mTORC2 Balances AKT Activation and eIF2α Serine 51 Phosphorylation to Promote Survival under Stress

The mTOR nucleates two complexes, namely mTOR complex 1 and 2 (mTORC1 and mTORC2), which are implicated in cell growth, survival, metabolism, and cancer. Phosphorylation of the alpha-subunit of translation initiation factor eIF2 at serine 51 (eIF2 alpha S51P) is a key event of mRNA translation initiation and a master regulator of cell fate during cellular stress. Recent studies have implicated mTOR signaling in the stress response, but its connection to eIF2 alpha S51P has remained unclear. Herein, we report that genetic as well as catalytic inhibition of mTORC2 induces eIF2 alpha S51P. On the other hand, the allosteric inhibitor rapamycin induces eIF2 alpha S51P through pathways that are independent of mTORC1 inactivation. Increased eIF2 alpha S51P by impaired mTORC2 depends on the inactivation of AKT, which primes the activation of the endoplasmic reticulum (ER)-resident kinase PERK/PEK. The biologic function of eIF2 alpha S51P was characterized in tuberous sclerosis complex (TSC)-mutant cells, which are defective in mTORC2 and AKT activity. TSC-mutant cells exhibit increased PERK activity, which is downregulated by the reconstitution of the cells with an activated form of AKT1. Also, TSC-mutant cells are increasingly susceptible to ER stress, which is reversed by AKT1 reconstitution. The susceptibility of TSC-mutant cells to ER stress is further enhanced by the pharmacologic inhibition of PERK or genetic inactivation of eIF2 alpha S51P. Thus, the PERK/eIF2 alpha S51P arm is an important compensatory prosurvival mechanism, which substitutes for the loss of AKT under ER stress. (C) 2015 AACR.