Zyxin-Siah2-Lats2 axis mediates cooperation between Hippo and TGF-β signalling pathways.
Zyxin-Siah2-Lats2 axis mediates cooperation between Hippo and TGF-β signalling pathways.
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Zyxin-Siah2-Lats2 轴介导 Hippo 和 TGF-β 信号通路之间的合作
DOI：
10.1038/ncomms11123
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发表时间：
2016-03-31
影响因子：
16.6
通讯作者：
Zhu Y
中科院分区：
文献类型：
--
作者：
Ma B;Cheng H;Gao R;Mu C;Chen L;Wu S;Chen Q;Zhu Y
进化上保守的Hippo途径是控制器官大小、细胞生长和组织稳态的调节剂。Hippo通路的上游信号已被广泛研究，但微环境因素如何协调调节该通路仍不清楚。在这项研究中，我们确定了LIM结构域蛋白Zyxin作为支架蛋白，其响应于缺氧和TGF-β刺激，与Lats 2和Siah 2形成三元复合物并稳定它们的相互作用。这种相互作用促进Lats 2泛素化和降解，雅普去磷酸化和随后的活化。我们发现，Zyxin是TGF-β和缺氧诱导的Lats 2下调和MDA-MB-231细胞中Hippo信号转导失活所必需的。Zyxin的耗尽损害异种移植模型中细胞迁移、增殖和肿瘤发生的能力。Zyxin在人乳腺癌中上调，并与组织学分期和转移呈正相关。我们的研究表明，Zyxin-Lats 2-Siah 2轴可能作为一个潜在的治疗癌症的治疗靶点。 Hippo和TGF-β是参与各种类型肿瘤发展的关键信号通路。在这里，作者证明了TGF-β可以通过稳定支架蛋白Zyxin直接调节Hippo通路，Zyxin与Siah 2和Lats 2形成三元复合物，促进Lats 2降解和雅普活化。
The evolutionarily conserved Hippo pathway is a regulator that controls organ size, cell growth and tissue homeostasis. Upstream signals of the Hippo pathway have been widely studied, but how microenvironmental factors coordinately regulate this pathway remains unclear. In this study, we identify LIM domain protein Zyxin, as a scaffold protein, that in response to hypoxia and TGF-β stimuli, forms a ternary complex with Lats2 and Siah2 and stabilizes their interaction. This interaction facilitates Lats2 ubiquitination and degradation, Yap dephosphorylation and subsequently activation. We show that Zyxin is required for TGF-β and hypoxia-induced Lats2 downregulation and deactivation of Hippo signalling in MDA-MB-231 cells. Depletion of Zyxin impairs the capability of cell migration, proliferation and tumourigenesis in a xenograft model. Zyxin is upregulated in human breast cancer and positively correlates with histological stages and metastasis. Our study demonstrates that Zyxin-Lats2–Siah2 axis may serve as a potential therapeutic target in cancer treatment. Hippo and TGF-β are crucial signalling pathways involved in the development of various types of tumours. Here, the authors demonstrate that TGF-β can directly regulate Hippo pathway through the stabilization of the scaffold protein Zyxin, which forms a ternary complex with Siah2 and Lats2 promoting Lats2 degradation and YAP activation.