Signaling by Rho GTPases (Homo sapiens)

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2, 1615, 24-26, 29...3, 5, 8, 13, 18...1, 4, 6-8, 14...9-12, 17, 19...11, 19, 21, 28, 32Rho GTPases [plasmamembrane]Rho GTPases[cytosol]Rho GTPases [plasmamembrane]Rho GTPases [plasmamembrane]RhoGTPase:GTP:Effectorscomplex [plasmamembrane]RhoBTB [plasmamembrane]GDI proteins[cytosol]cytosolRac [plasmamembrane]RhoBTB [plasmamembrane]Rac [cytosol]Rac [cytosol]Rho GTPases[cytosol]RhoGTPase:GTP[plasma membrane]Rac [plasmamembrane]RhoGTPase:GDP[cytosol]RhoBTB [plasmamembrane]Rac [plasmamembrane]RhoBTB [cytosol]RhoGTPase:GDP[plasma membrane]RhoGTPase:GDP[cytosol]RhoBTB [cytosol]InactivatedRhoGTPase:GDP:GDIcomplex [cytosol]GDPRHOBTB1 [cytosol]CDC42 [cytosol]RHOT2 [cytosol]RHOB [cytosol]RHOQ [cytosol]RHOH [cytosol]RAC2 [plasmamembrane]CDC42 [plasmamembrane]RHOF [cytosol]RHOF [cytosol]RHOV [plasmamembrane]RHOBTB1 [plasmamembrane]RHOBTB1 [plasmamembrane]RHOBTB2 [cytosol]RHOT1 [plasmamembrane]RAC2 [plasmamembrane]RHOJ [plasmamembrane]RHOBTB1 [cytosol]RHOG [cytosol]RHOH [plasmamembrane]RHOT1 [cytosol]CDC42 [plasmamembrane]RHOD [cytosol]RHOG [cytosol]GDP [plasmamembrane]RHOA [cytosol]effector proteinsGAP proteinsRHOU [cytosol]RHOH [plasmamembrane]GDI1 [cytosol]RAC2 [cytosol]GEFRhoGTPase:GDPRHOT2 [plasmamembrane]GTPRAC2 [cytosol]RHOU [plasmamembrane]RHOC [plasmamembrane]RHOT1 [cytosol]RHOJ [plasmamembrane]RAC3 [plasmamembrane]RHOV [plasmamembrane]RHOV [plasmamembrane]RHOV [cytosol]RHOBTB2 [plasmamembrane]ARHGDIG [cytosol]RHOB [plasmamembrane]RHOB [cytosol]RHOC [cytosol]RAC3 [plasmamembrane]RHOG [plasmamembrane]RHOBTB2 [plasmamembrane]CDC42 [cytosol]RHOQ [cytosol]GDP [cytosol]RHOF [plasmamembrane]RhoGTPase:GDPGTP [plasmamembrane]RAC3 [cytosol]RHOA [plasmamembrane]RHOBTB2 [cytosol]RHOG [plasmamembrane]RHOC [plasmamembrane]RHOH [cytosol]GDI proteinsRHOQ [plasmamembrane]RHOF [plasmamembrane]RHOC [plasmamembrane]InactivatedRhoGTPase:GDP:GDIcomplexCDC42 [plasmamembrane]RHOC [cytosol]RHOT1 [plasmamembrane]RAC3 [plasmamembrane]GTP [plasmamembrane]RHOJ [cytosol]RHOG [plasmamembrane]RHOU [plasmamembrane]RHOQ [plasmamembrane]GDI2 [cytosol]RHOT2 [cytosol]GDP [cytosol]RHOB [plasmamembrane]RHOT1 [plasmamembrane]RHOA [plasmamembrane]RHOA [cytosol]RHOBTB2 [plasmamembrane]RHOBTB1 [plasmamembrane]RHOT2 [plasmamembrane]RHOU [cytosol]RHOD [plasmamembrane]RHOD [plasmamembrane]ARHGDIA [cytosol]RHOV [cytosol]RAC2 [plasmamembrane]RHOD [plasmamembrane]RHOD [cytosol]RHOU [plasmamembrane]RHOQ [plasmamembrane]RHOJ [cytosol]RHOA [plasmamembrane]RAC3 [cytosol]RHOF [plasmamembrane]RHOH [plasmamembrane]RhoGTPase:GTP:EffectorscomplexPiARHGDIB [cytosol]RhoGTPase:GTPRHOB [plasmamembrane]RHOT2 [plasmamembrane]RHOJ [plasmamembrane]


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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History

