DEPTOR, an mTOR inhibitor, is a physiological substrate of SCF(βTrCP) E3 ubiquitin ligase and regulates survival and autophagy

Mol Cell. 2011 Oct 21;44(2):304-16. doi: 10.1016/j.molcel.2011.08.029.

Abstract

DEPTOR, an inhibitor of mTORC1 and mTORC2, is degraded via ubiquitin-proteasome pathway by an unknown E3 ubiquitin ligase. Here we report that DEPTOR is a physiological substrate of SCF(βTrCP) E3 ligase for targeted degradation. Upon growth factor stimulation, RSK1 and S6K1 kinases are activated to phosphorylate DEPTOR, which is then recognized by the F box protein, βTrCP, via its degron sequence for subsequent ubiquitination and degradation by SCF E3. Endogenous DEPTOR levels are negatively regulated by βTrCP. DEPTOR half-life is shortened by βTrCP but extended by a dominant-negative mutant of βTrCP, by RSK1/S6K1 inhibition, and by βTrCP degron site mutations. Biologically, DEPTOR accumulation upon βTrCP knockdown inactivates mTORC1 and activates AKT in cancer cells to confer resistance to rapamycin and paclitaxel. Furthermore, DEPTOR accumulates upon glucose deprivation and mTOR inhibition to induce autophagy. Thus, βTrCP-DEPTOR-mTOR intertwine to regulate cell survival and autophagy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Autophagy*
  • Cell Line, Tumor
  • Cell Survival
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mutation
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*
  • beta-Transducin Repeat-Containing Proteins / metabolism*

Substances

  • Intracellular Signaling Peptides and Proteins
  • beta-Transducin Repeat-Containing Proteins
  • Ubiquitin-Protein Ligases
  • DEPTOR protein, human
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • RPS6KA1 protein, human
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Ribosomal Protein S6 Kinases, 90-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 1