Tumor suppression by PTEN requires the activation of the PKR-eIF2alpha phosphorylation pathway.
Inhibition of protein synthesis by phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2) at Ser(51) occurs as a result of the activation of a family of kinases in response to various forms of stress. Although some consequences of eIF2alpha phosphorylation are cytoprotective, phosphorylation of eIF2alpha 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 eIF2alpha phosphorylation pathway is downstream of PTEN. Inactivation of PTEN in human melanoma cells reduced eIF2alpha 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 eIF2alpha phosphorylation. The antiproliferative and proapoptotic effects of PTEN were compromised in mouse embryonic fibroblasts that lacked PKR or contained a phosphorylation-defective variant of eIF2alpha. Induction of the pathway leading to phosphorylation of eIF2alpha 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.
Mounir
Zineb
Z
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
Krishnamoorthy
Jothi Latha
JL
Robertson
Gavin P
GP
Scheuner
Donalyn
D
Kaufman
Randal J
RJ
Georgescu
Maria-Magdalena
MM
Koromilas
Antonis E
AE
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003114:Colony-Forming Units Assay; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018613:Microscopy, Confocal; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011500:Protein Synthesis Inhibitors / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism*
D015852:Eukaryotic Initiation Factor-2; D011500:Protein Synthesis Inhibitors; D025521:Tumor Suppressor Proteins; D019892:eIF-2 Kinase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human