Tyrosine phosphorylation of DEPTOR functions as a molecular switch to activate mTOR signaling
| Autor: | Nicolas Bisson, Frédérick A. Mallette, Laurence M. Gagné, Marc-Étienne Huot, Jean-Philippe Lambert, Nadine Morin, Noémie Lavoie |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
PTM
post-translational modification mTORC1 Biochemistry mTORC2 chemistry.chemical_compound 0302 clinical medicine EPHB2 Phosphorylation CIP calf intestinal alkaline phosphatase 0303 health sciences biology mTOR mechanistic target of rapamycin TOR Serine-Threonine Kinases mTORC2 mTOR complex 2 Intracellular Signaling Peptides and Proteins IP immunoprecipitation 3. Good health Cell biology 030220 oncology & carcinogenesis mTOR Research Article Signal Transduction Fer Feline sarcoma–related protein DEPTOR FRQS Fonds de Recherche du Québec—Santé R-2HG R-2-hydroxyglutarate SYK spleen tyrosine kinase 03 medical and health sciences Humans Molecular Biology Protein kinase B Mechanistic target of rapamycin PI3K/AKT/mTOR pathway 030304 developmental biology tyrosine phosphorylation EPH erythropoietin-producing hepatocellular carcinoma Tyrosine phosphorylation Cell Biology Tyr tyrosine PTEN phosphatase and tensin homolog HEK293 Cells chemistry biology.protein β-TRCP1 β-transducin repeat–containing protein 1 Tyrosine mTORC1 mTOR complex 1 Protein Processing Post-Translational HA hemagglutinin HeLa Cells |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | Metabolic dysfunction is a major driver of tumorigenesis. The serine/threonine kinase mechanistic target of rapamycin (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 phosphatase and tensin homolog/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 complexes 1 and 2, we investigated the different post-translational modification that could affect its inhibitory function. We found that tyrosine (Tyr) 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 Tyr 289 phosphorylation in an ephrin (erythropoietin-producing hepatocellular carcinoma) receptor–dependent manner. Altogether, our work reveals that phosphorylation of Tyr 289 of DEPTOR represents a novel molecular switch involved in the regulation of both mTOR complex 1 and mTOR complex 2. |
| Databáze: | OpenAIRE |
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