A molecular mechanism that links Hippo signalling to the inhibition of Wnt/β-catenin signalling

EMBO J. 2012 Mar 7;31(5):1109-22. doi: 10.1038/emboj.2011.487. Epub 2012 Jan 10.

Abstract

The Hippo signalling pathway has emerged as a key regulator of organ size, tissue homeostasis, and patterning. Recent studies have shown that two effectors in this pathway, YAP/TAZ, modulate Wnt/β-catenin signalling through their interaction with β-catenin or Dishevelled, depending on biological contexts. Here, we identify a novel mechanism through which Hippo signalling inhibits Wnt/β-catenin signalling. We show that YAP and TAZ, the transcriptional co-activators in the Hippo pathway, suppress Wnt signalling without suppressing the stability of β-catenin but through preventing its nuclear translocation. Our results show that YAP/TAZ binds to β-catenin, thereby suppressing Wnt-target gene expression, and that the Hippo pathway-stimulated phosphorylation of YAP, which induces cytoplasmic translocation of YAP, is required for the YAP-mediated inhibition of Wnt/β-catenin signalling. We also find that downregulation of Hippo signalling correlates with upregulation of β-catenin signalling in colorectal cancers. Remarkably, our analysis demonstrates that phosphorylated YAP suppresses nuclear translocation of β-catenin by directly binding to it in the cytoplasm. These results provide a novel mechanism, in which Hippo signalling antagonizes Wnt signalling by regulating nuclear translocation of β-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases
  • Cell Cycle Proteins
  • Cell Line
  • Gene Expression Regulation*
  • Humans
  • Models, Biological
  • Nuclear Proteins / metabolism*
  • Signal Transduction*
  • Transcription Factors / metabolism*
  • Wnt Proteins / metabolism*
  • beta Catenin / metabolism*

Substances

  • Cell Cycle Proteins
  • Nuclear Proteins
  • Transcription Factors
  • Wnt Proteins
  • YY1AP1 protein, human
  • beta Catenin
  • Acyltransferases
  • TAFAZZIN protein, human