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PI3K regulation of the SKP-2/p27 axis through mTORC2

K Shanmugasundaram1, K Block, B K Nayak

  • 1Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229 , USA.

Oncogene
|June 27, 2012
PubMed

Insights

Mammalian target of rapamycin complex 2 (mTORC2) signaling activates S-phase kinase-associated protein 2 (SKP-2) expression, reducing nuclear p27 levels and promoting cell proliferation in renal cell carcinoma (RCC). This highlights mTORC2

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • The cyclin-dependent kinase inhibitor p27 regulates cell-cycle progression and its altered expression is significant in malignancies like renal cell carcinoma (RCC).
  • S-phase kinase-associated protein 2 (SKP-2) targets nuclear p27 for degradation, and its overexpression is common in tumors.
  • Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling regulates the SKP-2/p27 axis, with potential involvement of mammalian target of rapamycin complex 2 (mTORC2).

Purpose of the Study:

  • To investigate the role of mTORC2 in mediating the effects of PI3K signaling on the SKP-2/p27 axis.
  • To determine if PI3K signaling activates mTORC2 kinase activity.
  • To elucidate the novel role of mTORC2 in regulating nuclear p27 levels and its impact on cancer cell proliferation.

Main Methods:

  • Genetic analysis to confirm PI3K signaling activation of mTORC2.
  • Assessment of mTORC2's effect on nuclear p27 protein levels.
  • Evaluation of SKP-2 protein expression in response to mTORC2 signaling.
  • Cell proliferation assays in RCC cells to determine the impact of mTORC2 activity on cell cycle progression.

Main Results:

  • Provided genetic evidence that PI3K signaling activates mTORC2 kinase activity.
  • Demonstrated a novel role for mTORC2 in reducing nuclear p27 levels by increasing SKP-2 protein expression.
  • Showed that mTORC2 activity promotes proliferation of RCC cells at the G1-S interphase.
  • Established a role for mTOR in the regulation of SKP-2.

Conclusions:

  • mTORC2 signaling is implicated in the regulation of the SKP-2/p27 axis, a critical pathway frequently altered in cancer.
  • mTORC2 activation leads to decreased nuclear p27, promoting cell proliferation in RCC.
  • These findings identify mTORC2 as a potential therapeutic target in cancers with dysregulated SKP-2/p27 signaling.

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