Rho GTP exchange factor ARHGEF11 regulates the integrity of epithelial junctions by connecting ZO-1 and RhoA-Myosin II signaling
Rho GTP exchange factor ARHGEF11 regulates the integrity of epithelial junctions by connecting ZO-1 and RhoA-Myosin II signaling
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DOI：
10.1073/pnas.1115063109
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发表时间：
2012-06-19
影响因子：
11.1
通讯作者：
Sugimoto, Hiroyuki
中科院分区：
文献类型：
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作者：
Itoh, Masahiko;Tsukita, Sachiko;Sugimoto, Hiroyuki
顶端连接复合体的组织及其与细胞骨架的联系对于上皮细胞的功能是必不可少的。然而，关于调控这些过程的信号通路的知识仍然是零散的。在这里，我们发现RGS-Rhogef家族的成员ARHGEF11通过与ZO-1结合而与紧密连接(TJ)结合，但不与极化上皮细胞中高度同源的ZO-2结合。在细胞-细胞接触的早期阶段，ARHGEF11定位于原始黏附连接，然后随着上皮极性的建立，其定位改变为TJs，与ZO-1非常相似。ARHGEF11基因的敲除减少了肌球蛋白轻链的磷酸化，延缓了细胞间连接的组装和细胞旁屏障的发展。此外，ARHGEF11和ZO-2的同时敲除导致TJs和周围肌动球蛋白环的显著损伤；当ZO-1和ZO-2都被耗尽时，也会出现类似的缺陷。这些结果表明，ARHGEF11在细胞-细胞连接处介导RhoA-肌球蛋白轻链信号通路，与ZO-1协同发挥作用，调节上皮细胞的细胞旁屏障、顶端连接复合体和连接周围肌球蛋白环的组织。
The organization of the apical junctional complex and its association with the cytoskeleton is essential for the function of epithelial cells. However, knowledge about the signaling pathways that regulate these processes is still fragmentary. Here we found that ARHGEF11, a member of the RGS-RhoGEF family, associates with tight junctions ( TJs) by binding to ZO-1, but not to the highly homologous ZO-2, in polarized epithelial cells. In the early phases of cell-cell contact, ARHGEF11 was located at primordial adherens junctions, and then its localization was altered to TJs as epithelial polarity was established, much like ZO-1. Knockdown of ARHGEF11 reduced the phosphorylation of myosin light chain, retarding the assembly of cell-cell junctions and the development of the paracellular barrier. Furthermore, the simultaneous knockdown of ARHGEF11 and ZO-2 resulted in significant impairment of TJs and of the perijunctional actomyosin ring; similar defects arise when both ZO-1 and ZO-2 are depleted. These results suggest that ARHGEF11 mediates RhoA-myosin light chain signaling pathways at cell-cell junctions, functioning in cooperation with ZO-1, to regulate the paracellular barrier and the organization of the apical junctional complex and perijunctional actomyosin ring of epithelial cells.