Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial-mesenchymal transition.
Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial-mesenchymal transition.
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DOI：
10.1091/mbc.e12-02-0166
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发表时间：
2012-10
影响因子：
3.3
通讯作者：
Nelson CM
中科院分区：
文献类型：
--
作者：
Lee K;Chen QK;Lui C;Cichon MA;Radisky DC;Nelson CM
基质硬度控制Rac 1b的亚细胞定位，Rac 1b是小GTTR Rac 1的高度活化的剪接变体。在坚硬的基质上，Rac 1b定位于质膜，与NADPH氧化酶形成复合物并产生ROS，从而诱导转录因子Snail的表达和下游信号传导至EMT。上皮-间质转化（EMT）是一种与纤维化和肿瘤转移有关的上皮可塑性形式。在这里，我们表明，微环境的机械刚度起着关键作用，通过控制亚细胞定位和下游信号转导的Rac GTP酶的EMT的促进。柔软的基质，具有与正常乳腺组织相当的顺应性，可防止EMT，而较硬的基质，具有乳腺肿瘤特有的顺应性，可促进EMT。Rac 1b是在肿瘤中发现的Rac 1的高度活化的剪接变体，定位于在坚硬基质上培养的细胞的质膜或人乳腺肿瘤的富含胶原蛋白的区域。在膜上，Rac 1b与NADPH氧化酶形成复合物，促进活性氧的产生、Snail的表达和EMT程序的激活。相反，软微环境抑制Rac 1b的膜定位和随后的氧化还原变化。这些结果揭示了一种新的机械转导途径，通过EMT调节上皮可塑性。
Substratum stiffness controls the subcellular localization of Rac1b, a highly activated splice variant of the small GTPase Rac1. On stiff substrata, Rac1b localizes to the plasma membrane, forming a complex with NADPH oxidase and generating ROS, thus inducing the expression of the transcription factor Snail and downstream signaling to EMT. Epithelial–mesenchymal transition (EMT) is a form of epithelial plasticity implicated in fibrosis and tumor metastasis. Here we show that the mechanical rigidity of the microenvironment plays a pivotal role in the promotion of EMT by controlling the subcellular localization and downstream signaling of Rac GTPases. Soft substrata, with compliances comparable to that of normal mammary tissue, are protective against EMT, whereas stiffer substrata, with compliances characteristic of breast tumors, promote EMT. Rac1b, a highly activated splice variant of Rac1 found in tumors, localizes to the plasma membrane in cells cultured on stiff substrata or in collagen-rich regions of human breast tumors. At the membrane, Rac1b forms a complex with NADPH oxidase and promotes the production of reactive oxygen species, expression of Snail, and activation of the EMT program. In contrast, soft microenvironments inhibit the membrane localization of Rac1b and subsequent redox changes. These results reveal a novel mechanotransduction pathway in the regulation of epithelial plasticity via EMT.