AMPK directly activates mTORC2 to promote cell survival during acute energetic stress
AMPK directly activates mTORC2 to promote cell survival during acute energetic stress
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DOI：
10.1126/scisignal.aav3249
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发表时间：
2019-06-11
影响因子：
7.3
通讯作者：
Fingar, Diane C.
中科院分区：
文献类型：
--
作者：
Kazyken, Dubek;Magnuson, Brian;Fingar, Diane C.
AMP激活的蛋白激酶（AMPK）感受能量应激，反过来，促进分解代谢和抑制合成代谢协调恢复能量平衡。我们发现多种AMPK激活剂以AMPK依赖性方式增加培养细胞中mTOR复合物2（mTORC 2）信号传导。2型糖尿病药物二甲双胍（GlucoPhage）激活AMPK也以AMPK依赖性方式增加了体内肝脏和原代肝细胞中的mTORC 2信号传导。AMPK介导的mTORC 2激活不是由AMPK介导的mTORC 1抑制引起的，因此减少了对PI 3 K通量的负反馈。相反，AMPK与mTORC 2（mTOR与rictor复合）相关并直接磷酸化。通过两阶段体外激酶测定，重组AMPK对mTORC 2的磷酸化足以增加mTORC 2对Akt的催化活性。因此，AMPK直接磷酸化mTORC 2组分以增加mTORC 2活性和下游信号传导。在功能上，AMPK，mTORC 2和Akt的失活增加了急性能量应激期间的细胞凋亡。通过显示AMPK激活mTORC 2以增加细胞存活，这些数据提供了AMPK如何在某些情况下矛盾地促进肿瘤发生的潜在机制，尽管其通过抑制促进生长的mTORC 1而具有肿瘤抑制功能。总的来说，这些数据揭示了mTORC 2作为AMPK的靶点和AMPK-mTORC 2轴作为能量应激期间细胞存活的促进剂。
AMP-activated protein kinase (AMPK) senses energetic stress and, in turn, promotes catabolic and suppresses anabolic metabolism coordinately to restore energy balance. We found that a diverse array of AMPK activators increased mTOR complex 2 (mTORC2) signaling in an AMPK-dependent manner in cultured cells. Activation of AMPK with the type 2 diabetes drug metformin (GlucoPhage) also increased mTORC2 signaling in liver in vivo and in primary hepatocytes in an AMPK-dependent manner. AMPK-mediated activation of mTORC2 did not result from AMPK-mediated suppression of mTORC1 and thus reduced negative feedback on PI3K flux. Rather, AMPK associated with and directly phosphorylated mTORC2 (mTOR in complex with rictor). As determined by two-stage in vitro kinase assay, phosphorylation of mTORC2 by recombinant AMPK was sufficient to increase mTORC2 catalytic activity toward Akt. Hence, AMPK phosphorylated mTORC2 components directly to increase mTORC2 activity and downstream signaling. Functionally, inactivation of AMPK, mTORC2, and Akt increased apoptosis during acute energetic stress. By showing that AMPK activates mTORC2 to increase cell survival, these data provide a potential mechanism for how AMPK paradoxically promotes tumorigenesis in certain contexts despite its tumor-suppressive function through inhibition of growth-promoting mTORC1. Collectively, these data unveil mTORC2 as a target of AMPK and the AMPK-mTORC2 axis as a promoter of cell survival during energetic stress.