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Nat Cell Biol. 2015 Apr;17(4):500-10. doi: 10.1038/ncb3111. Epub 2015 Mar 9.

Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway.

Author information

1
Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
2
Department of Cardiology, Veterans Medical Research Foundation, 3350 La Jolla Village Dr., San Diego, California 92161, USA.
3
National Creative Research Initiatives Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.

Abstract

YAP (Yes-associated protein) is a transcription co-activator in the Hippo tumour suppressor pathway and controls cell growth, tissue homeostasis and organ size. YAP is inhibited by the kinase Lats, which phosphorylates YAP to induce its cytoplasmic localization and proteasomal degradation. YAP induces gene expression by binding to the TEAD family transcription factors. Dysregulation of the Hippo-YAP pathway is frequently observed in human cancers. Here we show that cellular energy stress induces YAP phosphorylation, in part due to AMPK-dependent Lats activation, thereby inhibiting YAP activity. Moreover, AMPK directly phosphorylates YAP Ser 94, a residue essential for the interaction with TEAD, thus disrupting the YAP-TEAD interaction. AMPK-induced YAP inhibition can suppress oncogenic transformation of Lats-null cells with high YAP activity. Our study establishes a molecular mechanism and functional significance of AMPK in linking cellular energy status to the Hippo-YAP pathway.

PMID:
25751140
PMCID:
PMC4380774
DOI:
10.1038/ncb3111
[Indexed for MEDLINE]
Free PMC Article

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