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

Daming Gao1, Hiroyuki Inuzuka, Meng-Kwang Marcus Tan

  • 1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Molecular Cell
|October 25, 2011
PubMed

Insights

The mechanistic target of rapamycin (mTOR) network

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Biochemistry

Background:

  • The mechanistic target of rapamycin (mTOR) pathway regulates cell growth and metabolism.
  • DEPTOR is a critical inhibitor of both mTORC1 and mTORC2 complexes.
  • The precise mechanism controlling DEPTOR stability and degradation was largely unknown.

Purpose of the Study:

  • To elucidate the mechanism of DEPTOR degradation.
  • To identify the signaling pathway regulating DEPTOR stability.
  • To understand the role of DEPTOR turnover in mTOR network regulation.

Main Methods:

  • Investigated DEPTOR phosphorylation and degradation using biochemical assays.
  • Utilized genetic approaches including degron mutations and protein depletion (e.g., βTrCP depletion).
  • Assessed mTOR activity, S6 kinase activity, and autophagy levels in response to pathway modulation.

Main Results:

  • Discovered an mTOR-dependent, CKI-assisted phosphorylation pathway for DEPTOR destruction.
  • Identified a phosphodegron on DEPTOR that mediates binding to SCF(βTrCP) for proteasomal degradation.
  • Demonstrated that impaired DEPTOR degradation leads to reduced mTOR activity and increased autophagy.

Conclusions:

  • DEPTOR degradation is tightly regulated by a positive feedback loop involving mTOR and CKI.
  • This pathway is crucial for maintaining appropriate mTOR network activity.
  • Dysregulation of DEPTOR turnover may contribute to diseases characterized by aberrant mTOR activation.

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