RHO GTPase cycle

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Homo sapiens
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RHO family of GTPases is large and diverse, with many of its members considered to be master regulators of actin cytoskeleton. RHO GTPases are involved in the regulation of many cellular processes that depend on dynamic reorganization of the cytoskeleton, including cell migration, cell adhesion, cell division, establishment of cellular polarity and intracellular transport. As a consequence, RHO GTPases play important roles in neuronal development, immunity and cardio-vascular homeostasis. RHO GTPases are involved in the etiology of infectious diseases, congenital immunodeficiencies, neurodegenerative diseases and cancer. For review, please refer to Jaffe and Hall 2005, Lemichez and Aktories 2013, Ridley 2015, Hodge and Ridley 2016, Haga and Ridley 2016, Olson 2018, and Kalpachidou et al. 2019.

Phylogenetically, RHO GTPases can be grouped into four clusters. The first cluster consists of three subfamilies: Rho, RhoD/RhoF and Rnd. The second cluster consists of three subfamilies: Rac, Cdc42 and RhoU/RhoV. The third cluster consists of the RhoH subfamily. The fourth cluster consists of the RhoBTB subfamily. Miro GTPases and RHOBTB3 ATPase are sometimes described as Rho family members, but they are phylogenetically distant from the Rho family and constitute two separate families of Ras-like GTPases, which, besides Rho, Miro and RHOBTB3 also includes Ran, Arf, Rab and Ras families (Boureux et al. 2007). Based on their activation type, RHO GTPases can be divided into classical (typical) and atypical (reviewed by Haga and Ridley 2016, and Kalpachidou et al. 2019). Classical RHO GTPases cycle between active GTP-bound states and inactive GDP-bound states through steps that are tightly controlled by members of three classes of proteins: (1) guanine nucleotide dissociation inhibitors or GDIs, which maintain Rho proteins in an inactive state in the cytoplasm, (2) guanine nucleotide exchange factors or GEFs, which destabilize the interaction between Rho proteins and their bound nucleotide, the net result of which is the exchange of bound GDP for the more abundant GTP, and (3) GTPase activating proteins or GAPs, which stimulate the low intrinsic GTP hydrolysis activity of Rho family members, thus promoting their inactivation. 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 (1) which allows them to associate with the plasma membrane (2), where they are activated by GEFs (3), and can signal to effector proteins (3.5). Then, GAPs inactivate the GTPases by accelerating the intrinsic GTPase activity, leading to the GDP bound form (4). Once again, the GDI molecules stabilize the inactive GDP bound form in the cytoplasm, waiting for further instructions (5) (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). 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 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). RHOF regulates cytoskeletal dynamics (Gad and Aspenstrom 2010; Aspenstrom et al. 2014) 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.

Atypical RHO GTPases do not possess GTPase activity. They therefore constitutively exist in the active GTP-bound state. Atypical RHO GTPases include three subfamilies: Rnd (includes RND1, RND2 and RND3), RhoBTB (includes RHOBTB1 and RHOBTB2), RhoH (RHOH is the only member) and RhoU/RhoV (includes RHOU and RHOV). RND1 and RND3 can antagonize RHOA activity, leading to loss of stress fibers and cell rounding (Haga and Ridley 2016). RND1, RND2 and RND3 regulate cell migration (Ridley 2015; Mouly et al. 2019). RHOBTB1 is a component of a signaling cascade that regulates vascular function and blood pressure (Ji and Rivero 2016). RHOBTB2 is involved in COP9 signalosome-regulated and CUL3-dependent protein ubiquitination (Berthold et al. 2008; Ji and Rivero 2016). RHOH expression is restricted to hematopoietic cells, and it is known to be involved in T cell receptor (TCR) signaling and T cell development (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).

Almost every classical RHO GTPase interacts with multiple GEFs, GAPs and GDIs, and every RHO GTPase activates multiple downstream effectors. There are 82 Rho GEFs (71 Dbl, reviewed in Fort and Blangy 2017, and 11 DOCK, reviewed in Meller et al. 2005), 66 Rho GAPs (Amin et al. 2016) and 3 Rho GDIs (Dransart et al. 2005) encoded by the human genome. To keep our reaction annotations compact, we have grouped the GEF, GAP, GDI and effector proteins associated with each RHO GTPase into sets. Within a set, we have distinguished full set members from candidate members on the basis of the amount of experimental evidence supporting the member’s molecular function. Note that members of a set can otherwise be functionally quite diverse. Annotation of upstream activators of GEFs, GAPs and GDIs was outside the scope of this catalogue pathway and is or will be shown elsewhere in Reactome. Signaling through downstream effectors is shown in more detail in the Reactome pathway “RHO GTPase Effectors”.

