Signaling by Rho GTPases (Homo sapiens)

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25, 363, 7, 8, 10, 15...2, 9, 13, 19, 26...7, 10, 15, 18, 344, 5, 11, 12, 23...1, 6, 14, 16, 17, 20...Rho GTPases Rho GTPases cytosolRho GTPases Rho GTPases RhoBTB RhoGTPaseGTP Rac Rho GTPases RhoBTB RhoGTPaseGDP RhoGTPaseGDP Rac Rac RhoGTPaseGDP Inactivated RhoGTPaseGDPGDI complex RhoBTB RhoGTPaseGTPEffectors complex RhoBTB RhoBTB Rac Rac GDI proteins RAC2 RHOQ RHOV RhoGTPaseGTPRHOT1 RHOH RHOV GDP ARHGDIB GDPRHOBTB1 RHOU RHOG RHOT1 RHOF RHOJ RhoGTPaseGDPRHOT1 RHOBTB2 GDP ARHGDIA RHOH RHOA RHOA RHOB ARHGDIG RHOB RHOD RHOB RHOT2 RHOB RHOF RHOA RHOBTB1 RHOT2 GDP RHOBTB1 RHOV RAC3 RHOU RHOC CDC42 RHOH GTPInactivated RhoGTPaseGDPGDI complexRHOJ RHOC RAC2 GDI proteinsRHOD RhoGTPaseGDPRHOH GDI2 RHOF RAC2 PiRHOH RHOBTB2 RHOJ RHOG RHOJ RHOT1 RHOV RHOC RHOB effector proteinsRHOBTB1 GEFRHOD RHOJ RHOC RHOBTB2 RHOF RHOD RHOU RHOV RAC3 RHOQ RHOG RAC3 RHOT2 RHOG GTP RHOBTB1 CDC42 RHOA RHOG RHOBTB2 RAC2 RAC3 GAP proteinsCDC42 CDC42 RHOQ CDC42 RHOQ RhoGTPaseGTPEffectors complexRHOT2 RHOU RHOA GTP RHOBTB2 RHOT2 RHOU RAC2 RHOD RHOQ RHOC RHOT1 GDI1 RAC3 RHOF


Description

The Rho family of small guanine nucleotide binding proteins is one of five generally recognized branches of the Ras superfamily. Like most Ras superfamily members, typical Rho proteins function as binary switches controlling a variety of biological processes. They perform this function by cycling between active GTP-bound and inactive GDP-bound conformations. Mammalian Rho GTPases include RhoA, RhoB and RhoC (Rho proteins), Rac1 3 (Rac proteins), Cdc42, TC10, TCL, Wrch1, Chp/Wrch2, RhoD and RhoG, to name some. The family also includes RhoH and Rnd1-3, which lack GTPase activity and are predicted to exist in a constitutively active state.

Members of the Rho family have been identified in all eukaryotes. Including the atypical RHOBTB1-3 and RHOT1-2 proteins, 24 Rho family members have been identified in mammals (Jaffe and Hall, 2005; Bernards, 2005; Ridley, 2006). Among Rho GTPases, RhoA, Rac1 and Cdc42 have been most extensively studied. These proteins are best known for their ability to induce dynamic rearrangements of the plasma membrane-associated actin cytoskeleton (Aspenstrom et al, 2004; Murphy et al, 1999; Govek et al, 2005). Beyond this function, Rho GTPases also regulate actomyosin contractility and microtubule dynamics. Rho mediated effects on transcription and membrane trafficking are believed to be secondary to these functions. At the more macroscopic level, Rho GTPases have been implicated in many important cell biological processes, including cell growth control, cytokinesis, cell motility, cell cell and cell extracellular matrix adhesion, cell transformation and invasion, and development (Govek et al., 2005). The illustration below lists Rho GTPase effectors implicated in actin and microtubule dynamics (courtesy: Govek et al., 2005, Genes and Development, CSHL Press). Detailed annotations of various biological processes regulated by Rho GTPases will be available in future releases. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=194315</div>

