Regulation of Hippo signalling by p38 signalling.
Regulation of Hippo signalling by p38 signalling.
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p38 信号传导对 Hippo 信号传导的调节
DOI：
10.1093/jmcb/mjw036
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发表时间：
2016-08
影响因子：
5.5
通讯作者：
Song H
中科院分区：
文献类型：
--
作者：
Huang D;Li X;Sun L;Huang P;Ying H;Wang H;Wu J;Song H
Hippo信号通路在发育过程中的生长控制中起着至关重要的作用，其失调有助于肿瘤发生。最近的研究揭示了Hippo信号传导的多个上游调控输入，其影响转录辅激活因子Yki/雅普/TAZ通过Wts/Lats的磷酸化。在这里，我们确定p38丝裂原活化蛋白激酶（MAPK）途径作为一个新的上游分支的Hippo途径。在果蝇中，MAPKK基因licorne（lic）或MAPKKK基因Mekk 1的过表达促进Yki活性并诱导Hippo靶基因表达。功能丧失研究表明，LIC调节卵巢滤泡细胞和翅盘中的Hippo信号。上位性分析表明Mekk 1和lic通过p38 b和wts影响Hippo信号传导。我们进一步证明Mekk 1-Lic-p38 b级联通过促进F-肌动蛋白积累和Jub磷酸化来抑制Hippo信号传导。此外，p38信号调节肌动蛋白丝和海马信号平行于小GTP酶Ras，Rac 1和Rho 1。最后，我们表明，p38信号调节海马信号在哺乳动物细胞系。Lic同源物MKK 3通过肌动蛋白细胞骨架促进雅普的核定位。p38通路的上调或下调调节YAP介导的转录。因此，我们的工作揭示了p38 MAPK通路和Hippo通路在生长调节中的保守串扰。
The Hippo signalling pathway has a crucial role in growth control during development, and its dysregulation contributes to tumorigenesis. Recent studies uncover multiple upstream regulatory inputs into Hippo signalling, which affects phosphorylation of the transcriptional coactivator Yki/YAP/TAZ by Wts/Lats. Here we identify the p38 mitogen-activated protein kinase (MAPK) pathway as a new upstream branch of the Hippo pathway. In Drosophila, overexpression of MAPKK gene licorne (lic), or MAPKKK gene Mekk1, promotes Yki activity and induces Hippo target gene expression. Loss-of-function studies show that lic regulates Hippo signalling in ovary follicle cells and in the wing disc. Epistasis analysis indicates that Mekk1 and lic affect Hippo signalling via p38b and wts. We further demonstrate that the Mekk1-Lic-p38b cascade inhibits Hippo signalling by promoting F-actin accumulation and Jub phosphorylation. In addition, p38 signalling modulates actin filaments and Hippo signalling in parallel to small GTPases Ras, Rac1, and Rho1. Lastly, we show that p38 signalling regulates Hippo signalling in mammalian cell lines. The Lic homologue MKK3 promotes nuclear localization of YAP via the actin cytoskeleton. Upregulation or downregulation of the p38 pathway regulates YAP-mediated transcription. Our work thus reveals a conserved crosstalk between the p38 MAPK pathway and the Hippo pathway in growth regulation.