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A molecular mechanism that links Hippo signalling to the inhibition of Wnt/β‐catenin signalling
Author(s) -
Imajo Masamichi,
Miyatake Koichi,
Iimura Akira,
Miyamoto Atsumu,
Nishida Eisuke
Publication year - 2012
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2011.487
Subject(s) - biology , signalling , wnt signaling pathway , mechanism (biology) , microbiology and biotechnology , catenin , beta catenin , hippo signaling pathway , hedgehog signaling pathway , signalling pathways , signal transduction , philosophy , epistemology
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.