mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation
mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation
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DOI：
10.1016/j.molcel.2008.04.027
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发表时间：
2008-06-20
期刊：
影响因子：
16
通讯作者：
Slingerland, Joyce M.
中科院分区：
文献类型：
--
作者：
Hong, Feng;Larrea, Michelle D.;Slingerland, Joyce M.
mTORC 1的细胞周期效应尚未完全了解。我们提供了mTOR-猛禽磷酸化SGK 1调节p27功能的证据。细胞mTOR激活，通过重新喂养氨基酸剥夺的细胞或TSC 2 shRNA，激活SGK 1和p27磷酸化在T157，都被短期雷帕霉素处理和SGK 1 shRNA抑制。mTOR过表达激活Akt和SGK 1，通过受损的核输入和p27的细胞质积累引起TGF-β抵抗。雷帕霉素或raptor shRNA损害mTOR驱动的p70和SGK 1激活，但不影响Akt，并降低细胞质p27。在细胞中检测到mTOR/raptor/SGK 1复合物。mTOR在体外磷酸化SGK 1，但不磷酸化SGK 1-S422 A。SGK 1在体外磷酸化p27。这些数据表明SGK 1是mTORC 1（mTOR-raptor）的底物。mTOR可能部分通过SGK 1激活促进G1期进展，并通过Akt和SGK介导的p27 T157磷酸化和细胞质p27错误定位解除癌症中细胞周期的调控。
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.