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114825view16:32, 25 January 2021ReactomeTeamReactome version 75
113270view11:34, 2 November 2020ReactomeTeamReactome version 74
112483view15:43, 9 October 2020ReactomeTeamReactome version 73
101394view11:28, 1 November 2018ReactomeTeamreactome version 66
100932view21:04, 31 October 2018ReactomeTeamreactome version 65
100470view19:38, 31 October 2018ReactomeTeamreactome version 64
100016view16:21, 31 October 2018ReactomeTeamreactome version 63
99569view14:54, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99192view12:43, 31 October 2018ReactomeTeamreactome version 62
93909view13:44, 16 August 2017ReactomeTeamreactome version 61
93484view11:24, 9 August 2017ReactomeTeamreactome version 61
86580view09:21, 11 July 2016ReactomeTeamreactome version 56
83049view09:47, 18 November 2015ReactomeTeamVersion54
81350view12:52, 21 August 2015ReactomeTeamVersion53
76820view08:04, 17 July 2014ReactomeTeamFixed remaining interactions
76524view11:45, 16 July 2014ReactomeTeamFixed remaining interactions
75857view09:50, 11 June 2014ReactomeTeamRe-fixing comment source
75557view10:35, 10 June 2014ReactomeTeamReactome 48 Update
74912view13:44, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74556view08:35, 30 April 2014ReactomeTeamReactome46
68961view17:39, 8 July 2013MaintBotUpdated to 2013 gpml schema
45211view17:23, 7 October 2011KhanspersOntology Term : 'signaling pathway' added !
42133view21:59, 4 March 2011MaintBotAutomatic update
39943view05:57, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ARHGDIA ProteinP52565 (Uniprot-TrEMBL)
ARHGDIB ProteinP52566 (Uniprot-TrEMBL)
ARHGDIG ProteinQ99819 (Uniprot-TrEMBL)
CDC42 ProteinP60953 (Uniprot-TrEMBL)
GAP proteinsREACT_10748 (Reactome)
GDI proteinsProteinREACT_10263 (Reactome)
GDI1 ProteinP31150 (Uniprot-TrEMBL)
GDI2 ProteinP50395 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GEFREACT_10196 (Reactome)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
Inactivated RhoGTPase

GDP

GDI complex		ComplexREACT_10882 (Reactome)
PiMetaboliteCHEBI:18367 (ChEBI)
RAC2 ProteinP15153 (Uniprot-TrEMBL)
RAC3 ProteinP60763 (Uniprot-TrEMBL)
RHOA ProteinP61586 (Uniprot-TrEMBL)
RHOB ProteinP62745 (Uniprot-TrEMBL)
RHOBTB1 ProteinO94844 (Uniprot-TrEMBL)
RHOBTB2 ProteinQ9BYZ6 (Uniprot-TrEMBL)
RHOC ProteinP08134 (Uniprot-TrEMBL)
RHOD ProteinO00212 (Uniprot-TrEMBL)
RHOF ProteinQ9HBH0 (Uniprot-TrEMBL)
RHOG ProteinP84095 (Uniprot-TrEMBL)
RHOH ProteinQ15669 (Uniprot-TrEMBL)
RHOJ ProteinQ9H4E5 (Uniprot-TrEMBL)
RHOQ ProteinP17081 (Uniprot-TrEMBL)
RHOT1 ProteinQ8IXI2 (Uniprot-TrEMBL)
RHOT2 ProteinQ8IXI1 (Uniprot-TrEMBL)
RHOU ProteinQ7L0Q8 (Uniprot-TrEMBL)
RHOV ProteinQ96L33 (Uniprot-TrEMBL)
RhoGTPase GDPComplexREACT_10155 (Reactome)
RhoGTPase GDPComplexREACT_10889 (Reactome)
RhoGTPase

GTP

Effectors complex		ComplexREACT_10149 (Reactome)
RhoGTPase GTPComplexREACT_10731 (Reactome)
effector proteinsREACT_10469 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
GAP proteinsmim-catalysisREACT_9982 (Reactome)
GDI proteinsArrowREACT_10051 (Reactome)
GDI proteinsREACT_10055 (Reactome)
GDPArrowREACT_10098 (Reactome)
GEFmim-catalysisREACT_10098 (Reactome)
GTPREACT_10098 (Reactome)
PiArrowREACT_9982 (Reactome)
REACT_10051 (Reactome) GDIs sequester the inactive GTPases, preventing the dissociation of GDP and interactions with regulatory and effector molecules. They maintain Rho GTPases as soluble cytosolic proteins by forming high affinity complexes. In these complexes, the geranylgeranyl membrane targeting moiety present at the C terminus of the Rho GTPases is shielded from the solvent by its insertion into the hydrophobic pocket formed by the immunoglobulin like beta sandwich of the GDI (DerMardirossian and Bokoch, 2005).