Literature References
PubMed ID Title Journal Year
24622787 Atypical Rho GTPases RhoD and Rif integrate cytoskeletal dynamics and membrane trafficking

Aspenström, P

Biol. Chem. 2014
26555387 Atypical RhoV and RhoU GTPases control development of the neural crest

Faure, S, Fort, P

Small GTPases 2015
26363959 Rho GTPase signalling in cell migration

Ridley, AJ

Curr. Opin. Cell Biol. 2015
12636908 RhoD, Src, and hDia2C in endosome motility

Randazzo, PA

Dev. Cell 2003
28541439 The Evolutionary Landscape of Dbl-Like RhoGEF Families: Adapting Eukaryotic Cells to Environmental Signals

Fort, P, Blangy, A

Genome Biol Evol 2017
19818399 Rif proteins take to the RhoD: Rho GTPases at the crossroads of actin dynamics and membrane trafficking

Gad, AK, Aspenström, P

Cell. Signal. 2010
28664531 The role of RhoC in malignant tumor invasion, metastasis and targeted therapy

Guan, X, Chen, S, Zhao, Y

Histol. Histopathol. 2018
27548350 Rho GTPases, their post-translational modifications, disease-associated mutations and pharmacological inhibitors

Olson, MF

Small GTPases 2018
27301673 Regulating Rho GTPases and their regulators

Hodge, RG, Ridley, AJ

Nat. Rev. Mol. Cell Biol. 2016
22103495 The role of RhoJ in endothelial cell biology and angiogenesis

Leszczynska, K, Kaur, S, Wilson, E, Bicknell, R, Heath, VL

Biochem. Soc. Trans. 2011
28029388 Emerging role of Cdc42-specific guanine nucleotide exchange factors as regulators of membrane trafficking in health and disease

Egorov, MV, Polishchuk, RS

Tissue Cell 2017
31208035 Rho GTPases in the Physiology and Pathophysiology of Peripheral Sensory Neurons

Kalpachidou, T, Spiecker, L, Kress, M, Quarta, S

Cells 2019
16190977 RhoGDIs revisited: novel roles in Rho regulation

Dransart, E, Olofsson, B, Cherfils, J

Traffic 2005
16254241 CZH proteins: a new family of Rho-GEFs

Meller, N, Merlot, S, Guda, C

J Cell Sci 2005
31894645 Peroxisomal fission is modulated by the mitochondrial Rho-GTPases, Miro1 and Miro2

Covill-Cooke, C, Toncheva, VS, Drew, J, Birsa, N, Lopez-Domenech, G, Kittler, JT

EMBO Rep 2020
29330095 Crosstalk between Rac1-mediated actin regulation and ROS production

Acevedo, A, González-Billault, C

Free Radic. Biol. Med. 2018
22931484 From mechanical force to RhoA activation

Lessey, EC, Guilluy, C, Burridge, K

Biochemistry 2012
29222186 New splicing variants of mitochondrial Rho GTPase-1 (Miro1) transport peroxisomes

Okumoto, K, Ono, T, Toyama, R, Shimomura, A, Nagata, A, Fujiki, Y

J Cell Biol 2018
27314390 Atypical Rho GTPases of the RhoBTB Subfamily: Roles in Vesicle Trafficking and Tumorigenesis

Ji, W, Rivero, F

Cells 2016
15546864 Regulation of cystic fibrosis transmembrane regulator trafficking and protein expression by a Rho family small GTPase TC10

Cheng, J, Wang, H, Guggino, WB

J. Biol. Chem. 2005
26707701 Miro sculpts mitochondrial dynamics in neuronal health and disease

Devine, MJ, Birsa, N, Kittler, JT

Neurobiol. Dis. 2016
29596304 Regulating Cdc42 and Its Signaling Pathways in Cancer: Small Molecules and MicroRNA as New Treatment Candidates

