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

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/?-catenin signalling through their interaction with ?-catenin or Dishevelled, depending on biological contexts. Here, we identify a novel mechanism through which Hippo signalling inhibits Wnt/?-catenin signalling. We show that YAP and TAZ, the transcriptional co-activators in the Hippo pathway, suppress Wnt signalling without suppressing the stability of ?-catenin but through preventing its nuclear translocation. Our results show that YAP/TAZ binds to ?-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/?-catenin signalling. We also find that downregulation of Hippo signalling correlates with upregulation of ?-catenin signalling in colorectal cancers. Remarkably, our analysis demonstrates that phosphorylated YAP suppresses nuclear translocation of ?-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 ?-catenin.

SUBMITTER: Imajo M 

PROVIDER: S-EPMC3297994 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature