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mTOR drives its own activation via SCF(βTrCP)-dependent degradation of the mTOR inhibitor DEPTOR.

The activities of both mTORC1 and mTORC2 are negatively regulated by their endogenous inhibitor, DEPTOR. As such, the abundance of DEPTOR is a critical determinant in the activity status of the mTOR network. DEPTOR stability is governed by the 26S-proteasome through a largely unknown mechanism. Here we describe an mTOR-dependent phosphorylation-driven pathway for DEPTOR destruction via SCF(βTrCP). DEPTOR phosphorylation by mTOR in response to growth signals, and in collaboration with casein kinase I (CKI), generates a phosphodegron that binds βTrCP. Failure to degrade DEPTOR through either degron mutation or βTrCP depletion leads to reduced mTOR activity, reduced S6 kinase activity, and activation of autophagy to reduce cell growth. This work expands the current understanding of mTOR regulation by revealing a positive feedback loop involving mTOR and CKI-dependent turnover of its inhibitor, DEPTOR, suggesting that misregulation of the DEPTOR destruction pathway might contribute to aberrant activation of mTOR in disease.

Pubmed ID: 22017875

Authors

  • Gao D
  • Inuzuka H
  • Tan MK
  • Fukushima H
  • Locasale JW
  • Liu P
  • Wan L
  • Zhai B
  • Chin YR
  • Shaik S
  • Lyssiotis CA
  • Gygi SP
  • Toker A
  • Cantley LC
  • Asara JM
  • Harper JW
  • Wei W

Journal

Molecular cell

Publication Data

October 21, 2011

Associated Grants

  • Agency: NIA NIH HHS, Id: AG011085
  • Agency: NCI NIH HHS, Id: CA122099
  • Agency: NIGMS NIH HHS, Id: GM0089877
  • Agency: NIGMS NIH HHS, Id: GM054137
  • Agency: NIGMS NIH HHS, Id: GM089763
  • Agency: NIA NIH HHS, Id: R01 AG011085
  • Agency: NIA NIH HHS, Id: R01 AG011085-17
  • Agency: NIA NIH HHS, Id: R01 AG011085-18
  • Agency: NCI NIH HHS, Id: R01 CA122099
  • Agency: NCI NIH HHS, Id: R01 CA122099-04
  • Agency: NCI NIH HHS, Id: R01 CA122099-05
  • Agency: NIGMS NIH HHS, Id: R01 GM054137
  • Agency: NIGMS NIH HHS, Id: R01 GM054137-08
  • Agency: NIGMS NIH HHS, Id: R01 GM054137-09
  • Agency: NIGMS NIH HHS, Id: R01 GM056203
  • Agency: NIGMS NIH HHS, Id: R01 GM089763
  • Agency: NIGMS NIH HHS, Id: R01 GM089763-02
  • Agency: NIGMS NIH HHS, Id: R01 GM089763-03
  • Agency: NIGMS NIH HHS, Id: R01 GM089763-04
  • Agency: NIGMS NIH HHS, Id: R01 GM095567

Mesh Terms

  • Autophagy
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Phosphorylation
  • SKP Cullin F-Box Protein Ligases
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Transfection