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Cellular Metabolism Regulates Hippo–YAP Signaling through AMPK-mediated Phosphorylation and Stabilization of Angiomotin Like-1 Protein

Liu, Jun and Peters, Eric and Yang, Jiayi and DeRan, Michael and Shen, Che-Hung and Julien, Fitamant and Asara, John and Bardeesy, Nabeel and Zheng, Bin and Wu, Xu (2014) Cellular Metabolism Regulates Hippo–YAP Signaling through AMPK-mediated Phosphorylation and Stabilization of Angiomotin Like-1 Protein. Cell reports, 9 (2). pp. 495-503. ISSN 2211-1247

Abstract

Hippo signaling is a tumor-suppressor pathway involved in organ size control and tumorigenesis through the inhibition of YAP and TAZ. Here, we show that energy stress induces YAP cytoplasmic retention and S127 phosphorylation and inhibits YAP transcriptional activity and YAP-dependent transformation. These effects require the central metabolic sensor AMP-activated protein kinase (AMPK) and the upstream Hippo pathway components Lats1/Lats2 and angiomotin-like 1 (AMOTL1). Furthermore, we show that AMPK directly phosphorylates S793 of AMOTL1. AMPK activation stabilizes and increases AMOTL1 steady-state protein levels, contributing to YAP inhibition. The phosphorylation-deficient S793Ala mutant of AMOTL1 showed a shorter half-life and conferred resistance to energy-stress-induced YAP inhibition. Our findings link energy sensing to the Hippo-YAP pathway and suggest that YAP may integrate spatial (contact inhibition), mechanical, and metabolic signals to control cellular proliferation and survival.

Item Type: Article
Date Deposited: 15 Sep 2016 00:45
Last Modified: 15 Sep 2016 00:45
URI: https://oak.novartis.com/id/eprint/9936

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