Tyrosine Phosphorylation of DEPTOR Functions as a Molecular Switch to Activate mTOR Signaling.

ABSTRACT: Metabolic dysfunction is a major driver of tumorigenesis. The serine/threonine kinase mTOR constitutes a key central regulator of metabolic pathways promoting cancer cell proliferation and survival. mTOR activity is regulated by metabolic sensors as well as by numerous factors comprising the PTEN/PI3K/AKT canonical pathway, which are often mutated in cancer. However, some cancers displaying constitutively active mTOR do not carry alterations within this canonical pathway, suggesting alternative modes of mTOR regulation. Since DEPTOR, an endogenous inhibitor of mTOR, was previously found to modulate both mTOR complexe 1 and 2, we investigated the different post-transltionnal modification that could affect its inhibitory function. We found that tyrosine 289 phosphorylation of DEPTOR impairs its interaction with mTOR, leading to increased mTOR activation. Using proximity biotinylation assays, we identified SYK (Spleen tyrosine kinase) as a kinase involved in DEPTOR tyrosine 289 phosphorylation in an ephrin (EPH) receptor-dependent manner. Altogether, our work reveals that phosphorylation of tyrosine 289 of DEPTOR represents a novel molecular switch involved in the regulation of both mTORC1 and mTORC2.

SUBMITTER: Gagne LM 

PROVIDER: S-EPMC8551655 | biostudies-literature |

REPOSITORIES: biostudies-literature