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Originally published In Press as doi:10.1074/jbc.M112402200 on February 27, 2002

J. Biol. Chem., Vol. 277, Issue 19, 16632-16638, May 10, 2002
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Substitution of the Autophosphorylation Site Thr516 with a Negatively Charged Residue Confers Constitutive Activity to Mouse 3-Phosphoinositide-dependent Protein Kinase-1 in Cells*

Michael J. WickDagger , KeriLyn R. WickDagger §, Hui Chen, Huili HeDagger , Lily Q. DongDagger , Michael J. Quon, and Feng LiuDagger ||**

From the Departments of Dagger  Pharmacology and || Biochemistry, The University of Texas Health Science Center, San Antonio, Texas 78229 and the  Cardiology Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892

3-Phosphoinositide-dependent protein kinase-1 (PDK-1)is a serine/threonine kinase that has been found to phosphorylate and activate several members of the AGC protein kinase family including protein kinase B (Akt), p70 S6 kinase, and protein kinase Czeta . However, the mechanism(s) by which PDK-1 is regulated remains unclear. Here we show that mouse PDK-1 (mPDK-1) undergoes autophosphorylation in vitro on both serine and threonine residues. In addition, we have identified Ser399 and Thr516 as the major mPDK-1 autophosphorylation sites in vitro. Furthermore, we have found that these two residues, as well as Ser244 in the activation loop, are phosphorylated in cells and demonstrated that Ser244 is a major in vivo phosphorylation site. Abolishment of phosphorylation at Ser244, but not at Ser399 or Thr516, led to a significant decrease of mPDK-1 autophosphorylation and kinase activity in vitro, indicating that autophosphorylation at Ser399 or Thr516 is not essential for mPDK-1 autokinase activity. However, overexpression of mPDK-1T516E, but not of mPDK-1S244E or mPDK-1S399D, in Chinese hamster ovary and HEK293 cells was sufficient to induce Akt phosphorylation at Thr308 to a level similar to that of insulin stimulation. Furthermore, this increase in phosphorylation was independent of the Pleckstrin homology domain of Akt. Taken together, our results suggest that mPDK-1 undergoes autophosphorylation at multiple sites and that this phosphorylation may be essential for PDK-1 to interact with and phosphorylate its downstream substrates in vivo.

* This study is supported by National Institutes of Health Grants DK56166 (to F. L. and L. Q. D.) and a Research Award from the American Diabetes Association (to F. L.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported by a National Institutes of Health Postdoctoral Training Grant 2T32AG00205-11.

** To whom correspondence should be addressed. E-mail: liuf@uthscsa.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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