Spatially restricted activation of RhoA signalling at epithelial junctions by p114RhoGEF drives junction formation and morphogenesis.
Spatially restricted activation of RhoA signalling at epithelial junctions by p114RhoGEF drives junction formation and morphogenesis.
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DOI：
10.1038/ncb2156
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发表时间：
2011-02
影响因子：
21.3
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通过GTdR RhoA（上皮细胞行为的关键调节剂）的信号传导可以刺激相反的过程：RhoA可以促进连接形成和顶端收缩，以及减少粘附和细胞扩散。因此，需要分子机制，以确保空间限制和过程特异性RhoA激活。对于许多基本过程，包括上皮连接复合体的组装，这样的机制仍然是未知的。在这里，我们表明，p114 RhoGEF是一个连接相关的蛋白，驱动RhoA信号在连接复合物和调节紧密连接组装和上皮形态发生。p114 RhoGEF是细胞-细胞连接处RhoA活化所必需的，其缺失刺激非连接Rho信号传导和诱导肌球蛋白磷酸化沿着基底结构域。GEF-H1是一种受连接募集抑制的RhoA激活剂，GEF-H1的耗竭不会减少连接相关的RhoA激活。p114 RhoGEF与含有肌球蛋白II、Rock II和连接适配器扣带蛋白的复合物相关联，表明p114 RhoGEF是连接相关Rho信号传导模块的一个组成部分，该模块驱动RhoA的空间限制性激活以调节连接形成和上皮形态发生。
Signalling by the GTPase RhoA, a key regulator of epithelial cell behaviour, can stimulate opposing processes: RhoA can promote junction formation and apical constriction, as well as reduced adhesion and cell spreading. Molecular mechanisms are thus required that ensure spatially restricted and process-specific RhoA activation. For many fundamental processes, including assembly of the epithelial junctional complex, such mechanisms are still unknown. Here we show that p114RhoGEF is a junction-associated protein that drives RhoA signalling at the junctional complex and regulates tight junction assembly and epithelial morphogenesis. p114RhoGEF is required for RhoA activation at cell-cell junctions, and its depletion stimulates non-junctional Rho signalling and induction of myosin phosphorylation along the basal domain. Depletion of GEF-H1, a RhoA activator inhibited by junctional recruitment, does not reduce junction-associated RhoA activation. p114RhoGEF associates with a complex containing myosin II, Rock II and the junctional adaptor cingulin, indicating that p114RhoGEF is a component of a junction-associated Rho signalling module that drives spatially restricted activation of RhoA to regulate junction formation and epithelial morphogenesis.