RHO GTPases activate IQGAPs (Homo sapiens)

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2, 5, 7-9, 13...2, 5, 8, 9, 163, 8, 9, 122, 7-9, 141, 4, 6, 1011, 15cytosolGTP CDC42 RAC1 Microtubule protofilament IQGAP3 Microtubule protofilament MEN1 CDC42 IQGAP2 IQGAP1 dimerCALM1 GTP Ca2+ CDH1dimer:CTTNB1:CTTNA1:IQGAP1:MEN1CALM1 IQGAP1 Ca2+ RAC1:GTP,CDC42:GTP:IQGAPs:CALM1:4Ca2+IQGAP2 CDH1(155-882) RAC1 IQGAP1 IQGAP1 F-actin CLIP1IQGAP2 IQGAP2 CDC42 IQGAP1 RAC1 CDC42 RAC1,CDC42:GTP:IQGAP:F-actinIQGAP1 MicrotubuleRAC1,CDC42:GTP:IQGAP1:CLIP1:microtubuleCTNNA1 RAC1,CDC42:GTP:IQGAPsRAC1,CDC42:GTP:IQGAP1IQGAP3 CDH1dimer:CTNNB1:CTNNA1IQGAP1 CTNNA1 CLIP1 GTP IQGAP3 IQGAP1 GTP CDH1(155-882) CTNNB1 RAC1 MEN1IQGAP1 GTP IQGAP3 F-actinCa2+ CDC42 GTP RAC1 CDC42:GTP, RAC1:GTPCa2+ CTNNB1 CDC42 IQGAPCALM1:4Ca2+RAC1 9112, 8


Description

IQGAPs constitute a family of scaffolding proteins characterized by a calponin homology (CH) domain, a polyproline binding region (WW domain), a tandem of four IQ (isoleucine and glutamine-rich) repeats and a RAS GTPase-activating protein-related domain (GRD). Three IQGAPs have been identified in human, IQGAP1, IQGAP2 and IQGAP3. The best characterized is IQGAP1 and over 90 proteins have been reported to bind to it. IQGAPs integrate multiple signaling pathways and coordinate a large variety of cellular activities (White et al. 2012). IQGAP proteins IQGAP1, IQGAP2 and IQGAP3, bind activated RHO GTPases RAC1 and CDC42 via their GRD 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 via the CH domain 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 binding to the IQ repeats (Bashour et al. 1997, Pelikan-Conchaudron et al. 2011). Based on IQGAP1 studies, IQGAPs presumably function as homodimers (Bashour et al. 1997).

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

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Reactome-Converter 
Pathway is converted from Reactome ID: 5626467
Reactome-version 
Reactome version: 62
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

