Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms.,Nature Cell Biology

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Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms.
Nature Cell Biology ( IF 17.3 ) Pub Date : 2019-12-23 , DOI: 10.1038/s41556-019-0438-7
Halil Bagci _{1,

2} , Neera Sriskandarajah _{1,

3} , Amélie Robert ₁ , Jonathan Boulais ₁ , Islam E Elkholi _{1,

4} , Viviane Tran _{1,

5} , Zhen-Yuan Lin ₆ , Marie-Pier Thibault ₁ , Nadia Dubé ₁ , Denis Faubert ₁ , David R Hipfner _{1,

3,

4,

7} , Anne-Claude Gingras _{6,

8} , Jean-François Côté _{1,

2,

4,

7}

Affiliation

Guanine nucleotide exchange factors (RhoGEFs) and GTPase-activating proteins (RhoGAPs) coordinate the activation state of the Rho family of GTPases for binding to effectors. Here, we exploited proximity-dependent biotinylation to systematically define the Rho family proximity interaction network from 28 baits to produce 9,939 high-confidence proximity interactions in two cell lines. Exploiting the nucleotide states of Rho GTPases, we revealed the landscape of interactions with RhoGEFs and RhoGAPs. We systematically defined effectors of Rho proteins to reveal candidates for classical and atypical Rho proteins. We used optogenetics to demonstrate that KIAA0355 (termed GARRE here) is a RAC1 interactor. A functional screen of RHOG candidate effectors identified PLEKHG3 as a promoter of Rac-mediated membrane ruffling downstream of RHOG. We identified that active RHOA binds the kinase SLK in Drosophila and mammalian cells to promote Ezrin-Radixin-Moesin phosphorylation. Our proximity interactions data pave the way for dissecting additional Rho signalling pathways, and the approaches described here are applicable to the Ras family.

中文翻译：

绘制 Rho 家族 GTP 酶的邻近相互作用网络图揭示了信号通路和调控机制。

鸟嘌呤核苷酸交换因子 (RhoGEF) 和 GTP 酶激活蛋白 (RhoGAP) 协调 GTP 酶 Rho 家族的激活状态，以与效应物结合。在这里，我们利用邻近依赖性生物素化从 28 个诱饵系统地定义 Rho 家族邻近相互作用网络，在两个细胞系中产生 9,939 个高置信度邻近相互作用。利用 Rho GTPase 的核苷酸状态，我们揭示了与 RhoGEF 和 RhoGAP 相互作用的情况。我们系统地定义了 Rho 蛋白的效应器，以揭示经典和非典型 Rho 蛋白的候选者。我们使用光遗传学来证明 KIAA0355（此处称为 GARRE）是 RAC1 相互作用子。RHOG 候选效应器的功能筛选确定 PLEKHG3 是 Rac 介导的 RHOG 下游膜起皱的启动子。我们发现活性 RHOA 与果蝇和哺乳动物细胞中的激酶 SLK 结合以促进 Ezrin-Radixin-Moesin 磷酸化。我们的邻近交互数据为剖析额外的 Rho 信号通路铺平了道路，这里描述的方法适用于 Ras 家族。

更新日期：2019-12-23

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