Xiao, XH, Lv, LC, Duan, J, Wu, YM, He, SJ, Hu, ZZ, Xiong, LX

Molecules 2018
31514269 The Rac3 GTPase in Neuronal Development, Neurodevelopmental Disorders, and Cancer

de Curtis, I

Cells 2019
28350208 Polarity establishment by Cdc42: Key roles for positive feedback and differential mobility

Woods, B, Lew, DJ

Small GTPases 2019
27875099 The RhoB small GTPase in physiology and disease

Vega, FM, Ridley, AJ

Small GTPases 2018
27556037 The Role of RhoJ in Endothelial Cell Biology and Tumor Pathology

Shi, TT, Li, G, Xiao, HT

Biomed Res Int 2016
18311041 The atypical small GTPase RhoH : a novel role in T cell development

Suzuki, H, Oda, H

Nihon Rinsho Meneki Gakkai Kaishi 2008
9308960 Rho GTPases and signaling networks

Van Aelst, L, D'Souza-Schorey, C

Genes Dev 1997
23732472 Mitochondrial trafficking in neurons

Schwarz, TL

Cold Spring Harb Perspect Biol 2013
27481945 Deciphering the Molecular and Functional Basis of RHOGAP Family Proteins: A SYSTEMATIC APPROACH TOWARD SELECTIVE INACTIVATION OF RHO FAMILY PROTEINS

Amin, E, Jaiswal, M, Derewenda, U, Reis, K, Nouri, K, Koessmeier, KT, Aspenström, P, Somlyo, AV, Dvorsky, R, Ahmadian, MR

J. Biol. Chem. 2016
23850828 Hematopoietic-specific Rho GTPases Rac2 and RhoH and human blood disorders

Troeger, A, Williams, DA

Exp. Cell Res. 2013
24071720 Structural coupling of the EF hand and C-terminal GTPase domains in the mitochondrial protein Miro

Klosowiak, JL, Focia, PJ, Chakravarthy, S, Landahl, EC, Freymann, DM, Rice, SE

EMBO Rep 2013
22260703 The small Rho GTPase Rif and actin cytoskeletal remodelling

Fan, L, Mellor, H

Biochem. Soc. Trans. 2012
23648569 Hijacking of Rho GTPases during bacterial infection

Lemichez, E, Aktories, K

Exp. Cell Res. 2013
17035353 Evolution of the Rho family of ras-like GTPases in eukaryotes

Boureux, A, Vignal, E, Faure, S, Fort, P

Mol Biol Evol 2007
27628050 Rho GTPases: Regulation and roles in cancer cell biology

Haga, RB, Ridley, AJ

Small GTPases 2016
27314616 GEFs: Dual regulation of Rac1 signaling

Marei, H, Malliri, A

Small GTPases 2017
31344837 The RND1 Small GTPase: Main Functions and Emerging Role in Oncogenesis

Mouly, L, Gilhodes, J, Lemarié, A, Cohen-Jonathan Moyal, E, Toulas, C, Favre, G, Sordet, O, Monferran, S

Int J Mol Sci 2019
29364559 A role for Mitochondrial Rho GTPase 1 (MIRO1) in motility and membrane dynamics of peroxisomes

Castro, IG, Richards, DM, Metz, J, Costello, JL, Passmore, JB, Schrader, TA, Gouveia, A, Ribeiro, D, Schrader, M

Traffic 2018
25482645 Rho GTPase isoforms in cell motility: Don't fret, we have FRET

Donnelly, SK, Bravo-Cordero, JJ, Hodgson, L

Cell Adh Migr 2014
16212495 Rho GTPases: biochemistry and biology

Jaffe, AB, Hall, A

Annu Rev Cell Dev Biol 2005
31113848 Regulation of Cdc42 and its effectors in epithelial morphogenesis

Pichaud, F, Walther, RF, Nunes de Almeida, F

J. Cell. Sci. 2019
17222083 Current knowledge of the large RhoGAP family of proteins

Tcherkezian, J, Lamarche-Vane, N

Biol Cell 2007
28610953 A thirty-year quest for a role of R-Ras in cancer: from an oncogene to a multitasking GTPase

Liu, WN, Yan, M, Chan, AM

Cancer Lett. 2017
18298893 Rho GTPases of the RhoBTB subfamily and tumorigenesis

Berthold, J, Schenkova, K, Rivero, F

Acta Pharmacol. Sin. 2008
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