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mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation

Feng Hong1, Michelle D Larrea, Cheryl Doughty

  • 1Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA.

Molecular Cell
|June 24, 2008
PubMed

Insights

The mechanistic target of rapamycin complex 1 (mTORC1) phosphorylates serum- and glucocorticoid-induced kinase 1 (SGK1) to control cell cycle progression. This pathway is implicated in cancer by regulating p27 protein localization.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The precise role of mTORC1 in cell cycle regulation remains incompletely understood.
  • mTORC1 is a key regulator of cell growth, proliferation, and metabolism.
  • Dysregulation of cell cycle control is a hallmark of cancer.

Purpose of the Study:

  • To elucidate the role of mTORC1 in regulating cell cycle progression.
  • To identify downstream targets of mTORC1 involved in cell cycle control.
  • To investigate the mechanism by which mTORC1 influences p27 function.

Main Methods:

  • Utilized cell culture models with controlled mTORC1 activation and inhibition.
  • Employed shRNA to deplete specific proteins like TSC2, raptor, and SGK1.
  • Performed Western blotting to assess protein phosphorylation and localization.
  • Conducted in vitro kinase assays to confirm direct phosphorylation events.

Main Results:

  • mTORC1 activation led to the phosphorylation and activation of SGK1 and p27 at T157.
  • Inhibition of mTORC1 or SGK1 reversed these phosphorylation events.
  • mTORC1 overexpression caused p27 mislocalization to the cytoplasm, conferring TGF-beta resistance.
  • Direct phosphorylation of SGK1 by mTOR and p27 by SGK1 was demonstrated in vitro.
  • mTORC1, raptor, and SGK1 form functional complexes within cells.

Conclusions:

  • SGK1 is a direct substrate of mTORC1, mediating its effects on p27.
  • mTORC1 promotes G1 phase progression partly via SGK1 activation.
  • Aberrant mTORC1 signaling contributes to cancer by deregulating the cell cycle through SGK1-mediated p27 phosphorylation and mislocalization.

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