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

K. Shanmugasundaram, K. Block, B. K. Nayak, C. B. Livi, M. A. Venkatachalam, S. Sudarshan

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

The cyclin-dependent kinase inhibitor p27 is a key regulator of cell-cycle progression. Its expression and localization are altered in several types of malignancies, which has prognostic significance in cancers such as renal cell carcinoma (RCC). S-phase kinase-associated protein 2 (SKP-2) is an F-box protein that is part of the SKP-1/Cul1/F-box ubiquitin ligase complex that targets nuclear p27 among many other cell-cycle proteins for proteosomal degradation. Its overexpression has been observed in several tumor types. Signaling by phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) has previously been shown to regulate the SKP-2/p27 axis. Recent evidence suggests that PI3K signaling may activate mammalian target of rapamycin complex 2 (mTORC2) activity. As PI3K signaling is known to regulate SKP-2 and p27, we sought to determine whether these effects were mediated by mTORC2. Here we provide additional genetic evidence that PI3K signaling activates mTORC2 kinase activity. We also demonstrate a novel role for mTORC2 in the modulation of nuclear p27 levels. In particular, mTORC2 signaling promotes the reduction of nuclear p27 protein levels through the increased protein expression of SKP-2. These are the first data to demonstrate a role for mTOR in the regulation of SKP-2. In concordance with these findings, mTORC2 activity promotes cell proliferation of RCC cells at the G1-S interphase of the cell cycle. Collectively, these data implicate mTORC2 signaling in the regulation of the SKP-2/p27 axis, a signaling node commonly altered in cancer.

Original languageEnglish (US)
Pages (from-to)2027-2036
Number of pages10
JournalOncogene
Volume32
Issue number16
DOIs
StatePublished - Apr 18 2013

Keywords

  • RICTOR
  • SKP-2
  • mTOR
  • p27

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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