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A Positive Feedback Loop between Akt and mTORC2 via SIN1 Phosphorylation

Guang Yang1, Danielle S Murashige2, Sean J Humphrey3

  • 1Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; The Charles Perkins Centre, The School of Molecular Bioscience, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.

Cell Reports
|August 4, 2015
PubMed

Insights

Akt is the primary kinase phosphorylating SIN1, a key step in activating the Akt-mTORC2 signaling pathway. This clarifies how Akt and mTORC2 (mechanistic target of rapamycin complex 2) fully activate Akt for cell survival and organization.

Area of Science:

  • Cellular Biology
  • Molecular Signaling
  • Biochemistry

Background:

  • The mechanistic target of rapamycin complex 2 (mTORC2) is crucial for cell survival and cytoskeletal organization.
  • Regulation of mTORC2 itself remains incompletely understood, with conflicting reports on SIN1 phosphorylation.
  • Akt and S6K have been implicated in phosphorylating SIN1 at T86, with differing effects on mTORC2 activity.

Purpose of the Study:

  • To elucidate the precise kinase responsible for SIN1 phosphorylation at T86.
  • To clarify the regulatory feedback loop between Akt and mTORC2.
  • To refine the understanding of the Akt-mTORC2 signaling pathway activation.

Main Methods:

  • Extensive analysis of SIN1 phosphorylation.
  • Inhibition of key kinases: Akt, S6K, and mTOR.
  • Experiments conducted across diverse cellular contexts and cell lines.

Main Results:

  • Akt was identified as the major kinase phosphorylating SIN1 at T86 across all tested conditions.
  • S6K's role in SIN1 phosphorylation was found to be minor or context-dependent.
  • Established a refined model for Akt-mTORC2 activation: PDK1 activates Akt, Akt phosphorylates SIN1, enhancing mTORC2, which then phosphorylates Akt at S473 for full activation.

Conclusions:

  • Akt is the predominant kinase regulating SIN1 phosphorylation, thereby activating mTORC2.
  • The findings clarify a positive feedback loop essential for full Akt activation.
  • This work refines the mechanistic understanding of the Akt-mTORC2 signaling pathway, impacting cell survival and cytoskeletal dynamics.

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