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Tumor suppression by PTEN requires the activation of the PKR-eIF2alpha phosphorylation pathway

Zineb Mounir1, Jothi Latha Krishnamoorthy, Gavin P Robertson

  • 1Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.

Science Signaling
|December 24, 2009
PubMed

Insights

Tumor suppressor PTEN regulates protein synthesis inhibition via eukaryotic translation initiation factor 2 alpha (eIF2α) phosphorylation. This pathway, involving RNA-dependent protein kinase (PKR), is crucial for PTEN

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Signaling

Background:

  • Protein synthesis is regulated by eIF2α phosphorylation, a stress response.
  • RNA-dependent protein kinase (PKR) mediates proapoptotic eIF2α phosphorylation.
  • PTEN is a tumor suppressor with diverse functions, often lost in cancer.

Purpose of the Study:

  • To investigate the role of PTEN in regulating eIF2α phosphorylation.
  • To determine if PTEN's tumor suppressive functions are linked to protein synthesis inhibition.
  • To elucidate the specific pathways downstream of PTEN involved in eIF2α phosphorylation.

Main Methods:

  • Utilized human melanoma, glioblastoma, and prostate cancer cell lines.
  • Assessed eIF2α phosphorylation levels following PTEN manipulation (inactivation/reconstitution).
  • Employed PKR-deficient and eIF2α phosphorylation-defective mouse embryonic fibroblasts.

Main Results:

  • PTEN inactivation reduced eIF2α phosphorylation; PTEN reconstitution induced it.
  • PTEN's antiproliferative and proapoptotic effects were dependent on PKR and eIF2α phosphorylation.
  • PTEN's PDZ-binding motif was essential for inducing the eIF2α phosphorylation pathway.

Conclusions:

  • PTEN directly regulates the eIF2α phosphorylation pathway, impacting protein synthesis.
  • This PTEN-mediated inhibition of protein synthesis is independent of PI3K signaling.
  • The findings link PTEN's tumor suppressor activity to the control of protein synthesis.

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