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

Jung Soon Mo, Zhipeng Meng, Young Chul Kim, Hyun Woo Park, Carsten Gram Hansen, Soohyun Kim, Dae Sik Lim, Kun Liang Guan

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207 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)500-510
Number of pages11
JournalNature Cell Biology
Volume17
Issue number4
DOIs
Publication statusPublished - 2015 Apr 30

All Science Journal Classification (ASJC) codes

  • Cell Biology

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    Mo, J. S., Meng, Z., Kim, Y. C., Park, H. W., Hansen, C. G., Kim, S., Lim, D. S., & Guan, K. L. (2015). Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway. Nature Cell Biology, 17(4), 500-510. https://doi.org/10.1038/ncb3111