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Cell Rep. 2014 Oct 23;9(2):495-503. doi: 10.1016/j.celrep.2014.09.036. Epub 2014 Oct 16.

Energy stress regulates hippo-YAP signaling involving AMPK-mediated regulation of angiomotin-like 1 protein.

Author information

1
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
2
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
3
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
4
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
5
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: xwu@cbrc2.mgh.harvard.edu.

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.

PMID:
25373897
PMCID:
PMC4223634
DOI:
10.1016/j.celrep.2014.09.036
[Indexed for MEDLINE]
Free PMC Article

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