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

Nat Cell Biol. 2015 Apr;17(4):500-10. doi: 10.1038/ncb3111. Epub 2015 Mar 9.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • AMP-Activated Protein Kinases / genetics*
  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Line
  • Cell Transformation, Neoplastic / genetics
  • Cytoplasm
  • DNA-Binding Proteins / metabolism
  • Energy Metabolism
  • Enzyme Activation
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Nude
  • Nuclear Proteins / metabolism
  • Phosphoproteins / antagonists & inhibitors*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • RNA, Small Interfering
  • Signal Transduction*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Phosphoproteins
  • RNA, Small Interfering
  • TEAD1 protein, human
  • Transcription Factors
  • YAP1 protein, human
  • TAFAZZIN protein, human
  • LATS1 protein, human
  • Hippo protein, human
  • PRKAA1 protein, human
  • PRKAA2 protein, human
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases