, December 5, 2005.

^* This work was supported by National Institutes of Health Grants DK 55003 and DK 56930 (to E. R.) and K01CA097956 (to O. R.) and by the Morphology/Imaging Core of the CURE Center Grant 5 P30 DK41301. 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.

² The Ronald S. Hirshberg Professor of Translational Pancreatic Cancer Research.

¹ To whom correspondence should be addressed: 900 Veteran Ave., Warren Hall Rm.11-115, Dept. of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095-1786. Tel.: 310-794-5902; Fax: 310-267-2399; E-mail: orey{at}mednet.ucla.edu.

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