Pathway Human Homo sapiens

RHO GTPase cycle

R-HSA-9012999 in Reactome release 97: under Signaling by Rho GTPases, with 451 genes placed in it by the mapping files and 19 child pathways in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-9012999 (mouse), R-RNO-9012999 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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This page reads the pathway's record from its source while you read the rest; with scripts off the card stays at its loading line. Reload with scripts on to see it, or open the source's own page from the link in the card.

01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-9012999.4
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2007-05-15
Last updated: 2021-09-15
Events inside: 19, counted from the record

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, 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).

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 Reactome attaches

Rho GTPases and signaling networksGenes Dev, 1997, vol. 11, p. 2295-322PubMed 9308960
Current knowledge of the large RhoGAP family of proteinsBiol Cell, 2007, vol. 99, p. 67-86PubMed 17222083
Rho GTPases: biochemistry and biologyAnnu Rev Cell Dev Biol, 2005, vol. 21, p. 247-69PubMed 16212495
Hijacking of Rho GTPases during bacterial infectionExp. Cell Res., 2013, vol. 319, p. 2329-36PubMed 23648569
Rho GTPase signalling in cell migrationCurr. Opin. Cell Biol., 2015, vol. 36, p. 103-12PubMed 26363959
Regulating Rho GTPases and their regulatorsNat. Rev. Mol. Cell Biol., 2016, vol. 17, p. 496-510PubMed 27301673
Rho GTPases: Regulation and roles in cancer cell biologySmall GTPases, 2016, vol. 7, p. 207-221PubMed 27628050

Reactome's record lists 13 orthologous events, R-RNO-9012999 (Rattus norvegicus), R-MMU-9012999 (Mus musculus) among the species this site serves, and 11 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-10-05 ET · Reactome pathway browser"RHO GTPase cycle". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-9012999 with StableID: R-HSA-9012999.4 (accessed 2026-10-05 ET). Reactome version 97 (CC0).

