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Sci. Signal., 22 December 2009
Vol. 2, Issue 102, p. ra85
[DOI: 10.1126/scisignal.2000389]

RESEARCH ARTICLES

Tumor Suppression by PTEN Requires the Activation of the PKR-eIF2{alpha} Phosphorylation Pathway

Zineb Mounir1,2, Jothi Latha Krishnamoorthy1, Gavin P. Robertson3, Donalyn Scheuner4, Randal J. Kaufman4, Maria-Magdalena Georgescu5, and Antonis E. Koromilas1,6*

1 Lady Davis Institute for Medical Research, Sir Mortimer B. Davis–Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2.
2 Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada H3A 1A3.
3 Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
4 Biological Chemistry and Internal Medicine and the Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
5 Department of Molecular Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
6 Department of Oncology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada H2W 1S6.

Abstract: Inhibition of protein synthesis by phosphorylation of the {alpha} subunit of eukaryotic translation initiation factor 2 (eIF2) at Ser51 occurs as a result of the activation of a family of kinases in response to various forms of stress. Although some consequences of eIF2{alpha} phosphorylation are cytoprotective, phosphorylation of eIF2{alpha} by RNA-dependent protein kinase (PKR) is largely proapoptotic and tumor suppressing. Phosphatase and tensin homolog deleted from chromosome 10 (PTEN) is a tumor suppressor protein that is mutated or deleted in various human cancers, with functions that are mediated through phosphatase-dependent and -independent pathways. Here, we demonstrate that the eIF2{alpha} phosphorylation pathway is downstream of PTEN. Inactivation of PTEN in human melanoma cells reduced eIF2{alpha} phosphorylation, whereas reconstitution of PTEN-null human glioblastoma or prostate cancer cells with either wild-type PTEN or phosphatase-defective mutants of PTEN induced PKR activity and eIF2{alpha} phosphorylation. The antiproliferative and proapoptotic effects of PTEN were compromised in mouse embryonic fibroblasts that lacked PKR or contained a phosphorylation-defective variant of eIF2{alpha}. Induction of the pathway leading to phosphorylation of eIF2{alpha} required an intact PDZ-binding motif in PTEN. These findings establish a link between tumor suppression by PTEN and inhibition of protein synthesis that is independent of PTEN’s effects on phosphoinositide 3'-kinase signaling.

* To whom correspondence should be addressed. E-mail: antonis.koromilas{at}mcgill.ca

Citation: Z. Mounir, J. L. Krishnamoorthy, G. P. Robertson, D. Scheuner, R. J. Kaufman, M.-M. Georgescu, A. E. Koromilas, Tumor Suppression by PTEN Requires the Activation of the PKR-eIF2{alpha} Phosphorylation Pathway. Sci. Signal. 2, ra85 (2009).

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