Energy stress regulates hippo-YAP signaling involving AMPK-mediated regulation of angiomotin-like 1 protein

Cell Rep. 2014 Oct 23;9(2):495-503. doi: 10.1016/j.celrep.2014.09.036. Epub 2014 Oct 16.

Abstract

Hippo signaling is a tumor-suppressor pathway involved in organ size control and tumorigenesis through the inhibition of YAP and TAZ. Here, we show that energy stress induces YAP cytoplasmic retention and S127 phosphorylation and inhibits YAP transcriptional activity and YAP-dependent transformation. These effects require the central metabolic sensor AMP-activated protein kinase (AMPK) and the upstream Hippo pathway components Lats1/Lats2 and angiomotin-like 1 (AMOTL1). Furthermore, we show that AMPK directly phosphorylates S793 of AMOTL1. AMPK activation stabilizes and increases AMOTL1 steady-state protein levels, contributing to YAP inhibition. The phosphorylation-deficient S793Ala mutant of AMOTL1 showed a shorter half-life and conferred resistance to energy-stress-induced YAP inhibition. Our findings link energy sensing to the Hippo-YAP pathway and suggest that YAP may integrate spatial (contact inhibition), mechanical, and metabolic signals to control cellular proliferation and survival.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adenylate Kinase / metabolism*
  • Amino Acid Sequence
  • Energy Metabolism
  • HEK293 Cells
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Molecular Sequence Data
  • Mutation, Missense
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Protein Stability
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction*
  • Stress, Physiological*
  • Transcription Factors
  • Tumor Suppressor Proteins / metabolism

Substances

  • AMOTL1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Membrane Proteins
  • Phosphoproteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • YAP1 (Yes-associated) protein, human
  • LATS1 protein, human
  • LATS2 protein, human
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases
  • Adenylate Kinase