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


Editor's Summary

Stopping Translation
Growth factors and other stimuli activate phosphoinositide 3-kinase (PI3K), which generates phosphatidylinositol 3,4,5-trisphosphate (PIP3), and leads, through the activation of kinases such as Akt and mTOR, to the stimulation of protein synthesis, cell growth, and proliferation. The dual-specificity phosphatase PTEN antagonizes PI3K signaling by dephosphorylating PIP3, thus inhibiting cellular proliferation. PTEN is often mutated or absent in cancer cells, which enables unchecked PI3K signaling to occur. Mounir et al. found that deletion of PTEN in human melanoma cells correlated with the decreased abundance of the phosphorylated {alpha} subunit of eukaryotic translation initiation factor 2 (eIF2{alpha}); phosphorylation of eIF2{alpha} prevents the translation of mRNA, which inhibits protein synthesis and proliferation. Reconstitution of PTEN-deficient cells with wild-type PTEN or with phosphatase-defective mutants of PTEN resulted in the increased phosphorylation of eIF2{alpha} by RNA-dependent protein kinase (PKR). Inhibition of the proliferation of mouse embryonic fibroblasts by PTEN required both PKR and eIF2{alpha} and the presence of a PDZ-binding motif in PTEN. Thus, PTEN inhibits cellular proliferation through two mechanisms, phosphatase-dependent termination of PI3K signaling and phosphatase-independent inhibition of translation.

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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Synthetic Lethal Targeting of PTEN-Deficient Cancer Cells Using Selective Disruption of Polynucleotide Kinase/Phosphatase.
T. R. Mereniuk, M. A. M. El Gendy, A. M. Mendes-Pereira, C. J. Lord, S. Ghosh, E. Foley, A. Ashworth, and M. Weinfeld (2013)
Mol. Cancer Ther. 12, 2135-2144
   Abstract »    Full Text »    PDF »
Haploinsufficiency of the genes encoding the tumor suppressor Pten predisposes zebrafish to hemangiosarcoma.
S. Choorapoikayil, R. V. Kuiper, A. de Bruin, and J. den Hertog (2012)
Dis. Model. Mech. 5, 241-247
   Abstract »    Full Text »    PDF »
Adaptive Basal Phosphorylation of eIF2{alpha} Is Responsible for Resistance to Cellular Stress-Induced Cell Death in Pten-Null Hepatocytes.
N. Zeng, Y. Li, L. He, X. Xu, V. Galicia, C. Deng, and B. L. Stiles (2011)
Mol. Cancer Res. 9, 1708-1717
   Abstract »    Full Text »    PDF »
Akt Determines Cell Fate Through Inhibition of the PERK-eIF2{alpha} Phosphorylation Pathway.
Z. Mounir, J. L. Krishnamoorthy, S. Wang, B. Papadopoulou, S. Campbell, W. J. Muller, M. Hatzoglou, and A. E. Koromilas (2011)
Science Signaling 4, ra62
   Abstract »    Full Text »    PDF »
The Unfolded Protein Response Is a Major Mechanism by Which LRP1 Regulates Schwann Cell Survival after Injury.
E. Mantuano, K. Henry, T. Yamauchi, N. Hiramatsu, K. Yamauchi, S. Orita, K. Takahashi, J. H. Lin, S. L. Gonias, and W. M. Campana (2011)
J. Neurosci. 31, 13376-13385
   Abstract »    Full Text »    PDF »
Distinct functional outputs of PTEN signalling are controlled by dynamic association with {beta}-arrestins.
E. Lima-Fernandes, H. Enslen, E. Camand, L. Kotelevets, C. Boularan, L. Achour, A. Benmerah, L. C. D. Gibson, G. S. Baillie, J. A. Pitcher, et al. (2011)
EMBO J. 30, 2557-2568
   Abstract »    Full Text »    PDF »
PTEN Tumor Suppressor Network in PI3K-Akt Pathway Control.
M.-M. Georgescu (2010)
Genes & Cancer 1, 1170-1177
   Abstract »    Full Text »    PDF »
From man to mouse and back again: advances in defining tumor AKTivities in vivo.
D. F. Restuccia and B. A. Hemmings (2010)
Dis. Model. Mech. 3, 705-720
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eIF2{alpha} Kinase PKR Modulates the Hypoxic Response by Stat3-Dependent Transcriptional Suppression of HIF-1{alpha}.
A. I. Papadakis, E. Paraskeva, P. Peidis, H. Muaddi, S. Li, L. Raptis, K. Pantopoulos, G. Simos, and A. E. Koromilas (2010)
Cancer Res. 70, 7820-7829
   Abstract »    Full Text »    PDF »
Phosphorylation of eIF2{alpha} at Serine 51 Is an Important Determinant of Cell Survival and Adaptation to Glucose Deficiency.
H. Muaddi, M. Majumder, P. Peidis, A. I. Papadakis, M. Holcik, D. Scheuner, R. J. Kaufman, M. Hatzoglou, and A. E. Koromilas (2010)
Mol. Biol. Cell 21, 3220-3231
   Abstract »    Full Text »    PDF »
PI(3)King Apart PTEN's Role in Cancer.
S. Zhang and D. Yu (2010)
Clin. Cancer Res. 16, 4325-4330
   Abstract »    Full Text »    PDF »

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