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

doi:10.1038/ncb3111

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

Research output: Contribution to journal › Article › peer-review

358 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 language	English
Pages (from-to)	500-510
Number of pages	11
Journal	Nature Cell Biology
Volume	17
Issue number	4
DOIs	https://doi.org/10.1038/ncb3111
Publication status	Published - 2015 Apr 30

Bibliographical note

Funding Information:
We would like to thank A. Hong and F. Flores for critical reading of the manuscript. This work was supported by grants from National Institutes of Health (CA132809, EY022611, DEO15964 and CA23100, K-L.G.). C.G.H. is supported by a Postdoctoral Fellowship from the Danish Council for Independent Research, Natural Sciences.

Publisher Copyright:
© 2015 Macmillan Publishers Limited.

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Cell Biology

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title = "Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway",

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.",

author = "Mo, {Jung Soon} and Zhipeng Meng and Kim, {Young Chul} and Park, {Hyun Woo} and Hansen, {Carsten Gram} and Soohyun Kim and Lim, {Dae Sik} and Guan, {Kun Liang}",

note = "Funding Information: We would like to thank A. Hong and F. Flores for critical reading of the manuscript. This work was supported by grants from National Institutes of Health (CA132809, EY022611, DEO15964 and CA23100, K-L.G.). C.G.H. is supported by a Postdoctoral Fellowship from the Danish Council for Independent Research, Natural Sciences. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited.",

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doi = "10.1038/ncb3111",

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AU - Mo, Jung Soon

AU - Meng, Zhipeng

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AU - Hansen, Carsten Gram

AU - Kim, Soohyun

AU - Lim, Dae Sik

AU - Guan, Kun Liang

N1 - Funding Information: We would like to thank A. Hong and F. Flores for critical reading of the manuscript. This work was supported by grants from National Institutes of Health (CA132809, EY022611, DEO15964 and CA23100, K-L.G.). C.G.H. is supported by a Postdoctoral Fellowship from the Danish Council for Independent Research, Natural Sciences. Publisher Copyright: © 2015 Macmillan Publishers Limited.

PY - 2015/4/30

Y1 - 2015/4/30

N2 - 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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Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway

Abstract

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