AMPK directly activates mTORC2 to promote cell survival during acute energetic stress

Dubek Kazyken, Brian Magnuson, Cagri Bodur, Hugo A. Acosta-Jaquez, Deqiang Zhang, Xin Tong, Tammy M. Barnes, Gabrielle K. Steinl, Nicole E. Patterson, Christopher H. Altheim, Naveen Sharma, Ken Inoki, Gregory D. Cartee, Dave Bridges, Lei Yin, Steven M. Riddle, Diane C. Fingar

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

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.

Original languageEnglish
Article numbereaav3249
JournalScience Signaling
Volume12
Issue number585
DOIs
StatePublished - Jun 11 2019
Externally publishedYes

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