title: A molecular mechanism that links Hippo signalling to the inhibition of Wnt/β-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/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.
authors.affiliation: Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Imajo
authors.forename: Koichi
authors.initials: K
authors.lastname: Miyatake
authors.forename: Akira
authors.initials: A
authors.lastname: Iimura
authors.forename: Atsumu
authors.initials: A
authors.lastname: Miyamoto
authors.forename: Eisuke
authors.initials: E
authors.lastname: Nishida
mesh_terms: D000217:Acyltransferases; D018797:Cell Cycle Proteins; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; C456659:YY1AP1 protein, human; D051176:beta Catenin; D000217:Acyltransferases; C108675:TAFAZZIN protein, human