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.
Bibliographical noteFunding 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.
© 2015 Macmillan Publishers Limited.
All Science Journal Classification (ASJC) codes
- Cell Biology