Translation initiation factor eIF2a serine 51 phosphorylation couples with the mammalian target of rapamycin (mTOR) to determine cell fate and tumorigenesis under stress

Background: The mammalian target of rapamycin (mTOR) nucleates two complexes, namely mTOR complex 1 and 2 (mTORCI and mTORC2), which are implicated in cell growth, survival, metabolism and cancer. Phosphorylation of the α-subunit of translation initiation factor elF2 at serine 51 (herein referred to as elF2αP) is a key event of mRNA translation initiation and a master regulator of cell fate during stress. Materials and Methods: We employed mouse and human tumor cells with mutations in tuberous sclerosis complex (TSC), which contain decreased mTORC2 and hyper-activated mTORCI. Results: We demonstrate that disruption of mTORC2 activity induces elF2aP, which acts in place of AKT/protein kinase B to promote TSC tumor cell survival in response to endoplasmic reticulum (ER) stress. Increased levels of mTORCI activity renders TSC tumor cells increasingly susceptible to death in response to oxidative stress. mTORCI hyper-activation under oxidative stress decreases the activity of the ER-resident kinase PERK and upregulates the activity of the dsRNA-dependent protein kinase PKR leading to c-Jun N-terminal kinase (JNK) activation and induction of cell death. Hyper-activated mTORCI inhibits TSC tumor initiation in mice owing to select activation of the PKR-elF2αP arm under pro-oxidant conditions. Conclusions: Our findings demonstrate that elF2αP is a key mediator of mTORCI function under stress and an important determinant for the formation and chemotherapeutic treatment of tumors with hyper-activated mTORC1.