Akt Determines Cell Fate Through Inhibition of the PERK-eIF2α Phosphorylation Pathway

Metazoans respond to various forms of environmental stress by inducing the phosphorylation of the a subunit of eukaryotic translation initiation factor 2 (eIF2 alpha) at serine-51, a modification that leads to global inhibition of mRNA translation. We demonstrate induction of the phosphorylation of eIF2 alpha in mammalian cells after either pharmacological inhibition of the phosphoinositide 3-kinase (PI3K)-Akt pathway or genetic or small interfering RNA-mediated ablation of Akt. This increase in the extent of eIF2 alpha phosphorylation also occurred in Drosophila cells and depended on the endoplasmic reticulum (ER)-resident protein kinase PERK, which was inhibited by Akt-dependent phosphorylation at threonine-799. The activity of PERK and the abundance of phosphorylated eIF2 alpha (eIF2 alpha P) were reduced in mouse mammary gland tumors that contained activated Akt, as well as in cells exposed to ER stress or oxidative stress. In unstressed cells, the PERK-eIF2 alpha P pathway mediated survival and facilitated adaptation to the deleterious effects of the inactivation of PI3K or Akt. Inactivation of the PERK-eIF2 alpha P pathway increased the susceptibility of tumor cells to death by pharmacological inhibitors of PI3K or Akt. Thus, we suggest that the PERK-eIF2 alpha P pathway provides a link between Akt signaling and translational control, which has implications for tumor formation and treatment.