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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 [cytosol]ProteinP52565 (Uniprot-TrEMBL)
ARHGDIB [cytosol]ProteinP52566 (Uniprot-TrEMBL)
ARHGDIG [cytosol]ProteinQ99819 (Uniprot-TrEMBL)
CDC42 [cytosol]ProteinP60953 (Uniprot-TrEMBL)
CDC42 [plasma membrane]ProteinP60953 (Uniprot-TrEMBL)
GAP proteinsREACT_10748 (Reactome)
GDI proteinsProteinREACT_10263 (Reactome)
GDI1 [cytosol]ProteinP31150 (Uniprot-TrEMBL)
GDI2 [cytosol]ProteinP50395 (Uniprot-TrEMBL)
GDP [cytosol]MetaboliteCHEBI:17552 (ChEBI)
GDP [plasma membrane]MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GEFREACT_10196 (Reactome)
GTP [plasma membrane]MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
Inactivated

RhoGTPase:GDP:GDI

complex
ComplexREACT_10882 (Reactome)
PiMetaboliteCHEBI:18367 (ChEBI)
RAC2 [cytosol]ProteinP15153 (Uniprot-TrEMBL)
RAC2 [plasma membrane]ProteinP15153 (Uniprot-TrEMBL)
RAC3 [cytosol]ProteinP60763 (Uniprot-TrEMBL)
RAC3 [plasma membrane]ProteinP60763 (Uniprot-TrEMBL)
RHOA [cytosol]ProteinP61586 (Uniprot-TrEMBL)
RHOA [plasma membrane]ProteinP61586 (Uniprot-TrEMBL)
RHOB [cytosol]ProteinP62745 (Uniprot-TrEMBL)
RHOB [plasma membrane]ProteinP62745 (Uniprot-TrEMBL)
RHOBTB1 [cytosol]ProteinO94844 (Uniprot-TrEMBL)
RHOBTB1 [plasma membrane]ProteinO94844 (Uniprot-TrEMBL)
RHOBTB2 [cytosol]ProteinQ9BYZ6 (Uniprot-TrEMBL)
RHOBTB2 [plasma membrane]ProteinQ9BYZ6 (Uniprot-TrEMBL)
RHOC [cytosol]ProteinP08134 (Uniprot-TrEMBL)
RHOC [plasma membrane]ProteinP08134 (Uniprot-TrEMBL)
RHOD [cytosol]ProteinO00212 (Uniprot-TrEMBL)
RHOD [plasma membrane]ProteinO00212 (Uniprot-TrEMBL)
RHOF [cytosol]ProteinQ9HBH0 (Uniprot-TrEMBL)
RHOF [plasma membrane]ProteinQ9HBH0 (Uniprot-TrEMBL)
RHOG [cytosol]ProteinP84095 (Uniprot-TrEMBL)
RHOG [plasma membrane]ProteinP84095 (Uniprot-TrEMBL)
RHOH [cytosol]ProteinQ15669 (Uniprot-TrEMBL)
RHOH [plasma membrane]ProteinQ15669 (Uniprot-TrEMBL)
RHOJ [cytosol]ProteinQ9H4E5 (Uniprot-TrEMBL)
RHOJ [plasma membrane]ProteinQ9H4E5 (Uniprot-TrEMBL)
RHOQ [cytosol]ProteinP17081 (Uniprot-TrEMBL)
RHOQ [plasma membrane]ProteinP17081 (Uniprot-TrEMBL)
RHOT1 [cytosol]ProteinQ8IXI2 (Uniprot-TrEMBL)
RHOT1 [plasma membrane]ProteinQ8IXI2 (Uniprot-TrEMBL)
RHOT2 [cytosol]ProteinQ8IXI1 (Uniprot-TrEMBL)
RHOT2 [plasma membrane]ProteinQ8IXI1 (Uniprot-TrEMBL)
RHOU [cytosol]ProteinQ7L0Q8 (Uniprot-TrEMBL)
RHOU [plasma membrane]ProteinQ7L0Q8 (Uniprot-TrEMBL)
RHOV [cytosol]ProteinQ96L33 (Uniprot-TrEMBL)
RHOV [plasma membrane]ProteinQ96L33 (Uniprot-TrEMBL)
RhoGTPase:GDPComplexREACT_10155 (Reactome)
RhoGTPase:GDPComplexREACT_10889 (Reactome)
RhoGTPase:GTP:Effectors complexComplexREACT_10149 (Reactome)
RhoGTPase:GTPComplexREACT_10731 (Reactome)
effector proteinsREACT_10469 (Reactome)

Annotated Interactions

View all...
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)
Inactivated

RhoGTPase:GDP:GDI

complex
ArrowREACT_10055 (Reactome)
Inactivated

RhoGTPase:GDP:GDI

complex
REACT_10051 (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:GTP:Effectors complexArrowREACT_10126 (Reactome)
RhoGTPase:GTPArrowREACT_10098 (Reactome)
RhoGTPase:GTPREACT_10126 (Reactome)
RhoGTPase:GTPREACT_9982 (Reactome)
effector proteinsREACT_10126 (Reactome)

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