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Papers In Press, published online ahead of print February 27, 2002
Department of Pharmacology, UTHSCSA, San Antonio, TX 78284
Corresponding Author: liuf{at}uthscsa.edu
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 (PKB/Akt), p70 S6 kinase, and PKC{z}. 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 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 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 this phosphorylation may be essential for PDK-1 to interact with and phosphorylate its downstream substrates in vivo.
J. Biol. Chem, 10.1074/jbc.M112402200
Submitted on December 27, 2001
Revised on February 6, 2002
Accepted on February 27, 2002
Substitution of the autophosphorylation site Thr516 with a negatively-charged residue confers constitutive activity to mouse PDK-1 in cells
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