The functional interplay between eIF2alpha phosphorylation and mTOR signaling pathways: implications in Tuberous Sclerosis Complex disorder

The mammalian target of rapamycin (mTOR) nucleates two complexes, namely mTOR complex 1 (mTORC1) and mTORC2, which are implicated in cell growth, survival, metabolism and cancer. The phosphorylation of the alpha subunit of the eukaryotic initiation factor eIF2 at serine 51 (eIF2αP) is a key regulator of mRNA translation and an important mechanism of adaptation of cells to various forms of environmental stress frequently associated with cancer formation. eIF2αP can act either as a promoter of cell survival or as an inducer of cell death in response to different forms of stress. Increased eIF2αP is mediated by a family of four kinases consisting of PKR, PERK, GCN2 and HRI, each of which becomes activated by distinct stimuli. In this study, we show that disruption of mTORC2, but not of mTORC1, induces eIF2αP through the activation of PERK. mTORC2 deficiency increases PERK activity owing to the ineffecive activation of AKT, which negatively controls PERK by phosphorylation at threonine 799. Moreover, pharmacological inhibition of mTOR with either rapamycin or the new generation of catalytic inhibitors also increases PERK activity and eIF2αP. Interestingly, rapamycin treatment induces eIF2αS51P through a mechanism that is independent of mTORC1 inhibition.The physiological relevance of our findings was substantiated in cells deficient in tuberous sclerosis complex (TSC), which have impaired mTORC2/AKT function, but increased mTORC1 activity. Our research shows that TSC-deficient cells exposed to ER stress exhibit increased levels of the PERK-eIF2αP arm, which functions as a compensatory mechanism to substitute for the loss of AKT and facilitate cell survival. TSC-deficient cells subjected to oxidative stress on the other hand, downregulate PERK-eIF2αP but activate the PKR-eIF2αP arm instead in an mTORC1-S6K1-mediated mechanism to promote cell death. Furthermore, we show that TSC-null cells deficient in eIF2αP have a greater tolerance to oxidative stress, leading to an increase in their tumorigenic potential and therefore allowing an earlier tumor incidence. Our study reveals that eIF2αP acts downstream of either mTORC2-AKT or mTORC1-S6K1 to promote either the survival or death of TSC-mutant cells in response to different stress-inducing drugs.

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