mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation.
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.
Mesh Terms:
Cell Cycle, Cell Line, Tumor, Cell Nucleus, Cytoplasm, Enzyme Activation, Homeostasis, Humans, Immediate-Early Proteins, Kinetics, Melanoma, Phosphorylation, Proliferating Cell Nuclear Antigen, Protein Binding, Protein Kinases, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, Recombinant Proteins, TOR Serine-Threonine Kinases, Transfection
Cell Cycle, Cell Line, Tumor, Cell Nucleus, Cytoplasm, Enzyme Activation, Homeostasis, Humans, Immediate-Early Proteins, Kinetics, Melanoma, Phosphorylation, Proliferating Cell Nuclear Antigen, Protein Binding, Protein Kinases, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, Recombinant Proteins, TOR Serine-Threonine Kinases, Transfection
Mol. Cell
Date: Jun. 20, 2008
PubMed ID: 18570873
View in: Pubmed Google Scholar
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