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

RESEARCH ARTICLES

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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