Ma Biao, Cheng Hongcheng, Gao Ruize, Mu Chenglong, Chen Ling, Wu Shian, Chen Quan, Zhu Yushan
State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin 300071, China.
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Nat Commun. 2016 Mar 31;7:11123. doi: 10.1038/ncomms11123.
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.
进化上保守的Hippo信号通路是一种控制器官大小、细胞生长和组织稳态的调节因子。Hippo信号通路的上游信号已得到广泛研究，但微环境因素如何协同调节该信号通路仍不清楚。在本研究中，我们鉴定出含LIM结构域的蛋白桩蛋白（Zyxin）作为一种支架蛋白，其在低氧和转化生长因子-β（TGF-β）刺激下，与大肿瘤抑制激酶2（Lats2）和含Siah结构域的蛋白2（Siah2）形成三元复合物并稳定它们之间的相互作用。这种相互作用促进Lats2的泛素化和降解、Yes相关蛋白（Yap）的去磷酸化及随后的激活。我们发现，在MDA-MB-231细胞中，桩蛋白对于TGF-β和低氧诱导的Lats2下调及Hippo信号失活是必需的。在异种移植模型中，桩蛋白的缺失损害细胞迁移、增殖及肿瘤发生能力。桩蛋白在人类乳腺癌中上调，且与组织学分期和转移呈正相关。我们的研究表明，桩蛋白-Lats2-Siah2轴可能是癌症治疗中的一个潜在治疗靶点。
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