Signaling by Rho GTPases (Homo sapiens)

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26, 4810, 11, 15, 28, 45...1, 17, 21, 32, 61...10, 11, 55, 68, 974, 20, 23, 27, 47...5, 24, 33, 36, 62...cytosolMCF2 ARHGAP27 RACGAP1 STARD13 ARHGAP11A A2M ARHGEF16 RHOG RHO GTPase EffectorsCDC42 ARHGEF3 NET1 OCRL RHOV ARHGAP9 PIK3R2 RHOT1 RHOT1 CHN1 RHOV RHOC ABR RHOF ARHGEF39 ARHGEF2 GMIP RHOF GTPGDP STARD8 RHOB FGD3 SRGAP2 PiRHOQ ARHGEF1 ARHGEF4 FAM13B VAV3 RHOU ARHGAP44 ARHGAP31 SOS2 INPP5B(321-993) RHOJ RHOQ ARHGEF38 RAC2 RHOB RHOV ARHGDIB VAV2 FGD1 ARHGAP28 TIAM2 SRGAP1 GNA13 GTP RHOB RHOU FAM13A RHOD RHOG ARHGAP33 RAC3 GEFsRHOB ARHGAP19 GDI proteinsMCF2L RAC1 RHOG DLC1 RHOB ARHGAP25 RHOV TAGAP RHOA effector proteinsNGEF DEPDC7 ARAP1 RHOG FGD2 Rac ARHGAP22 ARHGEF5 ARHGAP24 SYDE2 PLEKHG2 GTP RAC2 ARHGAP29 RAC2 RHOQ RASGRF2 RHOF RHOC InactivatedRhoGTPase:GDP:GDIcomplexARHGAP6 RHOA RHOH RHOT2 RHOQ RHOG RAC1 RHOH GDP ARHGEF10 RhoGTPase:GTPRHOA PREX1 RHOU RHOQ PLEKHG5 ARHGDIA ARHGAP12 ARHGAP1 ECT2 ARAP2 RHOT1 TRIP10 BPGAP1(1-?) ARHGAP4 ARHGEF9 SRGAP3 Rac ARHGAP21 ARHGEF11 RHOT2 ARHGEF12 RAC3 ARHGDIA RAC1 ARHGEF26 ARHGEF7 ARHGEF17 GAPsCDC42 ARHGAP11B RHOJ RHOC BCR RHOV RHOU RAC3 RHOH ITSN1 RHOC RHOT1 effector proteins RHOU CHN2 ARHGAP35 RhoGTPase:GDPARHGAP17 ARAP3 RHOA HMHA1 RHOH DEPDC1B ARHGAP30 p190 RHOT2 ARHGAP42 RHOD RHOBTB GTPase CycleABR ARHGDIG RHOC RHOT1 RHOT2 RHOD GDP KALRN SYDE1 ARHGEF37 ARHGAP15 RHOF OPHN1 RhoGTPase:GDPARHGAP18 ARHGAP36 RAC1 ARHGAP10 GDPRHOF RHOT2 ARHGEF19 ARHGAP39 ARHGAP8 RAC1 ARHGAP26 ARHGEF33 ARHGEF10L MYO9B RHOD KALRN ARHGEF35 CDC42 VAV1 ARHGAP32 ARHGDIG GTP ARHGDIB SOS1 ARHGEF18 TRIO ARHGEF40 ARHGAP5 FGD4 RhoGTPase:GTP:Effectors complexRHOJ CDC42 ARHGEF6 RHOD RHOJ ARHGEF15 RHOH CDC42 RHOA ARHGAP40 OBSCN ARHGAP20 MYO9A ARHGAP23 RHOJ TIAM1 RALBP1 AKAP13 2, 3, 6-9, 12...13, 18


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). View original pathway at Reactome.</div>

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Pathway is converted from Reactome ID: 194315
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Reactome version: 75
Reactome Author 
Reactome Author: Van Aelst, L

