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The mTOR (mammalian target of rapamycin) kinase maintains integrity of mTOR complex 2

Chien-Hung Chen1, Dos D Sarbassov

  • 1Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

The Journal of Biological Chemistry
|October 4, 2011
PubMed

Insights

The mammalian target of rapamycin complex 2 (mTORC2) kinase activity requires its functional mTOR kinase domain. This domain also stabilizes SIN1, maintaining mTORC2 integrity and Akt signaling crucial for cell growth.

Area of Science:

  • Cellular signaling pathways
  • Molecular and cell biology
  • Biochemistry

Background:

  • Growth factors activate the phosphoinositide 3-kinase (PI3K)/Akt pathway, regulating cell growth, proliferation, and survival.
  • Dysregulation of PI3K/Akt signaling is implicated in diseases like cancer and metabolic disorders.
  • The mTORC2 complex is a key regulator of Akt activity, but its own regulation is poorly understood.

Purpose of the Study:

  • To investigate the role of the mTOR kinase domain in mTORC2 assembly and activity.
  • To elucidate the mechanisms regulating mTORC2 complex integrity and function.

Main Methods:

  • Reconstitution of mTORC2 complex in vitro through assembly of its four core components: rictor, SIN1, mTOR, and mLST8.
  • Co-expression of the four essential mTORC2 components to study complex formation and function.

Main Results:

  • The functional kinase domain of mTOR is essential for mTORC2's ability to phosphorylate and activate Akt at Ser-473.
  • mTOR directly phosphorylates SIN1, preventing its degradation in lysosomes.
  • The kinase activity of mTOR is critical for maintaining the stability of the SIN1 subunit, thereby preserving mTORC2 integrity.

Conclusions:

  • The kinase domain of mTOR is indispensable for the catalytic activity of mTORC2.
  • mTORC2 integrity is maintained through mTOR-mediated phosphorylation and stabilization of SIN1.
  • These findings provide critical insights into the regulation of mTORC2, a key pathway in cellular growth and disease.

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