PI3K regulation of the SKP-2/p27 axis through mTORC2.
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.
Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229 , USA.
K
K
Shanmugasundaram
K
K
Block
B K
BK
Nayak
C B
CB
Livi
M A
MA
Venkatachalam
S
S
Sudarshan
D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014162:Transfection
D050760:Cyclin-Dependent Kinase Inhibitor p27; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D044786:S-Phase Kinase-Associated Proteins; D058570:TOR Serine-Threonine Kinases