Rho proteins, when released from the sequestering cytosolic GDIs, insert into the lipid bilayer of the plasma membrane with their isoprenylated C termini. The membrane bound GEFs activate these free RhoGTPases and thereby trigger the downstream signaling events via respective effector proteins on the membrane (Robbe et al., 2003). Detailed annotation of the activities of farnesyltransferase / geranylgeranyltransferases on prenylation of Rho GTPases thereby enabling their subsequent localization to plasma membrane will be available in future releases.

REACT_10055 (Reactome) GDP dissociation inhibitors or GDIs confer an additional but important layer of Rho GTPase regulation along with GEFs and GAPs. GDIs mainly inhibit the dissociation of bound guanine nucleotide (usually GDP) from their partner GTPases. So far, three human GDIs with proven biological functions have been found: RhoGDI/GDIalpha/GDI1, hematopoietic cell selective Ly/D4GDI/GDIbeta/GDI2, and Rho GDIgamma/GDI3 (DerMardirossian and Bokoch, 2005). Three specific biochemical functions of GDIs have been established: inhibiting the dissociation of GDP from Rho proteins, maintaining the GTPases in an inactive form, and preventing GTPase activation by GEFs (Olofsson, 1999). Detailed annotations of GDIs will be available in future releases.
REACT_10098 (Reactome) Guanine nucleotide exchange factors (GEFs) activate GTPases by enhancing the exchange of bound GDP for GTP. Much evidence points to GEFs being critical mediators of Rho GTPase activation (Schmidt and Hall, 2002). Many GEFs are known to be highly specific for a particular GTPase, e.g. Fgd1/Cdc42 and p115RhoGEF/Rho (Hart et al., 1996, Zheng et al., 1996). Others have a broader spectrum and activate several GTPases, e.g. Vav1 for Rac, Rho, and Cdc42 (Hart et al, 1994).
REACT_10126 (Reactome) To transduce signals, the activated, GTP-bound Rho GTPases interact with specific effector molecules. It has been observed that GEFs contribute to the signaling specificity of their downstream target GTPase via association with scaffolding molecules that link them and the GTPase to specific GTPase effectors (Govek et al., 2005). Some of the effector molecules implicated in actin and microtubule dynamics include diaphanous-related formins, Toca 1, WIP, WASP, Pak, p35/Cdk5, Wave, Nap125, MLCK, MLC, IRSp53. Detailed annotations of the downstream events stimulated by activated, GTP bound Rho GTPases will be available in future releases.
REACT_9982 (Reactome) The human genome includes approximately 70 genes that are predicted to encode Rho-specific GTPase Activating Proteins (RhoGAPs). As in the case of GEFs, some RhoGAPs are believed to be highly specific, whereas others are more promiscuous with respect to their target GTPases. Increasing evidence suggests that GAPs are also regulated by external cues in addition to being signal terminators leading to Rho GTPase inactivation. These proteins play important role in many Rho mediated signaling pathways.

Some known GAPs include p190 A, cdGAP, ARAP3, MgcRacGAP, Chimaerin, Nadrin, TCGAP, DLC 1, 2, ArhGAP6, Myosin IXA. These and other GAPs have been implicated in many processes, such as exocytosis, endocytosis, cytokinesis, cell differentiation, migration, neuronal morphogenesis, angiogenesis and tumor suppression. Detailed annotations of the biological role of GAPs in Rho mediated signaling will be available in future releases.

RhoGTPase GDPArrowREACT_10051 (Reactome)
RhoGTPase GDPArrowREACT_9982 (Reactome)
RhoGTPase GDPREACT_10055 (Reactome)
RhoGTPase GDPREACT_10098 (Reactome)
RhoGTPase GTPArrowREACT_10098 (Reactome)
RhoGTPase GTPREACT_10126 (Reactome)
effector proteinsREACT_10126 (Reactome)

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