GTPases的RHO家族庞大而多样，其许多成员被认为是肌动蛋白细胞骨架的主要调控因子。RHO GTPases参与调控许多依赖于细胞骨架动态重组的细胞过程，包括细胞迁移、细胞粘附、细胞分裂、细胞极性建立和细胞内运输。因此，RHO GTPases在神经元发育、免疫和心血管稳态中发挥重要作用。RHO GTPases参与感染性疾病、先天性免疫缺陷、神经退行性疾病和癌症的病因学。回顾请参考Jaffe and Hall 2005, Lemichez and Aktories 2013, Ridley 2015, Hodge and Ridley 2016, Haga and Ridley 2016, Olson 2018, Kalpachidou et al. 2019。

系统发育学上，RHO GTPases可分为4个簇。第一簇由三个亚科组成:Rho, RhoD/RhoF和Rnd。第二簇由三个亚家族组成:Rac, Cdc42和RhoU/RhoV。第三簇由RhoH亚家族组成。第四簇由RhoBTB亚家族组成。Miro GTPases和RHOBTB3 ATPase有时被描述为Rho家族成员，但它们与Rho家族的系统发育距离较远，构成两个独立的Ras-like GTPases家族，其中除Rho外，Miro和RHOBTB3还包括Ran、Arf、Rab和Ras家族(Boureux et al. 2007)。根据其激活类型，RHO GTPases可分为经典(典型)和非典型(Haga and Ridley 2016, Kalpachidou et al. 2019)。经典RHO GTPases在gtp结合的活性状态和gtp结合的非活性状态之间循环，其步骤由三类蛋白质的成员紧密控制:(1)鸟嘌呤核苷酸分解抑制剂或gdi,维持ρ蛋白质在细胞质中的一个不活跃的状态,(2)鸟嘌呤核苷酸交换因子或gef,破坏ρ蛋白质之间的相互作用及其核苷酸,最终的结果是更丰富的交换绑定GDP三磷酸鸟苷,(3) GTPase激活蛋白或gap，刺激Rho家族成员固有的低GTP水解活性，从而促进其失活。 GDIs, GEFs, and GAPs are themselves subject to tight regulation, and the overall level of Rho activity reflects the balance of their activities. Many of the Rho-specific GEFs, GAPs, and GDIs act on multiple Rho GTPases, so that regulation of these control proteins can have complex effects on the functions of multiple Rho GTPases (reviewed by Van Aelst and D'Souza-Schorey 1997, and Hodge and Ridley 2016). The classical Rho GTPase cycle is diagrammed in the figure below. External or internal cues promote the release of Rho GTPases from the GDI inhibitory complexes, which allows them to associate with the plasma membrane, where they are activated by GEFs (1), and can signal to effector proteins (4). Then, GAPs inactivate the GTPases by accelerating the intrinsic GTPase activity, leading to the GDP bound form (2). Once again, the GDI molecules stabilize the inactive GDP bound form in the cytoplasm, waiting for further instructions (3) (Tcherkezian and Lamarche-Vane, 2007). Classical RHO GTPases include four subfamilies: Rho (includes RHOA, RHOB and RHOC), Rac (includes RAC1, RAC2, RAC3 and RHOG), Cdc42 (includes CDC42, RHOJ and RHOQ) and RhoD/RhoF (includes RHOD and RHOF) (reviewed in Haga and Ridley 2016). RHOA, the founding member of the RHO GTPase family, regulates the actin cytoskeleton, formation of stress fibers and cell contractility, which is implicated in cell adhesion and migration (Lessey et al. 2012). RHOB and RHOC functions resemble RHOA (Vega and Ridley 2018; Guan et al. 2018). RHOB is also involved in membrane trafficking and DNA repair (Vega and Ridley 2018). RAC1 regulates the cytoskeleton and the production of reactive oxygen species (ROS) (Acevedo and Gonzalez-Billault 2018), and is involved in cell adhesion and cell migration (Marei and Malliri 2017). RAC2 expression is restricted to hematopoietic cells and RAC2 is a component of the phagocytic oxidase complex in neutrophils (Troeger and Williams 2013). RAC3 shares 92% sequence identity with RAC1 and is highly expressed in neurons (de Curtis 2019). CDC42 regulate the cytoskeleton and cell polarity, and is involved in cell adhesion and migration as well as in intracellular membrane trafficking (Egorov and Polishchuk 2017; Xiao et al. 2018; Pichaud et al. 2019; Woods and Lew 2019). RHOJ is highly expressed in endothelial cells, regulating their motility and vascular morphogenesis (Leszczynska et al. 2011; Shi et al. 2016). RHOQ (also known as TC10) is highly activated on exocytosing vesicles and recycling endosomes (Donnelly et al. 2014) and is involved in trafficking of CFTR (cystic fibrosis transmembrane conductance regulator) (Cheng et al. 2005). RHOD regulates cytoskeletal dynamics and intracellular transport of vesicles (Randazzo 2003; Gad and Aspenstrom 2010; Aspenstrom et al. 2014, Aspenstrom et al. 2020). RHOF regulates cytoskeletal dynamics (Gad and Aspenstrom 2010; Aspenstrom et al. 2014, Aspenstrom et al. 2020) and promotes the formation of filopodia and stress fibers (Fan and Mellor 2012). RHOD and RHOF do possess GTPase activity and are therefore grouped with classical RHO GTPases, but they are atypical in the sense that they possess high intrinsic guanine nucleotide exchange activity and do not require GEFs for activation (Aspenstrom et al. 2020).

非典型RHO GTPases不具有GTPase活性。因此，它们本构存在于活动的gtp绑定状态中。非典型RHO GTPases包括三个亚家族:Rnd(包括RND1、RND2和RND3)、RhoBTB(包括RHOBTB1和RHOBTB2)、RhoH (RhoH是唯一成员)和RhoV /RhoV(包括RhoH和RhoV)。RND1和RND3可以拮抗RHOA活性，导致应力纤维的丢失和细胞圆缩(Haga和Ridley 2016)。RND1, RND2和RND3调节细胞迁移(Ridley 2015;Mouly et al. 2019)。RHOBTB1是调节血管功能和血压的信号级联的一个组成部分(Ji和Rivero 2016)。RHOBTB2参与COP9信号体调控和cul3依赖的蛋白泛素化(Berthold et al. 2008;Ji and Rivero 2016)。RHOH的表达仅限于造血细胞，已知它参与T细胞受体(TCR)信号传导和T细胞发育(Suzuki and Oda 2008; Troeger and Williams 2013). RHOU and RHOV expression is induced by WNT signaling and they are involved in regulation of cell shape and cell adhesion (Faure and Fort 2015; and Hodge and Ridley 2016).

几乎每一个经典RHO GTPase都能与多个gef、gap和GDIs相互作用，每一个RHO GTPase都能激活多个下游效应子。人类基因组编码了82个Rho gef (71 Dbl, Fort and Blangy 2017年综述，11个DOCK, Meller et al. 2005年综述)，66个Rho gap (Amin et al. 2016)和3个Rho GDIs (Dransart et al. 2005)。为了保持我们的反应注释紧凑，我们将GEF、GAP、GDI和与每个RHO GTPase相关的效应蛋白分组。在一个集合中，我们根据支持成员分子功能的实验证据的数量，将完整集合的成员与候选成员区分开来。请注意，集合中的成员在功能上可能是非常不同的。gef、gap和GDIs上游激活剂的注释不在本目录路径的范围内，目前或将在Reactome的其他地方显示。下游效应子的信号传递在Reactome通路“RHO GTPase effectors”中有更详细的描述。