YAP Regulates Actin Dynamics through ARHGAP29 and Promotes Metastasis
YAP Regulates Actin Dynamics through ARHGAP29 and Promotes Metastasis
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DOI：
10.1016/j.celrep.2017.04.075
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发表时间：
2017-05-23
期刊：
影响因子：
8.8
通讯作者：
Sudol, Marius
中科院分区：
文献类型：
--
作者：
Qiao, Yiting;Chen, Jianxiang;Sudol, Marius
Yes相关蛋白（雅普）通过Hippo通路与细胞骨架的相互作用受到机械信号的调控。先前的研究表明，雅普通过抑制青鳉中的Rho GTPase来调节肌动球蛋白网络。在这里，我们确定Rho GT3激活蛋白29（ARHGAP 29）作为雅普在人胃癌细胞系中的转录靶点。雅普促进ARHGAP 29的表达以抑制RhoA-LIMK-cofilin途径，使F-肌动蛋白不稳定。雅普的过表达通过改变F-肌动蛋白/G-肌动蛋白转换的动力学引起细胞骨架重排，从而促进迁移。在小鼠模型中，与原发肿瘤部位的细胞相比，循环肿瘤细胞（CTC）表现出增加的ARHGAP 29 RNA水平，并且CTC的转移潜力与ARHGAP 29表达呈正相关。此外，ARHGAP 29表达增加与人胃癌患者生存期缩短相关。我们的研究提供了一个模型，以了解雅普的贡献，通过调节肌动蛋白动力学的癌症转移。
Yes-associated protein (YAP) is regulated by mechanical cues via the interaction of the Hippo pathway with cytoskeleton. Previous studies showed that YAP plays a role in regulating the actomyosin network by suppressing Rho GTPase in medaka fish. Here, we identify Rho GTPase activating protein 29 (ARHGAP29) as a transcriptional target of YAP in a human gastric cancer cell line. YAP promotes the expression of ARHGAP29 to suppress the RhoA-LIMK-cofilin pathway, destabilizing F-actin. The overexpression of YAP causes cytoskeletal rearrangement by altering the dynamics of F-actin/G-actin turnover, thus promoting migration. In a mouse model, circulating tumor cells (CTCs) exhibit an increased ARHGAP29 RNA level compared with cells at primary tumor sites, and the metastatic potential of CTCs is positively correlated with ARHGAP29 expression. Moreover, increased ARHGAP29 expression is correlated with shortened survival of human gastric cancer patients. Our study provides a model to understand YAP's contribution to cancer metastasis via regulation of actin dynamics.