Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions.,Nature Cell Biology

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Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions.
Nature Cell Biology ( IF 17.3 ) Pub Date : 2020-03-23 , DOI: 10.1038/s41556-020-0488-x
Paul M Müller ₁ , Juliane Rademacher ₁ , Richard D Bagshaw ₂ , Celina Wortmann ₁ , Carolin Barth ₁ , Jakobus van Unen ₃ , Keziban M Alp ₁ , Girolamo Giudice ₄ , Rebecca L Eccles ₁ , Louise E Heinrich ₅ , Patricia Pascual-Vargas ₅ , Marta Sanchez-Castro ₂ , Lennart Brandenburg ₁ , Geraldine Mbamalu ₂ , Monika Tucholska ₂ , Lisa Spatt ₁ , Maciej T Czajkowski _{1,

6} , Robert-William Welke ₁ , Sunqu Zhang ₂ , Vivian Nguyen ₂ , Trendelina Rrustemi ₁ , Philipp Trnka ₁ , Kiara Freitag ₁ , Brett Larsen ₂ , Oliver Popp _{1,

6} , Philipp Mertins _{1,

6} , Anne-Claude Gingras _{2,

7} , Frederick P Roth _{2,

8,

9} , Karen Colwill ₂ , Chris Bakal ₅ , Olivier Pertz ₃ , Tony Pawson _{2,

7} , Evangelia Petsalaki _{2,

4} , Oliver Rocks _{1,

2}

Affiliation

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：

RhoGEF 和 RhoGAP 调节蛋白的系统分析揭示了整合素粘附的空间组织 RAC1 信号传导。

Rho GTP 酶是细胞骨架的中央调节因子，在人类中由 145 个多域鸟嘌呤核苷酸交换因子 (RhoGEF) 和 GTP 酶激活蛋白 (RhoGAP) 控制。 Rho 信号传导模式如何在动态细胞空间中建立以控制细胞形态发生尚不清楚。通过底物特异性、相互作用组和定位的全家族表征，我们在系统水平上揭示了 RhoGEF 和 RhoGAP 如何情境化和时空控制 Rho 信号传导。这些蛋白质具有广泛的自抑制作用，可以进行局部调节，形成复合物来共同协调其网络并为信号传导提供位置信息。 RhoGAP 比 RhoGEF 更加混杂，可以限制 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多 RhoGEF 复合物。此外，我们发现整合素粘附在空间上分离 GEF 和 GAP，以响应机械信号塑造 RAC1 活动区。这种机制控制着细胞运动的基础的突出和收缩动力学。我们对 Rho 调节器的系统分析是揭示 Rho 信号的紧急组织原理的关键。

更新日期：2020-04-24

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