Signaling by Rho GTPases (Homo sapiens)

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49, 6019, 20, 28, 39, 56...7, 47, 50, 92, 10129, 33, 35, 47, 50...2, 9, 12, 23, 62...1, 44, 49, 66, 73...cytosolRHOBTB2 RHOBTB2 RHOBTB2 PiRHOD CDC42 RHOQ RHOG RAC3 RHOJ RHOBTB1 RHOF RHOB RHOG RHOT1 RHO GTPase EffectorsRAC1 RHOB RHOT1 RhoGTPase:GDPRHOU CDC42 GDP RHOJ RAC3 RHOC RHOA RHOC RHOU effector proteinsRAC2 GTP RHOF ARHGDIG RHOF RAC1 RHOT1 RHOT2 RhoGTPase:GTPRHOV GDP RHOC GDPRAC2 RHOV RHOBTB2 RAC3 RHOV RHOU RHOD RhoGTPase:GDPRHOQ RHOJ RHOF RHOBTB1 RHOG RHOBTB2 RHOJ RHOT1 RHOQ RHOU RhoGTPase:GTP:Effectors complexRHOA RHOA GDI proteinsRHOC CDC42 RHOT2 RHOH CDC42 RHOA RHOBTB1 RHOF RHOT2 RHOT2 RHOB GTPRHOD RHOD RHOBTB1 GDI1 GDP ARHGDIB GAP proteinsRHOQ RHOJ RAC2 RHOV RHOH RAC3 GTP GDI2 RHOG RHOC InactivatedRhoGTPase:GDP:GDIcomplexGEFCDC42 RHOB RAC1 RAC1 RHOU RHOH RHOH RHOV RHOA RAC2 RAC3 RHOT1 RHOQ RHOB RHOD RHOBTB1 RHOG RAC2 RHOT2 RHOH RAC1 ARHGDIA 3-6, 8, 10...


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. Source:Reactome.</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

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NameTypeDatabase referenceComment
ARHGDIA ProteinP52565 (Uniprot-TrEMBL)
ARHGDIB ProteinP52566 (Uniprot-TrEMBL)
ARHGDIG ProteinQ99819 (Uniprot-TrEMBL)
CDC42 ProteinP60953 (Uniprot-TrEMBL)
GAP proteinsR-HSA-194904 (Reactome)
GDI proteinsR-HSA-194862 (Reactome)
GDI1 ProteinP31150 (Uniprot-TrEMBL)
GDI2 ProteinP50395 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GEFR-HSA-194849 (Reactome)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
Inactivated

RhoGTPase:GDP:GDI

complex		ComplexR-HSA-194912 (Reactome)
PiMetaboliteCHEBI:18367 (ChEBI)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC2 ProteinP15153 (Uniprot-TrEMBL)
RAC3 ProteinP60763 (Uniprot-TrEMBL)
RHO GTPase EffectorsPathwayR-HSA-195258 (Reactome) RHO GTPases regulate cell behaviour by activating a number of downstream effectors that regulate cytoskeletal organization, intracellular trafficking and transcription (reviewed by Sahai and Marshall 2002).

One of the best studied RHO GTPase effectors are protein kinases ROCK1 and ROCK2, which are activated by binding RHOA, RHOB or RHOC. ROCK1 and ROCK2 phosphorylate many proteins involved in the stabilization of actin filaments and generation of actin-myosin contractile force, such as LIM kinases and myosin regulatory light chains (MRLC) (Amano et al. 1996, Ishizaki et al. 1996, Leung et al. 1996, Ohashi et al. 2000, Sumi et al. 2001, Riento and Ridley 2003, Watanabe et al. 2007).

PAK1, PAK2 and PAK3, members of the p21-activated kinase family, are activated by binding to RHO GTPases RAC1 and CDC42 and subsequent autophosphorylation and are involved in cytoskeleton regulation (Manser et al. 1994, Manser et al. 1995, Zhang et al. 1998, Edwards et al. 1999, Lei et al. 2000, Parrini et al. 2002; reviewed by Daniels and Bokoch 1999, Szczepanowska 2009).

RHOA, RHOB, RHOC and RAC1 activate protein kinase C related kinases (PKNs) PKN1, PKN2 and PKN3 (Maesaki et al. 1999, Zong et al. 1999, Owen et al. 2003, Modha et al. 2008, Hutchinson et al. 2011, Hutchinson et al. 2013), bringing them in proximity to the PIP3-activated PDPK1 (PDK1) and thus enabling PDPK1-mediated phosphorylation of PKN1, PKN2 and PKN3 (Flynn et al. 2000, Torbett et al. 2003). PKNs play important roles in cytoskeleton organization (Hamaguchi et al. 2000), regulation of cell cycle (Misaki et al. 2001), receptor trafficking (Metzger et al. 2003) and apoptosis (Takahashi et al. 1998). PKN1 is also involved in the ligand-dependent transcriptional activation by the androgen receptor (Metzger et al. 2003, Metzger et al. 2005, Metzger et al. 2008).

Citron kinase (CIT) binds RHO GTPases RHOA, RHOB, RHOC and RAC1 (Madaule et al. 1995), but the mechanism of CIT activation by GTP-bound RHO GTPases has not been elucidated. CIT and RHOA are implicated to act together in Golgi apparatus organization through regulation of the actin cytoskeleton (Camera et al. 2003). CIT is also involved in the regulation of cytokinesis through its interaction with KIF14 (Gruneberg et al. 2006, Bassi et al. 2013, Watanabe et al. 2013).

