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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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).

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 101 to 200, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 2 of 5
Gene	Authority id	Mapping file id	Evidence codes
GeneCAVIN1	AuthorityHGNC:9688	Mapping file id284119 NCBI file	EvidenceTAS
GeneCCDC187	AuthorityHGNC:30942	Mapping file id399693 NCBI file	EvidenceTAS
GeneCCDC88A	AuthorityHGNC:25523	Mapping file id55704 NCBI file	EvidenceTAS
GeneCCP110	AuthorityHGNC:24342	Mapping file id9738 NCBI file	EvidenceTAS
GeneCCT2	AuthorityHGNC:1615	Mapping file id10576 NCBI file	EvidenceTAS
GeneCCT6A	AuthorityHGNC:1620	Mapping file id908 NCBI file	EvidenceTAS
GeneCCT7	AuthorityHGNC:1622	Mapping file id10574 NCBI file	EvidenceTAS
GeneCDC37	AuthorityHGNC:1735	Mapping file id11140 NCBI file	EvidenceTAS
GeneCDC42	AuthorityHGNC:1736	Mapping file id998 NCBI file	EvidenceTAS
GeneCDC42BPA	AuthorityHGNC:1737	Mapping file id8476 NCBI file	EvidenceTAS
GeneCDC42BPB	AuthorityHGNC:1738	Mapping file id9578 NCBI file	EvidenceTAS
GeneCDC42EP1	AuthorityHGNC:17014	Mapping file id11135 NCBI file	EvidenceTAS
GeneCDC42EP2	AuthorityHGNC:16263	Mapping file id10435 NCBI file	EvidenceTAS
GeneCDC42EP3	AuthorityHGNC:16943	Mapping file id10602 NCBI file	EvidenceTAS
GeneCDC42EP4	AuthorityHGNC:17147	Mapping file id23580 NCBI file	EvidenceTAS
GeneCDC42EP5	AuthorityHGNC:17408	Mapping file id148170 NCBI file	EvidenceTAS
GeneCDC42SE2	AuthorityHGNC:18547	Mapping file id56990 NCBI file	EvidenceTAS
GeneCEP97	AuthorityHGNC:26244	Mapping file id79598 NCBI file	EvidenceTAS
GeneCFTR	AuthorityHGNC:1884	Mapping file id1080 NCBI file	EvidenceTAS
GeneCHN1	AuthorityHGNC:1943	Mapping file id1123 NCBI file	EvidenceTAS
GeneCHN2	AuthorityHGNC:1944	Mapping file id1124 NCBI file	EvidenceTAS
GeneCIT	AuthorityHGNC:1985	Mapping file id11113 NCBI file	EvidenceTAS
GeneCKAP4	AuthorityHGNC:16991	Mapping file id10970 NCBI file	EvidenceTAS
GeneCKB	AuthorityHGNC:1991	Mapping file id1152 NCBI file	EvidenceTAS
GeneCLTC	AuthorityHGNC:2092	Mapping file id1213 NCBI file	EvidenceTAS
GeneCOPS2	AuthorityHGNC:30747	Mapping file id9318 NCBI file	EvidenceTAS
GeneCOPS4	AuthorityHGNC:16702	Mapping file id51138 NCBI file	EvidenceTAS
GeneCPD	AuthorityHGNC:2301	Mapping file id1362 NCBI file	EvidenceTAS
GeneCPNE8	AuthorityHGNC:23498	Mapping file id144402 NCBI file	EvidenceTAS
GeneCPSF7	AuthorityHGNC:30098	Mapping file id79869 NCBI file	EvidenceTAS
GeneCSK	AuthorityHGNC:2444	Mapping file id1445 NCBI file	EvidenceTAS
