Zyxin links fat signaling to the hippo pathway.
Zyxin links fat signaling to the hippo pathway.
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DOI：
10.1371/journal.pbio.1000624
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发表时间：
2011-06
期刊：
影响因子：
9.8
通讯作者：
Irvine KD
中科院分区：
文献类型：
--
作者：
Rauskolb C;Pan G;Reddy BV;Oh H;Irvine KD
通过遗传和分子分析，作者将Zyx确定为Hippo信号传导的正调节因子，并描述了其在通路中的作用。Hippo信号通路在生长控制中具有保守的作用，并且在正常发育和肿瘤发生中具有根本的重要性。尽管近年来进展迅速，但对该途径的关键步骤仍然知之甚少，部分原因是对组分的鉴定不完整。通过遗传筛选，我们确定了果蝇Zyxin家族基因，Zyx 102（Zyx），作为Hippo通路的一个组成部分。Zyx积极调节河马途径转录共激活因子Yorkie，因为它的损失减少Yorkie活动和器官生长。通过上位性检验，我们将对Zyx的需求定位在Hippo信号传导的Fat分支内，Fat和Dco的下游，以及Yorkie激酶Warts的上游，并且我们发现Zyx是Fat对Warts蛋白水平的影响所必需的。Zyx定位于亚顶端膜，在细胞间顶点具有独特的积累峰。这部分地重叠肌球蛋白Dachs的膜定位，其对Fat-Hippo信号传导具有类似的作用。免疫共沉淀实验表明，Zyx可以结合Dachs和Dachs刺激Zyx的结合疣。我们还扩展了Ajuba LIM蛋白Jub的表征，并确定虽然Jub和Zyx共享C-末端LIM结构域，但它们以不同的方式调节Hippo信号传导。我们的研究结果确定了Zyx在海马通路中的作用，并提出了Dachs作用的机制：因为脂肪调节Dachs在膜上的定位，在那里它可以与Zyx重叠，我们提出Dachs的调节定位通过调节Zyx-Warts结合来影响下游信号传导。哺乳动物Zyxin蛋白质已经涉及将机械应变效应与细胞行为联系起来。因此，我们将Zyx鉴定为Hippo信号传导的调节剂也提高了机械应变可能与通过Hippo信号传导调节基因表达和生长有关的可能性。控制细胞数量的过程在正常发育过程中是必不可少的，当它们需要产生正确大小的器官时，以及在肿瘤发生过程中，当它们影响肿瘤生长时。Hippo通路是一种细胞间信号传导通路，其将关于细胞-细胞接触和细胞极性的信息传递到调节控制细胞数量的基因的转录的信号转导通路。从果蝇到人类，Hippo信号在控制生长中的作用是保守的，但Hippo信号转导途径的许多方面仍然知之甚少。在这篇文章中，我们确定Zyx作为一个以前未知的组成部分，河马在果蝇的途径，并表征其作用的途径。我们表明，Zyx在海马信号传导的分支中起着至关重要的作用，该分支涉及跨膜受体蛋白脂肪及其靶向Dachs，Dachs是肌球蛋白家族蛋白。我们的研究结果表明，脂肪调节Dachs的定位，Dachs随后结合Zyx，刺激其与激酶Warts/Lats的结合，从而调节下游信号传导事件的模型。Zyx在脊椎动物中是保守的，我们认为脊椎动物Zyx蛋白也可能参与Hippo信号的调节，从而参与器官生长。
Using genetic and molecular analyses, the authors identify Zyx as a positive regulator of Hippo signaling and characterize its role within the pathway. The Hippo signaling pathway has a conserved role in growth control and is of fundamental importance during both normal development and oncogenesis. Despite rapid progress in recent years, key steps in the pathway remain poorly understood, in part due to the incomplete identification of components. Through a genetic screen, we identified the Drosophila Zyxin family gene, Zyx102 (Zyx), as a component of the Hippo pathway. Zyx positively regulates the Hippo pathway transcriptional co-activator Yorkie, as its loss reduces Yorkie activity and organ growth. Through epistasis tests, we position the requirement for Zyx within the Fat branch of Hippo signaling, downstream of Fat and Dco, and upstream of the Yorkie kinase Warts, and we find that Zyx is required for the influence of Fat on Warts protein levels. Zyx localizes to the sub-apical membrane, with distinctive peaks of accumulation at intercellular vertices. This partially overlaps the membrane localization of the myosin Dachs, which has similar effects on Fat-Hippo signaling. Co-immunoprecipitation experiments show that Zyx can bind to Dachs and that Dachs stimulates binding of Zyx to Warts. We also extend characterization of the Ajuba LIM protein Jub and determine that although Jub and Zyx share C-terminal LIM domains, they regulate Hippo signaling in distinct ways. Our results identify a role for Zyx in the Hippo pathway and suggest a mechanism for the role of Dachs: because Fat regulates the localization of Dachs to the membrane, where it can overlap with Zyx, we propose that the regulated localization of Dachs influences downstream signaling by modulating Zyx-Warts binding. Mammalian Zyxin proteins have been implicated in linking effects of mechanical strain to cell behavior. Our identification of Zyx as a regulator of Hippo signaling thus also raises the possibility that mechanical strain could be linked to the regulation of gene expression and growth through Hippo signaling. Processes that control cell numbers are essential during normal development, when they are required to generate organs of the correct size, and during cancinogenesis, when they influence tumor growth. The Hippo pathway is an intercellular signaling pathway that relays information about cell-cell contact and cell polarity to a signal transduction pathway that regulates the transcription of genes controlling cell numbers. The role of Hippo signaling in controlling growth is conserved from fruit flies to humans, but many aspects of the Hippo signal transduction pathway remain poorly understood. In this article, we identify Zyx as a previously unknown component of the Hippo pathway in Drosophila, and characterize its role within the pathway. We show that Zyx plays an essential role in a branch of Hippo signaling that involves the transmembrane receptor protein Fat and its target Dachs, which is a myosin family protein. Our results suggest a model in which Fat regulates the localization of Dachs, Dachs subsequently binds Zyx, stimulating its binding with the kinase Warts/Lats, and thereby regulates downstream signaling events. Zyx is conserved in vertebrates and we suggest that vertebrate Zyx proteins might also be involved in the regulation of Hippo signaling and, thereby, organ growth.
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DOI：
10.1016/j.cub.2010.02.035
发表时间：
2010-04-13
期刊：
Current biology : CB
影响因子：
--
作者：
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
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作者：
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DOI：
10.1083/jcb.149.5.1073
发表时间：
2000-05-29
期刊：
The Journal of cell biology
影响因子：
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