AMPK phosphorylation of raptor mediates a metabolic checkpoint
AMPK phosphorylation of raptor mediates a metabolic checkpoint
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DOI：
10.1016/j.molcel.2008.03.003
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发表时间：
2008-04-25
期刊：
影响因子：
16
通讯作者：
Shaw, Reuben J.
中科院分区：
文献类型：
--
作者：
Gwinn, Dana M.;Shackelford, David B.;Shaw, Reuben J.
AMPK是一种高度保守的细胞能量状态感受器，在细胞内低ATP的条件下被激活。AMPK通过抑制细胞生长和生物合成过程来响应能量胁迫，部分是通过抑制雷帕霉素敏感的mTOR(MTORC1)途径。TSC2肿瘤抑制因子AMPK的磷酸化有助于抑制mTORC1；然而，TSC2缺陷细胞对能量应激仍有反应。利用蛋白质组学和生物信息学方法，我们试图确定AMPK的其他底物，这些底物介导其对生长控制的影响。我们在这里报道了AMPK直接在两个保守的丝氨酸残基上磷酸化mTOR结合伙伴猛禽，这种磷酸化诱导14-3-3与猛禽结合。AMPK对猛禽的磷酸化是抑制ImTORC1和能量应激诱导的细胞周期停滞所必需的。这些发现揭示了AMPK的一个保守的效应器，它介导了AMPK作为代谢检查点的作用，协调细胞生长和能量状态。
AMPK is a highly conserved sensor of cellular energy status that is activated under conditions of low intracellular ATP. AMPK responds to energy stress by suppressing cell growth and biosynthetic processes, in part through its inhibition of the rapamycin-sensitive mTOR (mTORC1) pathway. AMPK phosphorylation of the TSC2 tumor suppressor contributes to suppression of mTORC1; however, TSC2-deficient cells remain responsive to energy stress. Using a proteomic and bioinformatics approach, we sought to identify additional substrates of AMPK that mediate its effects on growth control. We report here that AMPK directly phosphorylates the mTOR binding partner raptor on two well-conserved serine residues, and this phosphorylation induces 14-3-3 binding to raptor. The phosphorylation of raptor by AMPK is required for the inhibition of ImTORC1 and cell-cycle arrest induced by energy stress. These findings uncover a conserved effector of AMPK that mediates its role as a metabolic checkpoint coordinating cell growth with energy status.