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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
A2M ProteinP01023 (Uniprot-TrEMBL)
ABR ProteinQ12979 (Uniprot-TrEMBL)
AKAP13 ProteinQ12802 (Uniprot-TrEMBL)
ARAP1 ProteinQ96P48 (Uniprot-TrEMBL)
ARAP2 ProteinQ8WZ64 (Uniprot-TrEMBL)
ARAP3 ProteinQ8WWN8 (Uniprot-TrEMBL)
ARHGAP1 ProteinQ07960 (Uniprot-TrEMBL)
ARHGAP10 ProteinA1A4S6 (Uniprot-TrEMBL)
ARHGAP11A ProteinQ6P4F7 (Uniprot-TrEMBL)
ARHGAP11B ProteinQ3KRB8 (Uniprot-TrEMBL)
ARHGAP12 ProteinQ8IWW6 (Uniprot-TrEMBL)
ARHGAP15 ProteinQ53QZ3 (Uniprot-TrEMBL)
ARHGAP17 ProteinQ68EM7 (Uniprot-TrEMBL)
ARHGAP18 ProteinQ8N392 (Uniprot-TrEMBL)
ARHGAP19 ProteinQ14CB8 (Uniprot-TrEMBL)
ARHGAP20 ProteinQ9P2F6 (Uniprot-TrEMBL)
ARHGAP21 ProteinQ5T5U3 (Uniprot-TrEMBL)
ARHGAP22 ProteinQ7Z5H3 (Uniprot-TrEMBL)
ARHGAP23 ProteinQ9P227 (Uniprot-TrEMBL)
ARHGAP24 ProteinQ8N264 (Uniprot-TrEMBL)
ARHGAP25 ProteinP42331 (Uniprot-TrEMBL)
ARHGAP26 ProteinQ9UNA1 (Uniprot-TrEMBL)
ARHGAP27 ProteinQ6ZUM4 (Uniprot-TrEMBL)
ARHGAP28 ProteinQ9P2N2 (Uniprot-TrEMBL)
ARHGAP29 ProteinQ52LW3 (Uniprot-TrEMBL)
ARHGAP30 ProteinQ7Z6I6 (Uniprot-TrEMBL)
ARHGAP31 ProteinQ2M1Z3 (Uniprot-TrEMBL)
ARHGAP32 ProteinA7KAX9 (Uniprot-TrEMBL)
ARHGAP33 ProteinO14559 (Uniprot-TrEMBL)
ARHGAP35 ProteinQ9NRY4 (Uniprot-TrEMBL)
ARHGAP36 ProteinQ6ZRI8 (Uniprot-TrEMBL)
ARHGAP39 ProteinQ9C0H5 (Uniprot-TrEMBL)
ARHGAP4 ProteinP98171 (Uniprot-TrEMBL)
ARHGAP40 ProteinQ5TG30 (Uniprot-TrEMBL)
ARHGAP42 ProteinA6NI28 (Uniprot-TrEMBL)
ARHGAP44 ProteinQ17R89 (Uniprot-TrEMBL)
ARHGAP5 ProteinQ13017 (Uniprot-TrEMBL)
ARHGAP6 ProteinO43182 (Uniprot-TrEMBL)
ARHGAP8 ProteinP85298 (Uniprot-TrEMBL)
ARHGAP9 ProteinQ9BRR9 (Uniprot-TrEMBL)
ARHGDIA ProteinP52565 (Uniprot-TrEMBL)
ARHGDIB ProteinP52566 (Uniprot-TrEMBL)
ARHGDIG ProteinQ99819 (Uniprot-TrEMBL)
ARHGEF1 ProteinQ92888 (Uniprot-TrEMBL)
ARHGEF10 ProteinO15013 (Uniprot-TrEMBL)
ARHGEF10L ProteinQ9HCE6 (Uniprot-TrEMBL)
ARHGEF11 ProteinO15085 (Uniprot-TrEMBL)
ARHGEF12 ProteinQ9NZN5 (Uniprot-TrEMBL)
ARHGEF15 ProteinO94989 (Uniprot-TrEMBL)
ARHGEF16 ProteinQ5VV41 (Uniprot-TrEMBL)
ARHGEF17 ProteinQ96PE2 (Uniprot-TrEMBL)
ARHGEF18 ProteinQ6ZSZ5 (Uniprot-TrEMBL)
ARHGEF19 ProteinQ8IW93 (Uniprot-TrEMBL)
ARHGEF2 ProteinQ92974 (Uniprot-TrEMBL)
ARHGEF26 ProteinQ96DR7 (Uniprot-TrEMBL)
ARHGEF3 ProteinQ9NR81 (Uniprot-TrEMBL)
ARHGEF33 ProteinA8MVX0 (Uniprot-TrEMBL)
ARHGEF35 ProteinA5YM69 (Uniprot-TrEMBL)
ARHGEF37 ProteinA1IGU5 (Uniprot-TrEMBL)
ARHGEF38 ProteinQ9NXL2 (Uniprot-TrEMBL)
ARHGEF39 ProteinQ8N4T4 (Uniprot-TrEMBL)
ARHGEF4 ProteinQ9NR80 (Uniprot-TrEMBL)
ARHGEF40 ProteinQ8TER5 (Uniprot-TrEMBL)
ARHGEF5 ProteinQ12774 (Uniprot-TrEMBL)
ARHGEF6 ProteinQ15052 (Uniprot-TrEMBL)
ARHGEF7 ProteinQ14155 (Uniprot-TrEMBL)
ARHGEF9 ProteinO43307 (Uniprot-TrEMBL)
BCR ProteinP11274 (Uniprot-TrEMBL)
BPGAP1(1-?) ProteinQ8IZM6 (Uniprot-TrEMBL)
CDC42 ProteinP60953 (Uniprot-TrEMBL)
CHN1 ProteinP15882 (Uniprot-TrEMBL)
CHN2 ProteinP52757 (Uniprot-TrEMBL)
DEPDC1B ProteinQ8WUY9 (Uniprot-TrEMBL)
DEPDC7 ProteinQ96QD5 (Uniprot-TrEMBL)
DLC1 ProteinQ96QB1 (Uniprot-TrEMBL)
ECT2 ProteinQ9H8V3 (Uniprot-TrEMBL)
FAM13A ProteinO94988 (Uniprot-TrEMBL)
FAM13B ProteinQ9NYF5 (Uniprot-TrEMBL)
FGD1 ProteinP98174 (Uniprot-TrEMBL)
FGD2 ProteinQ7Z6J4 (Uniprot-TrEMBL)
FGD3 ProteinQ5JSP0 (Uniprot-TrEMBL)
FGD4 ProteinQ96M96 (Uniprot-TrEMBL)
GAPsComplexR-HSA-194904 (Reactome)
GDI proteinsComplexR-HSA-194862 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GEFsComplexR-HSA-194849 (Reactome)
GMIP ProteinQ9P107 (Uniprot-TrEMBL)
GNA13 ProteinQ14344 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
HMHA1 ProteinQ92619 (Uniprot-TrEMBL)
INPP5B(321-993) ProteinP32019 (Uniprot-TrEMBL)
ITSN1 ProteinQ15811 (Uniprot-TrEMBL)
Inactivated

