Tumor Suppression by PTENR equires the activation of the PKR-eIF2α phosphorylation pathway

Zineb Mounir, Jothi Latha Krishnamoorthy, Gavin P. Robertson, Donalyn Scheuner, Randal J. Kaufman, Maria Magdalena Georgescu, Antonis E. Koromilas

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

Inhibition of protein synthesis by phosphorylation of the a 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 eIF2a phosphorylation are cytoprotective, phosphorylation of eIF2α 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 phosphatasedependent and -independent pathways. Here, we demonstrate that the eIF2a phosphorylation pathway is downstream of PTEN. Inactivation of PTEN in human melanoma cells reduced eIF2α 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 eIF2α phosphorylation. The antiproliferative and proapoptotic effects of PTENwere compromised inmouse embryonic fibroblasts that lacked PKR or contained a phosphorylation-defective variant of eIF2α. Induction of the pathway leading to phosphorylation of eIF2a required an intact PDZ-binding motif in PTEN. These findings establish a link between tumor suppression by PTENand inhibition of protein synthesis that is independent of PTEN's effects on phosphoinositide 3'-kinase signaling.

Original languageEnglish (US)
Pages (from-to)ra85
JournalScience signaling
Volume2
Issue number102
DOIs
StatePublished - Dec 22 2009

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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