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J. Biol. Chem., Vol. 276, Issue 40, 37459-37471, October 5, 2001
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From the Friedrich Miescher Institute, Maulbeerstrasse 66, Basel
CH-4058, Switzerland
3-Phosphoinositide-dependent
protein kinase-1 (PDK1) plays a central role in signal
transduction pathways that activate phosphoinositide 3-kinase. Despite
its key role as an upstream activator of enzymes such as protein kinase
B and p70 ribosomal protein S6 kinase, the regulatory mechanisms
controlling PDK1 activity are poorly understood. PDK1 has been reported
to be constitutively active in resting cells and not further
activated by growth factor stimulation (Casamayor, A., Morrice,
N. A., and Alessi, D. R. (1999) Biochem. J. 342, 287-292). Here, we report that PDK1 becomes tyrosine-phosphorylated and translocates to the plasma membrane in response to
pervanadate and insulin. Following pervanadate treatment, PDK1 kinase
activity increased 1.5- to 3-fold whereas the activity of PDK1
associated with the plasma membrane increased ~6-fold. The activity
of PDK1 localized to the plasma membrane was also increased by insulin treatment. Three tyrosine phosphorylation sites of PDK1 (Tyr-9 and
Tyr-373/376) were identified using in vivo labeling
and mass spectrometry. Using site-directed mutants, we show that,
although phosphorylation on Tyr-373/376 is important for PDK1 activity, phosphorylation on Tyr-9 has no effect on the activity of the kinase.
Both of these residues can be phosphorylated by v-Src tyrosine kinase
in vitro, and co-expression of v-Src leads to tyrosine
phosphorylation and activation of PDK1. Thus, these data suggest that
PDK1 activity is regulated by reversible phosphorylation, possibly by a
member of the Src kinase family.
Identification of Tyrosine Phosphorylation Sites
on 3-Phosphoinositide-dependent Protein Kinase-1
and Their Role in Regulating Kinase Activity*
*
This work was supported in part by a grant from the
Schweizerische Krebsliga (to M. M. H. and B. A. H.). The Friedrich
Miescher Institute is part of the Novartis Research Foundation.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.
To whom correspondence should be addressed: Tel.: 41-61-697-4046;
Fax: 41-61-697-3976; E-mail: hemmings@fmi.ch.
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