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J. Biol. Chem., Vol. 281, Issue 31, 21588-21593, August 4, 2006

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Fine Tuning PDK1 Activity by Phosphorylation at Ser^163*

Ramon A. Riojas, Chintan K. Kikani, Changhua Wang, Xuming Mao, Lijun Zhou, Paul R. Langlais, Derong Hu, James L. Roberts^¶, Lily Q. Dong^¶||, and Feng Liu^¶1

From the Departments of Biochemistry, Pharmacology, and ^||Cellular and Structural Biology and the ^¶Barshop Center for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, Texas 78229

3-Phosphoinositide-dependent protein kinase-1 (PDK1) mediates phosphorylation and activation of members of the AGC protein kinase family and plays an essential role in insulin signaling and action. However, whether and how PDK1 activity is regulated in cells remains largely uncharacterized. In the present study, we show that PDK1 undergoes insulin-stimulated and phosphatidylinositol 3-kinase-dependent phosphorylation at Ser²⁴⁴ in the activation loop and at a novel site: Ser¹⁶³ in the hinge region between the two lobes of the kinase domain. Sequence alignment studies revealed that the residue corresponding to Ser¹⁶³ of PDK1 in all other AGC kinases is glutamate, suggesting that a negative charge at this site may be important for PDK1 function. Replacing Ser¹⁶³ with a negatively charged residue, glutamate, led to a 2-fold increase in PDK1 activity. Molecular modeling studies suggested that phosphorylated Ser¹⁶³ may form additional hydrogen bonds with Tyr¹⁴⁹ and Gln²²³. In support of this, mutation of Tyr¹⁴⁹ to Ala is sufficient to reduce PDK1 activity. Taken together, our results suggest that PDK1 phosphorylation of Ser¹⁶³ may provide a mechanism to fine-tune PDK1 activity and function in cells.

Received for publication, January 17, 2006 , and in revised form, May 22, 2006.

^* This work was supported by a Research Award from the American Diabetes Association (to F. L.) and an National Institutes of Health Predoctoral Fellowship F31DK068874 (to R. A. R.). 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 To whom correspondence should be addressed: Dept. of Pharmacology, UTHSCSA, 7703 Floyd Curl Dr., San Antonio, TX 78229. E-mail: liuf{at}uthscsa.edu.

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