AMPK modulates Hippo pathway activity to regulate energy homeostasis

Nat Cell Biol. 2015 Apr;17(4):490-9. doi: 10.1038/ncb3113. Epub 2015 Mar 9.

Abstract

The Hippo pathway was discovered as a conserved tumour suppressor pathway restricting cell proliferation and apoptosis. However, the upstream signals that regulate the Hippo pathway in the context of organ size control and cancer prevention are largely unknown. Here, we report that glucose, the ubiquitous energy source used for ATP generation, regulates the Hippo pathway downstream effector YAP. We show that both the Hippo pathway and AMP-activated protein kinase (AMPK) were activated during glucose starvation, resulting in phosphorylation of YAP and contributing to its inactivation. We also identified glucose-transporter 3 (GLUT3) as a YAP-regulated gene involved in glucose metabolism. Together, these results demonstrate that glucose-mediated energy homeostasis is an upstream event involved in regulation of the Hippo pathway and, potentially, an oncogenic function of YAP in promoting glycolysis, thereby providing an exciting link between glucose metabolism and the Hippo pathway in tissue maintenance and cancer prevention.

Publication types

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

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Colonic Neoplasms / metabolism
  • Energy Metabolism
  • Enzyme Activation
  • Female
  • Glucose / metabolism*
  • Glucose Transporter Type 3 / biosynthesis
  • Glucose Transporter Type 3 / genetics
  • Glucose Transporter Type 3 / metabolism*
  • Glycolysis
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Liver Neoplasms / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Starvation
  • Transcription, Genetic
  • rho GTP-Binding Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Glucose Transporter Type 3
  • Phosphoproteins
  • Slc2a3 protein, mouse
  • Yap1 protein, mouse
  • Lats1 protein, mouse
  • Hippo protein, mouse
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • rho GTP-Binding Proteins
  • Glucose