2. Academic Validation
  3. Tyrosine phosphorylation of DEPTOR functions as a molecular switch to activate mTOR signaling

Tyrosine phosphorylation of DEPTOR functions as a molecular switch to activate mTOR signaling

  • J Biol Chem. 2021 Nov;297(5):101291. doi: 10.1016/j.jbc.2021.101291.
Laurence M Gagné 1,  Nadine Morin 1,  Noémie Lavoie 2,  Nicolas Bisson 3,  Jean-Philippe Lambert 4,  Frédérick A Mallette 5,  Marc-Étienne Huot 6
Affiliations

Affiliations

  • 1 Centre de Recherche sur le Cancer de l'Université Laval, Québec, Quebec, Canada; Centre de Recherche du CHU de Québec-Université Laval, Québec, Quebec, Canada.
  • 2 Centre de Recherche sur le Cancer de l'Université Laval, Québec, Quebec, Canada; Centre de Recherche du CHU de Québec-Université Laval, Québec, Quebec, Canada; PROTEO - Regroupement québécois de recherche sur la fonction, l'ingénierie et les applications des protéines, Québec, Quebec, Canada.
  • 3 Centre de Recherche sur le Cancer de l'Université Laval, Québec, Quebec, Canada; Centre de Recherche du CHU de Québec-Université Laval, Québec, Quebec, Canada; PROTEO - Regroupement québécois de recherche sur la fonction, l'ingénierie et les applications des protéines, Québec, Quebec, Canada; Département de Biologie moléculaire, biochimie médicale et pathologie, Université Laval, Québec, Quebec, Canada.
  • 4 Centre de Recherche sur le Cancer de l'Université Laval, Québec, Quebec, Canada; Centre de Recherche du CHU de Québec-Université Laval, Québec, Quebec, Canada; Département de Médecine Moléculaire, Université Laval, Québec, Quebec, Canada.
  • 5 Département de Biochimie et Médecine moléculaire, Université de Montréal, Montréal, Quebec, Canada; Chromatin Structure and Cellular Senescence Research Unit, Maisonneuve-Rosemont Hospital Research Centre, Montréal, Quebec, Canada; Département de Médecine, Université de Montréal, Montréal, Quebec, Canada.
  • 6 Centre de Recherche sur le Cancer de l'Université Laval, Québec, Quebec, Canada; Centre de Recherche du CHU de Québec-Université Laval, Québec, Quebec, Canada; Département de Biologie moléculaire, biochimie médicale et pathologie, Université Laval, Québec, Quebec, Canada. Electronic address: Marc-Etienne.Huot@crchudequebec.ulaval.ca.
PMID: 34634301 DOI: 10.1016/j.jbc.2021.101291
Abstract

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.

Keywords

DEPTOR; EPHB2; mTOR; tyrosine phosphorylation.

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