Abstract SY08-01: AMPK and mTOR in nutrient signaling, metabolism, and autophagy regulation.

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Abstract Autophagy is a stress response protecting cells from unfavorable conditions, such as nutrient starvation. The cellular energy sensor AMPK and key growth controller mTOR, both are regulated by nutrient status, play major roles in autophagy regulation. The class III phosphatidylinositol-3 kinase, Vps34, forms multiple complexes and regulates both intracellular vesicle trafficking and autophagy induction. We show that AMPK plays a key role in regulating different Vps34 complexes. AMPK inhibits the non-autophagy Vps34 complex by phosphorylating Vps34 and suppresses overall PI(3)P production and protects cells from starvation. In parallel, AMPK activates the pro-autophagy Vps34 complex by phosphorylating Beclin1 to induce autophagy. Atg14L, an autophagy essential gene present only in the pro-autophagy Vps34 complex, inhibits Vps34 phosphorylation but increases Beclin1 phosphorylation by AMPK. As such, Atg14L dictates the differential regulation (either inhibition or activation) of different Vps34 complexes in response to glucose starvation. In addition, the Vps34 complex is regulated by mTOR, which is inhibited by nutrient starvation. mTOR phosphorylates Beclin to inhibit the autophagy specific Vps34 complex. Our study reveals an intricate molecular regulation of Vps34 complexes by AMPK and mTOR in nutrient stress response and autophagy. Citation Format: Joungmok Kim, Ryan Russell, Haxin Yuan, Kun-Liang Guan. AMPK and mTOR in nutrient signaling, metabolism, and autophagy regulation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY08-01. doi:10.1158/1538-7445.AM2013-SY08-01