RHOA, RHOG, RAC1 and CDC42 bind kinectin (KTN1), a kinesin anchor protein involved in kinesin-mediated vesicle motility (Vignal et al. 2001, Hotta et al. 1996). The effect of RHOG activity on cellular morphology, exhibited in the formation of microtubule-dependent cellular protrusions, depends both on RHOG interaction with KTN1, as well as on the kinesin activity (Vignal et al. 2001). RHOG and KTN1 also cooperate in microtubule-dependent lysosomal transport (Vignal et al. 2001).

IQGAP proteins IQGAP1, IQGAP2 and IQGAP3, bind RAC1 and CDC42 and stabilize them in their GTP-bound state (Kuroda et al. 1996, Swart-Mataraza et al. 2002, Wang et al. 2007). IQGAPs bind F-actin filaments and modulate cell shape and motility through regulation of G-actin/F-actin equilibrium (Brill et al. 1996, Fukata et al. 1997, Bashour et al. 1997, Wang et al. 2007, Pelikan-Conchaudron et al. 2011). Binding of IQGAPs to F-actin is inhibited by calmodulin (Bashour et al. 1997, Pelikan-Conchaudron et al. 2011). IQGAP1 is involved in the regulation of adherens junctions through its interaction with E-cadherin (CDH1) and catenins (CTTNB1 and CTTNA1) (Kuroda et al. 1998, Hage et al. 2009). IQGAP1 contributes to cell polarity and lamellipodia formation through its interaction with microtubules (Fukata et al. 2002, Suzuki and Takahashi 2008).

RHOQ (TC10) regulates the trafficking of CFTR (cystic fibrosis transmembrane conductance regulator) by binding to the Golgi-associated protein GOPC (also known as PIST, FIG and CAL). In the absence of RHOQ, GOPC bound to CFTR directs CFTR for lysosomal degradation, while GTP-bound RHOQ directs GOPC:CFTR complex to the plasma membrane, thereby rescuing CFTR (Neudauer et al. 2001, Cheng et al. 2005).

RAC1 and CDC42 activate WASP and WAVE proteins, members of the Wiskott-Aldrich Syndrome protein family. WASPs and WAVEs simultaneously interact with G-actin and the actin-related ARP2/3 complex, acting as nucleation promoting factors in actin polymerization (reviewed by Lane et al. 2014).

RHOA, RHOB, RHOC, RAC1 and CDC42 activate a subset of formin family members. Once activated, formins bind G-actin and the actin-bound profilins and accelerate actin polymerization, while some formins also interact with microtubules. Formin-mediated cytoskeletal reorganization plays important roles in cell motility, organelle trafficking and mitosis (reviewed by Kuhn and Geyer 2014).

Rhotekin (RTKN) and rhophilins (RHPN1 and RHPN2) are effectors of RHOA, RHOB and RHOC and have not been studied in detail. They regulate the organization of the actin cytoskeleton and are implicated in the establishment of cell polarity, cell motility and possibly endosome trafficking (Sudo et al. 2006, Watanabe et al. 1996, Fujita et al. 2000, Peck et al. 2002, Mircescu et al. 2002). Similar to formins (Miralles et al. 2003), cytoskeletal changes triggered by RTKN activation may lead to stimulation of SRF-mediated transcription (Reynaud et al. 2000).

RHO GTPases RAC1 and RAC2 are needed for activation of NADPH oxidase complexes 1, 2 and 3 (NOX1, NOX2 and NOX3), membrane associated enzymatic complexes that use NADPH as an electron donor to reduce oxygen and produce superoxide (O2-). Superoxide serves as a secondary messenger and also directly contributes to the microbicidal activity of neutrophils (Knaus et al. 1991, Roberts et al. 1999, Kim and Dinauer 2001, Jyoti et al. 2014, Cheng et al. 2006, Miyano et al. 2006, Ueyama et al. 2006).

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:GDPComplexR-HSA-194900 (Reactome)
RhoGTPase:GDPComplexR-HSA-194915 (Reactome)
RhoGTPase:GTP:Effectors complexComplexR-HSA-194875 (Reactome)
RhoGTPase:GTPComplexR-HSA-194890 (Reactome)
effector proteinsR-HSA-194872 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
GAP proteinsmim-catalysisR-HSA-194922 (Reactome)
GDI proteinsArrowR-HSA-195146 (Reactome)
GDI proteinsR-HSA-194854 (Reactome)
GDPArrowR-HSA-194913 (Reactome)
GEFmim-catalysisR-HSA-194913 (Reactome)
GTPR-HSA-194913 (Reactome)
Inactivated

RhoGTPase:GDP:GDI

complex		ArrowR-HSA-194854 (Reactome)
Inactivated

RhoGTPase:GDP:GDI

complex		R-HSA-195146 (Reactome)
PiArrowR-HSA-194922 (Reactome)
R-HSA-194854 (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.
R-HSA-194894 (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.
R-HSA-194913 (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).
R-HSA-194922 (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.

R-HSA-195146 (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.

RhoGTPase:GDPArrowR-HSA-194922 (Reactome)
RhoGTPase:GDPArrowR-HSA-195146 (Reactome)
RhoGTPase:GDPR-HSA-194854 (Reactome)
RhoGTPase:GDPR-HSA-194913 (Reactome)
RhoGTPase:GTP:Effectors complexArrowR-HSA-194894 (Reactome)
RhoGTPase:GTPArrowR-HSA-194913 (Reactome)
RhoGTPase:GTPR-HSA-194894 (Reactome)
RhoGTPase:GTPR-HSA-194922 (Reactome)
effector proteinsR-HSA-194894 (Reactome)

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