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MBC in Press, published online ahead of print June 27, 2007
Mol. Biol. Cell 10.1091/mbc.E07-01-0053

A more recent version of this article appeared on September 1, 2007
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Submitted on January 24, 2007
Revised on May 24, 2007
Accepted on June 15, 2007

A Novel Function of eIF2{alpha} Kinases as Inducers of the Phosphoinositide-3 Kinase Signaling Pathway

Shirin Kazemi,* Zineb Mounir,* Dionissios Baltzis,* Jennifer F. Raven,*{dagger} Shuo Wang,*{dagger} Jothi Latha Krishnamoorthy,* Olivier Pluquet,* Jerry Pelletier,{ddagger} and Antonis E. Koromilas*

*Lady Davis Institute, Sir Mortimer B. Davis-Jewish General Hospital, Montréal, QC, Canada H3T 1E2; {ddagger}Department of Biochemistry and McGill Cancer Center, Montréal, QC, Canada H3G 1Y6

Monitoring Editor: J. Silvio Gutkind

Phosphoinositide-3 kinase (PI3K) plays an important role in signal transduction in response to a wide range of cellular stimuli involved in cellular processes that promote cell proliferation and survival. Phosphorylation of the {alpha} subunit of the eukaryotic translation initiation factor eIF2 at Ser51 takes place in response to various types of environmental stress and is essential for regulation of translation initiation. Herein, we show that a conditionally active form of the eIF2{alpha} kinase PKR acts upstream of PI3K and turns on the Akt/PKB-FRAP/mTOR pathway leading to S6 and 4E-BP1 phosphorylation. Also, induction of PI3K signaling antagonizes the apoptotic and protein synthesis inhibitory effects of the conditionally active PKR. Furthermore, induction of the PI3K pathway is impaired in PKR-/- or PERK-/- mouse embryonic fibroblasts (MEFs) in response to various stimuli that activate each eIF2{alpha} kinase. Mechanistically, PI3K signaling activation is indirect and requires the inhibition of protein synthesis by eIF2{alpha} phosphorylation as demonstrated by the inactivation of endogenous eIF2{alpha} by siRNA or utilization of MEFs bearing the eIF2{alpha} Ser51Ala mutation. Our data reveal a novel property of eIF2{alpha} kinases as activators of PI3K signaling and cell survival.

{dagger}These authors contributed equally to this work.

Address correspondence to: Antonis E. Koromilas (antonis.koromilas{at}mcgill.ca)




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