A molecular mechanism that links Hippo signalling to the inhibition of Wnt/β-catenin signalling
A molecular mechanism that links Hippo signalling to the inhibition of Wnt/β-catenin signalling
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DOI：
10.1038/emboj.2011.487
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发表时间：
2012-03-07
期刊：
影响因子：
11.4
通讯作者：
Nishida, Eisuke
中科院分区：
文献类型：
--
作者：
Imajo, Masamichi;Miyatake, Koichi;Nishida, Eisuke
Hippo信号通路已成为器官大小、组织稳态和模式的关键调节因子。最近的研究表明，该通路中的两种效应物YAP/TAZ通过与β -catenin或disheveled的相互作用来调节Wnt/ β -catenin信号传导，这取决于生物学背景。在这里，我们确定了一种新的机制，通过河马信号抑制Wnt/ β -连环蛋白信号。我们发现Hippo通路中的转录共激活因子YAP和TAZ抑制Wnt信号传导，但不抑制β -连环蛋白的稳定性，而是通过阻止其核易位。我们的研究结果表明，YAP/TAZ与β -catenin结合，从而抑制Wnt靶基因的表达，并且Hippo通路刺激的YAP磷酸化，诱导YAP的细胞质易位，是YAP介导的Wnt/ β -catenin信号传导抑制所必需的。我们还发现，结肠直肠癌中Hippo信号的下调与β -连环蛋白信号的上调相关。值得注意的是，我们的分析表明磷酸化的YAP通过直接与细胞质中的β -连环蛋白结合来抑制其核易位。这些结果提供了一种新的机制，其中Hippo信号通过调节b-连环蛋白的核易位来拮抗Wnt信号。EMBO杂志（2012）31,1109-1122。doi: 10.1038 / emboj.2011.487;2012年1月10日在线发布
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/beta-catenin signalling through their interaction with beta-catenin or Dishevelled, depending on biological contexts. Here, we identify a novel mechanism through which Hippo signalling inhibits Wnt/beta-catenin signalling. We show that YAP and TAZ, the transcriptional co-activators in the Hippo pathway, suppress Wnt signalling without suppressing the stability of beta-catenin but through preventing its nuclear translocation. Our results show that YAP/TAZ binds to beta-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/beta-catenin signalling. We also find that downregulation of Hippo signalling correlates with upregulation of beta-catenin signalling in colorectal cancers. Remarkably, our analysis demonstrates that phosphorylated YAP suppresses nuclear translocation of beta-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 b-catenin. The EMBO Journal ( 2012) 31, 1109-1122. doi: 10.1038/emboj.2011.487; Published online 10 January 2012