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Rictor forms a complex with Cullin-1 to promote SGK1 ubiquitination and destruction

Daming Gao1, Lixin Wan, Hiroyuki Inuzuka

  • 1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.

Molecular Cell
|September 14, 2010
PubMed

Insights

Rictor forms an E3 ubiquitin ligase with Cullin-1, targeting SGK1 for degradation. AGC kinase phosphorylation of Rictor disrupts this, increasing SGK1 levels, a mechanism implicated in cancer.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The Rictor/mTOR complex (mTORC2) is vital for cellular homeostasis, regulating AGC kinases like Akt and SGK.
  • The precise regulation and additional functions of mTORC2 are not fully understood.

Purpose of the Study:

  • To investigate the novel function of Rictor beyond its known role in mTORC2.
  • To elucidate the regulatory mechanisms controlling SGK1 levels and their implications in cancer.

Main Methods:

  • Co-immunoprecipitation assays to detect protein interactions.
  • Ubiquitination assays to assess SGK1 modification.
  • Analysis of Rictor null cells to observe SGK1 protein levels.
  • Site-directed mutagenesis to study Rictor phosphorylation at T1135.

Main Results:

  • Rictor, in conjunction with Cullin-1, forms a functional E3 ubiquitin ligase.
  • Rictor is essential for SGK1 ubiquitination, and its absence leads to elevated SGK1 protein.
  • Phosphorylation of Rictor at T1135 by AGC kinases inhibits Rictor/Cullin-1 ligase activity, reducing SGK1 ubiquitination.
  • This feedback loop regulates SGK1 levels.

Conclusions:

  • Rictor possesses E3 ubiquitin ligase activity through its association with Cullin-1.
  • This Rictor/Cullin-1 E3 ligase activity is subject to negative feedback regulation by AGC kinase phosphorylation of Rictor.
  • Dysregulation of this ubiquitination pathway may contribute to SGK1 overexpression in human cancers.

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