Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway.
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.
Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
Jung-Soon
JS
Mo
Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
Zhipeng
Z
Meng
Department of Cardiology, Veterans Medical Research Foundation, 3350 La Jolla Village Dr., San Diego, California 92161, USA.
Young Chul
YC
Kim
Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
Hyun Woo
HW
Park
Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
Carsten Gram
CG
Hansen
Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
Soohyun
S
Kim
National Creative Research Initiatives Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
Dae-Sik
DS
Lim
Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
Kun-Liang
KL
Guan
D016475:3T3 Cells; D055372:AMP-Activated Protein Kinases / Q000235:genetics*; D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003593:Cytoplasm; D004268:DNA-Binding Proteins / Q000378:metabolism; D004734:Energy Metabolism; D004789:Enzyme Activation; D057809:HEK293 Cells; D006367:HeLa Cells; D000090683:Hippo Signaling Pathway; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D000091262:TEA Domain Transcription Factors; C057182:TEAD1 protein, human; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; C092745:LATS1 protein, human; C526181:PRKAA2 protein, human; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human