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J. Biol. Chem., Vol. 283, Issue 2, 1084-1093, January 11, 2008

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Identification of Functionally Distinct Regions That Mediate Biological Activity of the Protein Kinase A Homolog Tpk2^*

Eileen J. Kennedy¹, Gourisankar Ghosh², and Lorraine Pillus³

From the Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0375 and the Division of Biological Sciences, Section of Molecular Biology, and the University of California San Diego Moores Cancer Center, University of California, San Diego, La Jolla, California 92093-0347

Kinases regulate key signaling processes that are increasingly implicated in development and disease. Kinase modulators have become important therapeutic tools and often target catalytic domains that are among the most structurally and functionally conserved regions of these enzymes. Such therapies lose efficacy as mutations conferring resistance arise. Because interactions between distinct and often distant regions of kinases can be critical, we took an unbiased genetic approach to identify sites within the protein kinase A homolog Tpk2 that contribute to its biological activity. Because many of these map outside the conserved core, this approach should be broadly useful in identifying new, more kinase-specific therapeutic targets.

Received for publication, May 16, 2007 , and in revised form, October 4, 2007.

^* This work was supported by a Minority Access to Science, Engineering, and Mathematics predoctoral fellowship from the National Science Foundation, a Cellular and Molecular Genetics training grant from the National Institutes of Health, and an American Heart Association predoctoral fellowship (to E. J. K.), funding from the National Institutes of Health (to L. P. and G. G.), and funding from the Human Frontier Science Program (to G. G.). 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-S3.

¹ Present address: Dept. of Chemistry and Chemical Biology, Harvard University, 12 Oxford St., Cambridge, MA 02138.

² To whom correspondence may be addressed: Dept. of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr., MC 0375, La Jolla, CA 92093-0375. Tel.: 858-822-0469; Fax: 858-534-7042; E-mail: gghosh{at}ucsd.edu.

³ To whom correspondence may be addressed: Division of Biological Sciences, Section of Molecular Biology, and UCSD Moores Cancer Center, University of California, San Diego, 9500 Gilman Dr., MC 0347, La Jolla, CA 92093-0347. Tel.: 858-822-2442; Fax: 858-534-0555; E-mail: lpillus{at}ucsd.edu.

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This article has been cited by other articles:

				J. Yang, E. J. Kennedy, J. Wu, M. S. Deal, J. Pennypacker, G. Ghosh, and S. S. Taylor Contribution of Non-catalytic Core Residues to Activity and Regulation in Protein Kinase A J. Biol. Chem., March 6, 2009; 284(10): 6241 - 6248. [Abstract] [Full Text] [PDF]