Hong Feng, Larrea Michelle D, Doughty Cheryl, Kwiatkowski David J, Squillace Rachel, Slingerland Joyce M
Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA.
Mol Cell. 2008 Jun 20;30(6):701-11. doi: 10.1016/j.molcel.2008.04.027.
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.
mTORC1对细胞周期的影响尚未完全明确。我们提供的证据表明，mTOR-猛禽蛋白磷酸化血清和糖皮质激素诱导激酶1（SGK1）以调节p27的功能。通过对氨基酸剥夺的细胞重新供给营养或通过TSC2短发夹RNA（shRNA）激活细胞内的mTOR，可激活SGK1以及p27在T157位点的磷酸化，而短期雷帕霉素处理和SGK1 shRNA均可抑制二者。mTOR过表达可同时激活Akt和SGK1，通过损害p27的核输入及导致其在细胞质中蓄积而引起转化生长因子-β（TGF-β）抵抗。雷帕霉素或猛禽蛋白shRNA可损害mTOR驱动的p70和SGK1激活，但不影响Akt的激活，并减少细胞质中的p27。在细胞中检测到了mTOR/猛禽蛋白/SGK1复合物。在体外，mTOR可磷酸化SGK1，但不能磷酸化SGK1-S422A。在体外，SGK1可磷酸化p27。这些数据表明SGK1是mTORC1（mTOR-猛禽蛋白）的一个底物。mTOR可能部分通过激活SGK1促进G1期进程，并在癌症中通过Akt和SGK介导的p27 T157磷酸化及p27在细胞质中的错误定位来失调细胞周期。
