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The Akt‐mTOR axis determines cell fate through the regulation of eIF2alpha phosphorylation pathway.
Author(s) -
Koromilas Antonis E.,
Tenkerian Clara,
Mounir Zineb,
Krishnamoorthy Jothi
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.835.9
Subject(s) - pi3k/akt/mtor pathway , protein kinase b , eif2 , phosphorylation , microbiology and biotechnology , endoplasmic reticulum , biology , unfolded protein response , signal transduction , programmed cell death , cancer research , chemistry , translation (biology) , apoptosis , biochemistry , gene , messenger rna
Metazoans respond to environmental stress by inducing the phosphorylation of the α subunit of translation initiation factor eIF2 at S51 (eIF2αP), a modification that leads to protein synthesis inhibition. We demonstrate that eIF2αP is induced by pharmacological inhibition or genetic ablation of the PI3K‐Aktm‐TOR pathway (1). Increased eIF2αP is an evolutionary conserved process that involves the endoplasmic reticulum (ER)‐resident protein kinase PERK, which is negatively regulated by Akt dependent phosphorylation at T799. The PERK‐eIF2αP arm is downregulated by Akt in cells exposed to ER stress or oxidative stress leading to the induction of cell survival or death respectively. In unstressed cells, the PERK‐eIF2αP pathway guards survival and facilitates adaptation to the deleterious effects of PI3K, Akt or mTOR inactivation. Inactivation of the PERK‐eIF2αP arm sensitizes tumor death from pharmacological inhibition of the PI3K‐Akt‐mTOR pathway. The PERK‐eIF2αP pathway links Akt and mTOR signaling to translational control with implications in tumor treatment with pharmacological inhibitors of PI3K‐Akt‐mTOR pathway.