RhoGTPase:GDP:GDI

complex		ComplexR-HSA-194912 (Reactome)
KALRN ProteinO60229 (Uniprot-TrEMBL)
MCF2 ProteinP10911 (Uniprot-TrEMBL)
MCF2L ProteinO15068 (Uniprot-TrEMBL)
MYO9A ProteinB2RTY4 (Uniprot-TrEMBL)
MYO9B ProteinQ13459 (Uniprot-TrEMBL)
NET1 ProteinQ7Z628 (Uniprot-TrEMBL)
NGEF ProteinQ8N5V2 (Uniprot-TrEMBL)
OBSCN ProteinQ5VST9 (Uniprot-TrEMBL)
OCRL ProteinQ01968 (Uniprot-TrEMBL)
OPHN1 ProteinO60890 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PLEKHG2 ProteinQ9H7P9 (Uniprot-TrEMBL)
PLEKHG5 ProteinO94827 (Uniprot-TrEMBL)
PREX1 ProteinQ8TCU6 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:43474 (ChEBI)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC2 ProteinP15153 (Uniprot-TrEMBL)
RAC3 ProteinP60763 (Uniprot-TrEMBL)
RACGAP1 ProteinQ9H0H5 (Uniprot-TrEMBL)
RALBP1 ProteinQ15311 (Uniprot-TrEMBL)
RASGRF2 ProteinO14827 (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)
RHOBTB GTPase CyclePathwayR-HSA-9706574 (Reactome) RHO BTB family belongs to atypical RHO GTPases, which are characterized by the absence of GTPase activity. RhoBTB family includes RHOBTB1, RHOBTB2, and the more divergent RHOBTB3. 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). RHOBTB3 participates in CUL3 dependent protein ubiquitination, vesicle transport, regulation of the cell cycle and modulating the adaptive response to hypoxia (Berthold et al. 2008; Ji and Rivero 2016).
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)
Rac R-HSA-195337 (Reactome)
RhoGTPase:GDPComplexR-HSA-194900 (Reactome)
RhoGTPase:GDPComplexR-HSA-194915 (Reactome)
RhoGTPase:GTP:Effectors complexComplexR-HSA-194875 (Reactome)
RhoGTPase:GTPComplexR-HSA-194890 (Reactome)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
SOS2 ProteinQ07890 (Uniprot-TrEMBL)
SRGAP1 ProteinQ7Z6B7 (Uniprot-TrEMBL)
SRGAP2 ProteinO75044 (Uniprot-TrEMBL)
SRGAP3 ProteinO43295 (Uniprot-TrEMBL)
STARD13 ProteinQ9Y3M8 (Uniprot-TrEMBL)
STARD8 ProteinQ92502 (Uniprot-TrEMBL)
SYDE1 ProteinQ6ZW31 (Uniprot-TrEMBL)
SYDE2 ProteinQ5VT97 (Uniprot-TrEMBL)
TAGAP ProteinQ8N103 (Uniprot-TrEMBL)
TIAM1 ProteinQ13009 (Uniprot-TrEMBL)
TIAM2 ProteinQ8IVF5 (Uniprot-TrEMBL)
TRIO ProteinO75962 (Uniprot-TrEMBL)
TRIP10 ProteinQ15642 (Uniprot-TrEMBL)
VAV1 ProteinP15498 (Uniprot-TrEMBL)
VAV2 ProteinP52735 (Uniprot-TrEMBL)
VAV3 ProteinQ9UKW4 (Uniprot-TrEMBL)
effector proteins R-HSA-194872 (Reactome)
effector proteinsR-HSA-194872 (Reactome)
p190 R-HSA-195116 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
GAPsmim-catalysisR-HSA-194922 (Reactome)
GDI proteinsArrowR-HSA-195146 (Reactome)
GDI proteinsR-HSA-194854 (Reactome)
GDPArrowR-HSA-194913 (Reactome)
GEFsmim-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).
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.
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.

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).

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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