GeneCUL3	AuthorityHGNC:2553	Mapping file id8452 NCBI file	EvidenceTAS
GeneCYBA	AuthorityHGNC:2577	Mapping file id1535 NCBI file	EvidenceTAS
GeneCYBB	AuthorityHGNC:2578	Mapping file id1536 NCBI file	EvidenceTAS
GeneCYFIP1	AuthorityHGNC:13759	Mapping file id23191 NCBI file	EvidenceTAS
GeneCYFIP2	AuthorityHGNC:13760	Mapping file id26999 NCBI file	EvidenceTAS
GeneDAAM1	AuthorityHGNC:18142	Mapping file id23002 NCBI file	EvidenceTAS
GeneDBN1	AuthorityHGNC:2695	Mapping file id1627 NCBI file	EvidenceTAS
GeneDBT	AuthorityHGNC:2698	Mapping file id1629 NCBI file	EvidenceTAS
GeneDDRGK1	AuthorityHGNC:16110	Mapping file id65992 NCBI file	EvidenceTAS
GeneDDX39B	AuthorityHGNC:13917	Mapping file id7919 NCBI file	EvidenceTAS
GeneDDX4	AuthorityHGNC:18700	Mapping file id54514 NCBI file	EvidenceTAS
GeneDEF6	AuthorityHGNC:2760	Mapping file id50619 NCBI file	EvidenceTAS
GeneDEPDC1B	AuthorityHGNC:24902	Mapping file id55789 NCBI file	EvidenceTAS
GeneDIAPH1	AuthorityHGNC:2876	Mapping file id1729 NCBI file	EvidenceTAS
GeneDIAPH2	AuthorityHGNC:2877	Mapping file id1730 NCBI file	EvidenceTAS
GeneDIAPH3	AuthorityHGNC:15480	Mapping file id81624 NCBI file	EvidenceTAS
GeneDLC1	AuthorityHGNC:2897	Mapping file id10395 NCBI file	EvidenceTAS
GeneDLG5	AuthorityHGNC:2904	Mapping file id9231 NCBI file	EvidenceTAS
GeneDNMBP	AuthorityHGNC:30373	Mapping file id23268 NCBI file	EvidenceTAS
GeneDOCK1	AuthorityHGNC:2987	Mapping file id1793 NCBI file	EvidenceTAS
GeneDOCK10	AuthorityHGNC:23479	Mapping file id55619 NCBI file	EvidenceTAS
GeneDOCK11	AuthorityHGNC:23483	Mapping file id139818 NCBI file	EvidenceTAS
GeneDOCK2	AuthorityHGNC:2988	Mapping file id1794 NCBI file	EvidenceTAS
GeneDOCK3	AuthorityHGNC:2989	Mapping file id1795 NCBI file	EvidenceTAS
GeneDOCK4	AuthorityHGNC:19192	Mapping file id9732 NCBI file	EvidenceTAS
GeneDOCK5	AuthorityHGNC:23476	Mapping file id80005 NCBI file	EvidenceTAS
GeneDOCK6	AuthorityHGNC:19189	Mapping file id57572 NCBI file	EvidenceTAS
GeneDOCK7	AuthorityHGNC:19190	Mapping file id85440 NCBI file	EvidenceTAS
GeneDOCK8	AuthorityHGNC:19191	Mapping file id81704 NCBI file	EvidenceTAS
GeneDOCK9	AuthorityHGNC:14132	Mapping file id23348 NCBI file	EvidenceTAS
GeneDSG1	AuthorityHGNC:3048	Mapping file id1828 NCBI file	EvidenceTAS
GeneDSG2	AuthorityHGNC:3049	Mapping file id1829 NCBI file	EvidenceTAS
GeneDSP	AuthorityHGNC:3052	Mapping file id1832 NCBI file	EvidenceTAS
GeneDST	AuthorityHGNC:1090	Mapping file id667 NCBI file	EvidenceTAS
GeneECT2	AuthorityHGNC:3155	Mapping file id1894 NCBI file	EvidenceTAS
GeneEFHD2	AuthorityHGNC:28670	Mapping file id79180 NCBI file	EvidenceTAS
