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Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress

Pengda Liu1, Wenjian Gan, Hiroyuki Inuzuka

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

Nature Cell Biology
|October 29, 2013
PubMed

Insights

Phosphorylation of Sin1 regulates mTORC2 activity, inhibiting Akt phosphorylation. A Sin1 mutation bypasses this regulation, causing mTORC2 hyper-activation and potentially promoting tumorigenesis.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • The mechanistic target of rapamycin (mTOR) pathway is crucial for cell growth and metabolism.
  • mTOR forms distinct complexes, mTORC1 and mTORC2, with varying functions.
  • Regulation of mTORC2 activity remains incompletely understood.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of mTORC2.
  • To investigate the role of Sin1 phosphorylation in mTORC2 activity.
  • To explore the implications of Sin1 mutations in cancer.

Main Methods:

  • Site-directed mutagenesis to study Sin1 phosphorylation at Thr86 and Thr398.
  • Biochemical assays to assess mTORC2 kinase activity and complex dissociation.
  • Analysis of Akt phosphorylation in response to growth factors and Sin1 mutations.

Main Results:

  • Phosphorylation of Sin1 at Thr86 and Thr398 suppresses mTORC2 activity by causing Sin1 dissociation.
  • Sin1 phosphorylation, induced by S6K or Akt, negatively regulates mTORC2-mediated Akt phosphorylation.
  • A cancer-derived Sin1 mutation (R81T) impairs Sin1 phosphorylation, leading to mTORC2 hyper-activation.

Conclusions:

  • Sin1 phosphorylation represents a novel negative regulatory mechanism for mTORC2.
  • Dysregulation of the mTORC1-S6K-Sin1 axis can lead to aberrant mTORC2-Akt pathway activation.
  • This pathway disruption offers a potential mechanism for tumorigenesis.

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