mTOR-Raptor Binds and Activates SGK1 to Regulate p27 Phosphorylation

Abstract

The cell-cycle effects of mTORC1 are not fully understood. We provide evidence that mTOR-raptor phosphorylates SGK1 to modulate p27 function. Cellular mTOR activation, by refeeding of amino acid-deprived cells or by TSC2 shRNA, activated SGK1 and p27 phosphorylation at T157, and both were inhibited by short-term rapamycin treatment and by SGK1 shRNA. mTOR overexpression activated both Akt and SGK1, causing TGF-beta resistance through impaired nuclear import and cytoplasmic accumulation of p27. Rapamycin or raptor shRNA impaired mTOR-driven p70 and SGK1 activation, but not that of Akt, and decreased cytoplasmic p27. mTOR/raptor/SGK1 complexes were detected in cells. mTOR phosphorylated SGK1, but not SGK1-S422A, in vitro. SGK1 phosphorylated p27 in vitro. These data implicate SGK1 as an mTORC1 (mTOR-raptor) substrate. mTOR may promote G1 progression in part through SGK1 activation and deregulate the cell cycle in cancers through both Akt- and SGK-mediated p27 T157 phosphorylation and cytoplasmic p27 mislocalization.

Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis

“…A previous report indicates that mTORC1 regulates p27 by activating serum-and glucocorticoidinducible kinase 1 (SGK1) (Hong et al, 2008), although a recent study showed that mTORC2, rather than mTORC1, is responsible for SGK1 activation (GarciaMartinez and Alessi, 2008). Our work cannot conciliate the differences between these two reports, but indicates that mTORC1 is not involved in regulating p27 in Tsc2-null cells.…”

mTORC2 promotes type I insulin-like growth factor receptor and insulin receptor activation through the tyrosine kinase activity of mTOR

“…These observations include: (a) mTOR is an atypical serine/ threonine kinase; (b) there are two mTOR complexes, mTORC1 and mTORC2; (c) mTORC1 and mTORC2 have different targets and varied sensitivity to rapamycin; (d) mTOR functions downstream of growth factor receptors; (e) inhibition of mTORC1 may paradoxically leads to Akt and ERK phosphorylation; and (f) mTORC2 is the hydrophobic motif kinase for Akt and SGK1 [6,32].…”

mTOR Signaling in Lymphangioleiomyomatosis

“…[105][106][107] In a cell line overexpressing mTOR, however, SGK was phosphorylated by mTORC1, and subsequently blocked cell cycle arrest. 108 In contrast to the mTORC2 substrate PKCa, PKCd is phosphorylated by mTORC1, phosphorylates 4E-BP1, and controls the initiation of translation. 104 Interestingly, PKCd is a kinase for the transcription factor STAT1 kinase, and was detected in a rapamycin-sensitive macromolecular complex with mTOR and STAT1.…”