GeneELMO2	AuthorityHGNC:17233	Mapping file id63916 NCBI file	EvidenceTAS
GeneEMC3	AuthorityHGNC:23999	Mapping file id55831 NCBI file	EvidenceTAS
GeneEMD	AuthorityHGNC:3331	Mapping file id2010 NCBI file	EvidenceTAS
GeneEPHA2	AuthorityHGNC:3386	Mapping file id1969 NCBI file	EvidenceTAS
GeneEPSTI1	AuthorityHGNC:16465	Mapping file id94240 NCBI file	EvidenceTAS
GeneERBIN	AuthorityHGNC:15842	Mapping file id55914 NCBI file	EvidenceTAS
GeneESYT1	AuthorityHGNC:29534	Mapping file id23344 NCBI file	EvidenceTAS
GeneFAF2	AuthorityHGNC:24666	Mapping file id23197 NCBI file	EvidenceTAS
GeneFAM135A	AuthorityHGNC:21084	Mapping file id57579 NCBI file	EvidenceTAS
GeneFAM13A	AuthorityHGNC:19367	Mapping file id10144 NCBI file	EvidenceTAS
GeneFAM13B	AuthorityHGNC:1335	Mapping file id51306 NCBI file	EvidenceTAS
GeneFAM169A	AuthorityHGNC:29138	Mapping file id26049 NCBI file	EvidenceTAS
GeneFAM91A1	AuthorityHGNC:26306	Mapping file id157769 NCBI file	EvidenceTAS
GeneFARP1	AuthorityHGNC:3591	Mapping file id10160 NCBI file	EvidenceTAS
GeneFARP2	AuthorityHGNC:16460	Mapping file id9855 NCBI file	EvidenceTAS
GeneFERMT2	AuthorityHGNC:15767	Mapping file id10979 NCBI file	EvidenceTAS
GeneFGD1	AuthorityHGNC:3663	Mapping file id2245 NCBI file	EvidenceTAS
GeneFGD2	AuthorityHGNC:3664	Mapping file id221472 NCBI file	EvidenceTAS
GeneFGD3	AuthorityHGNC:16027	Mapping file id89846 NCBI file	EvidenceTAS
GeneFGD4	AuthorityHGNC:19125	Mapping file id121512 NCBI file	EvidenceTAS
GeneFGD5	AuthorityHGNC:19117	Mapping file id152273 NCBI file	EvidenceTAS
GeneFILIP1	AuthorityHGNC:21015	Mapping file id27145 NCBI file	EvidenceTAS
GeneFLOT1	AuthorityHGNC:3757	Mapping file id10211 NCBI file	EvidenceTAS
GeneFLOT2	AuthorityHGNC:3758	Mapping file id2319 NCBI file	EvidenceTAS
GeneFMNL1	AuthorityHGNC:1212	Mapping file id752 NCBI file	EvidenceTAS
GeneFMNL2	AuthorityHGNC:18267	Mapping file id114793 NCBI file	EvidenceTAS
GeneFMNL3	AuthorityHGNC:23698	Mapping file id91010 NCBI file	EvidenceTAS
GeneFNBP1	AuthorityHGNC:17069	Mapping file id23048 NCBI file	EvidenceTAS
GeneFNBP1L	AuthorityHGNC:20851	Mapping file id54874 NCBI file	EvidenceTAS
GeneFRS2	AuthorityHGNC:16971	Mapping file id10818 NCBI file	EvidenceTAS
GeneFRS3	AuthorityHGNC:16970	Mapping file id10817 NCBI file	EvidenceTAS
GeneGARRE1	AuthorityHGNC:29016	Mapping file id9710 NCBI file	EvidenceTAS
GeneGFOD1	AuthorityHGNC:21096	Mapping file id54438 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

Genes Reactome places in this human pathway

Parents and children in this release's hierarchy

Parents

Children

Literature Reactome attaches