Rho GTPases are central regulators of the cytoskeleton and, in humans, are controlled by 145 multidomain guanine nucleotide exchange factors (RhoGEFs) and GTPase-activating proteins (RhoGAPs). How Rho signalling patterns are established in dynamic cell spaces to control cellular morphogenesis is unclear. Through a family-wide characterization of substrate specificities, interactomes and localization, we reveal at the systems level how RhoGEFs and RhoGAPs contextualize and spatiotemporally control Rho signalling. These proteins are widely autoinhibited to allow local regulation, form complexes to jointly coordinate their networks and provide positional information for signalling. RhoGAPs are more promiscuous than RhoGEFs to confine Rho activity gradients. Our resource enabled us to uncover a multi-RhoGEF complex downstream of G-protein-coupled receptors controlling CDC42-RHOA crosstalk. Moreover, we show that integrin adhesions spatially segregate GEFs and GAPs to shape RAC1 activity zones in response to mechanical cues. This mechanism controls the protrusion and contraction dynamics fundamental to cell motility. Our systems analysis of Rho regulators is key to revealing emergent organization principles of Rho signalling.

中文翻译：

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RhoGEF和RhoGAP调节蛋白的系统分析揭示了整联蛋白粘附的空间组织的RAC1信号传导。

Rho GTPases是细胞骨架的中央调节剂，在人类中，受到145个多域鸟嘌呤核苷酸交换因子（RhoGEFs）和GTPase激活蛋白（RhoGAPs）的控制。尚不清楚如何在动态细胞空间中建立Rho信号传导模式来控制细胞形态发生。通过对底物特异性，相互作用组和定位进行全家族的表征，我们在系统水平上揭示了RhoGEF和RhoGAP如何上下文化和时空控制Rho信号传导。这些蛋白质被广泛地自动抑制以允许局部调节，形成复合物以共同协调其网络并提供信号位置信息。RhoGAP比RhoGEF更为混杂，以限制Rho活性梯度。我们的资源使我们能够发现控制CDC42-RHOA串扰的G蛋白偶联受体下游的Multi-RhoGEF复合物。此外，我们表明整联蛋白粘附空间分隔GEFs和GAPs响应机械提示形状RAC1活动区。这种机制控制着细胞运动的根本性的动力学机制。我们对Rho调节器的系统分析是揭示Rho信号新兴组织原则的关键。