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 451 genes in this human pathway; showing 401 to 451, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 5 of 5
Gene	Authority id	Mapping file id	Evidence codes
GeneTAOK3	AuthorityHGNC:18133	Mapping file id51347 NCBI file	EvidenceTAS
GeneTEX2	AuthorityHGNC:30884	Mapping file id55852 NCBI file	EvidenceTAS
GeneTFRC	AuthorityHGNC:11763	Mapping file id7037 NCBI file	EvidenceTAS
GeneTIAM1	AuthorityHGNC:11805	Mapping file id7074 NCBI file	EvidenceTAS
GeneTIAM2	AuthorityHGNC:11806	Mapping file id26230 NCBI file	EvidenceTAS
GeneTJP2	AuthorityHGNC:11828	Mapping file id9414 NCBI file	EvidenceTAS
GeneTMEM59	AuthorityHGNC:1239	Mapping file id9528 NCBI file	EvidenceTAS
GeneTMEM87A	AuthorityHGNC:24522	Mapping file id25963 NCBI file	EvidenceTAS
GeneTMOD3	AuthorityHGNC:11873	Mapping file id29766 NCBI file	EvidenceTAS
GeneTMPO	AuthorityHGNC:11875	Mapping file id7112 NCBI file	EvidenceTAS
GeneTNFAIP1	AuthorityHGNC:11894	Mapping file id7126 NCBI file	EvidenceTAS
GeneTOR1AIP1	AuthorityHGNC:29456	Mapping file id26092 NCBI file	EvidenceTAS
GeneTPM3	AuthorityHGNC:12012	Mapping file id7170 NCBI file	EvidenceTAS
GeneTPM4	AuthorityHGNC:12013	Mapping file id7171 NCBI file	EvidenceTAS
GeneTRA2B	AuthorityHGNC:10781	Mapping file id6434 NCBI file	EvidenceTAS
GeneTRIO	AuthorityHGNC:12303	Mapping file id7204 NCBI file	EvidenceTAS
GeneTRIP10	AuthorityHGNC:12304	Mapping file id9322 NCBI file	EvidenceTAS
GeneTUBA1B	AuthorityHGNC:18809	Mapping file id10376 NCBI file	EvidenceTAS
GeneTWF1	AuthorityHGNC:9620	Mapping file id5756 NCBI file	EvidenceTAS
GeneTXNL1	AuthorityHGNC:12436	Mapping file id9352 NCBI file	EvidenceTAS
GeneUACA	AuthorityHGNC:15947	Mapping file id55075 NCBI file	EvidenceTAS
GeneUBXN11	AuthorityHGNC:30600	Mapping file id91544 NCBI file	EvidenceTAS
GeneUSP9X	AuthorityHGNC:12632	Mapping file id8239 NCBI file	EvidenceTAS
GeneVAMP3	AuthorityHGNC:12644	Mapping file id9341 NCBI file	EvidenceTAS
GeneVANGL1	AuthorityHGNC:15512	Mapping file id81839 NCBI file	EvidenceTAS
GeneVANGL2	AuthorityHGNC:15511	Mapping file id57216 NCBI file	EvidenceTAS
GeneVAPB	AuthorityHGNC:12649	Mapping file id9217 NCBI file	EvidenceTAS
GeneVAV1	AuthorityHGNC:12657	Mapping file id7409 NCBI file	EvidenceTAS
GeneVAV2	AuthorityHGNC:12658	Mapping file id7410 NCBI file	EvidenceTAS
GeneVAV3	AuthorityHGNC:12659	Mapping file id10451 NCBI file	EvidenceTAS
GeneVCP	AuthorityHGNC:12666	Mapping file id7415 NCBI file	EvidenceTAS
GeneVIM	AuthorityHGNC:12692	Mapping file id7431 NCBI file	EvidenceTAS
GeneVMA22	AuthorityHGNC:28178	Mapping file id84317 NCBI file	EvidenceTAS
GeneVRK2	AuthorityHGNC:12719	Mapping file id7444 NCBI file	EvidenceTAS
GeneWAS	AuthorityHGNC:12731	Mapping file id7454 NCBI file	EvidenceTAS
GeneWASF1	AuthorityHGNC:12732	Mapping file id8936 NCBI file	EvidenceTAS
GeneWASF2	AuthorityHGNC:12733	Mapping file id10163 NCBI file	EvidenceTAS
GeneWASF3	AuthorityHGNC:12734	Mapping file id10810 NCBI file	EvidenceTAS
GeneWASL	AuthorityHGNC:12735	Mapping file id8976 NCBI file	EvidenceTAS
GeneWDR11	AuthorityHGNC:13831	Mapping file id55717 NCBI file	EvidenceTAS
GeneWDR6	AuthorityHGNC:12758	Mapping file id11180 NCBI file	EvidenceTAS
GeneWDR81	AuthorityHGNC:26600	Mapping file id124997 NCBI file	EvidenceTAS
GeneWDR91	AuthorityHGNC:24997	Mapping file id29062 NCBI file	EvidenceTAS
GeneWHAMM	AuthorityHGNC:30493	Mapping file id123720 NCBI file	EvidenceTAS
GeneWIPF1	AuthorityHGNC:12736	Mapping file id7456 NCBI file	EvidenceTAS
GeneWIPF2	AuthorityHGNC:30923	Mapping file id147179 NCBI file	EvidenceTAS
GeneWIPF3	AuthorityHGNC:22004	Mapping file id644150 NCBI file	EvidenceTAS
GeneWWP2	AuthorityHGNC:16804	Mapping file id11060 NCBI file	EvidenceTAS
GeneYKT6	AuthorityHGNC:16959	Mapping file id10652 NCBI file	EvidenceTAS
GeneZAP70	AuthorityHGNC:12858	Mapping file id7535 NCBI file	EvidenceTAS
GeneZNF512B	AuthorityHGNC:29212	Mapping file id57473 NCBI file	EvidenceTAS

Evidence codes on this page: TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

RHO GTPase cycle

Reactome's own record of this pathway

Literature Reactome attaches

Genes Reactome places in this human pathway

Parents and children in this release's hierarchy

Parents

Children

Literature Reactome attaches