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

Nature Cell Biology
Jung-Soon MoKun-Liang Guan

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.

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Methods Mentioned

BETA
ubiquitination
co-immunoprecipitation
transfection
xenograft
PCR
genotyping
immunoprecipitation
confocal microscopy

Software Mentioned

FLUOVIEW viewer
PhosphoRS
Proteome Discover

Related Concepts