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mTOR Complex 2 Stabilizes Mcl-1 Protein by Suppressing Its Glycogen Synthase Kinase 3-Dependent and

Junghui Koo1, Ping Yue1, Xingming Deng2

  • 1Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia, USA.

Molecular and Cellular Biology
|April 29, 2015
PubMed

Insights

Mammalian target of rapamycin complex 2 (mTORC2) stabilizes the oncogenic protein Mcl-1. Inhibiting mTORC2 enhances Mcl-1 degradation via a GSK3/SCF-FBXW7 pathway, revealing a novel regulatory mechanism.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • Mammalian target of rapamycin complex 2 (mTORC2) is crucial for cell survival and growth.
  • Mcl-1, an oncogenic protein from the Bcl-2 family, plays a significant role in cancer progression.
  • The regulatory relationship between mTORC2 and Mcl-1 stability remained undefined.

Purpose of the Study:

  • To investigate the connection between mTORC2 and Mcl-1 protein stability.
  • To elucidate the molecular mechanisms underlying Mcl-1 regulation by mTORC2.

Main Methods:

  • Utilized mTOR kinase inhibitors (TORKinibs), gene knockdown (rictor), and gene knockout (rictor, Sin1) in cancer cells.
  • Assessed Mcl-1 mRNA and protein levels, protein stability, ubiquitination, and proteasome activity.
  • Investigated the roles of glycogen synthase kinase 3 (GSK3) and the SCF-FBXW7 complex in Mcl-1 degradation.
  • Examined the direct association between mTORC2 and SCF-FBXW7.

Main Results:

  • mTORC2 inhibition, via TORKinibs or rictor knockdown/knockout, decreased Mcl-1 protein levels without affecting mRNA.
  • TORKinib treatment reduced Mcl-1 protein stability and increased its ubiquitination, effects rescued by proteasome inhibition.
  • GSK3 inhibition or FBXW7 knockdown rescued TORKinib-induced Mcl-1 reduction.
  • A direct association between mTORC2 and SCF-FBXW7 was observed, which was disrupted by TORKinib treatment.

Conclusions:

  • mTORC2 inhibition promotes Mcl-1 degradation through a GSK3-dependent and SCF-FBXW7-mediated pathway.
  • mTORC2 directly associates with and inhibits the SCF-FBXW7 complex, thereby stabilizing Mcl-1.
  • This study reveals a novel mechanism where mTORC2 regulates cell survival and growth by controlling Mcl-1 stability.

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