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Bibliography

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  1. Kuroda S, Fukata M, Nakagawa M, Fujii K, Nakamura T, Ookubo T, Izawa I, Nagase T, Nomura N, Tani H, Shoji I, Matsuura Y, Yonehara S, Kaibuchi K.; ''Role of IQGAP1, a target of the small GTPases Cdc42 and Rac1, in regulation of E-cadherin- mediated cell-cell adhesion.''; PubMed Europe PMC Scholia
  2. Suzuki K, Takahashi K.; ''Regulation of lamellipodia formation and cell invasion by CLIP-170 in invasive human breast cancer cells.''; PubMed Europe PMC Scholia
  3. Kuroda S, Fukata M, Kobayashi K, Nakafuku M, Nomura N, Iwamatsu A, Kaibuchi K.; ''Identification of IQGAP as a putative target for the small GTPases, Cdc42 and Rac1.''; PubMed Europe PMC Scholia
  4. Pelikan-Conchaudron A, Le Clainche C, Didry D, Carlier MF.; ''The IQGAP1 protein is a calmodulin-regulated barbed end capper of actin filaments: possible implications in its function in cell migration.''; PubMed Europe PMC Scholia
  5. Wang S, Watanabe T, Noritake J, Fukata M, Yoshimura T, Itoh N, Harada T, Nakagawa M, Matsuura Y, Arimura N, Kaibuchi K.; ''IQGAP3, a novel effector of Rac1 and Cdc42, regulates neurite outgrowth.''; PubMed Europe PMC Scholia
  6. Atcheson E, Hamilton E, Pathmanathan S, Greer B, Harriott P, Timson DJ.; ''IQ-motif selectivity in human IQGAP2 and IQGAP3: binding of calmodulin and myosin essential light chain.''; PubMed Europe PMC Scholia
  7. Fukata M, Kuroda S, Fujii K, Nakamura T, Shoji I, Matsuura Y, Okawa K, Iwamatsu A, Kikuchi A, Kaibuchi K.; ''Regulation of cross-linking of actin filament by IQGAP1, a target for Cdc42.''; PubMed Europe PMC Scholia
  8. Fukata M, Watanabe T, Noritake J, Nakagawa M, Yamaga M, Kuroda S, Matsuura Y, Iwamatsu A, Perez F, Kaibuchi K.; ''Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170.''; PubMed Europe PMC Scholia
  9. Swart-Mataraza JM, Li Z, Sacks DB.; ''IQGAP1 is a component of Cdc42 signaling to the cytoskeleton.''; PubMed Europe PMC Scholia
  10. Yan J, Yan J, Yang Y, Zhang H, King C, Kan HM, Cai Y, Yuan CX, Bloom GS, Hua X.; ''Menin interacts with IQGAP1 to enhance intercellular adhesion of beta-cells.''; PubMed Europe PMC Scholia
  11. Brill S, Li S, Lyman CW, Church DM, Wasmuth JJ, Weissbach L, Bernards A, Snijders AJ.; ''The Ras GTPase-activating-protein-related human protein IQGAP2 harbors a potential actin binding domain and interacts with calmodulin and Rho family GTPases.''; PubMed Europe PMC Scholia
  12. Andrews WJ, Bradley CA, Hamilton E, Daly C, Mallon T, Timson DJ.; ''A calcium-dependent interaction between calmodulin and the calponin homology domain of human IQGAP1.''; PubMed Europe PMC Scholia
  13. Bashour AM, Fullerton AT, Hart MJ, Bloom GS.; ''IQGAP1, a Rac- and Cdc42-binding protein, directly binds and cross-links microfilaments.''; PubMed Europe PMC Scholia
  14. Fukata M, Kuroda S, Nakagawa M, Kawajiri A, Itoh N, Shoji I, Matsuura Y, Yonehara S, Fujisawa H, Kikuchi A, Kaibuchi K.; ''Cdc42 and Rac1 regulate the interaction of IQGAP1 with beta-catenin.''; PubMed Europe PMC Scholia
  15. Hage B, Meinel K, Baum I, Giehl K, Menke A.; ''Rac1 activation inhibits E-cadherin-mediated adherens junctions via binding to IQGAP1 in pancreatic carcinoma cells.''; PubMed Europe PMC Scholia
  16. White CD, Erdemir HH, Sacks DB.; ''IQGAP1 and its binding proteins control diverse biological functions.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114798view16:29, 25 January 2021ReactomeTeamReactome version 75
113241view11:31, 2 November 2020ReactomeTeamReactome version 74
112461view15:41, 9 October 2020ReactomeTeamReactome version 73
101368view11:25, 1 November 2018ReactomeTeamreactome version 66
100906view21:00, 31 October 2018ReactomeTeamreactome version 65
100447view19:35, 31 October 2018ReactomeTeamreactome version 64
99996view16:19, 31 October 2018ReactomeTeamreactome version 63
99550view14:53, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93837view13:40, 16 August 2017ReactomeTeamreactome version 61
93392view11:22, 9 August 2017ReactomeTeamreactome version 61
89083view08:01, 22 August 2016EgonwOntology Term : 'signaling pathway' added !
86478view09:19, 11 July 2016ReactomeTeamreactome version 56
83295view10:40, 18 November 2015ReactomeTeamVersion54
81429view12:57, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
CALM1 ProteinP0DP23 (Uniprot-TrEMBL)
CALM1:4Ca2+ComplexR-HSA-534997 (Reactome)
CDC42 ProteinP60953 (Uniprot-TrEMBL)
CDC42:GTP, RAC1:GTPComplexR-HSA-389778 (Reactome)
CDH1 dimer:CTNNB1:CTNNA1ComplexR-HSA-201938 (Reactome)
CDH1 dimer:CTTNB1:CTTNA1:IQGAP1:MEN1ComplexR-HSA-5672317 (Reactome)
CDH1(155-882) ProteinP12830 (Uniprot-TrEMBL)
CLIP1 ProteinP30622 (Uniprot-TrEMBL)
CLIP1ProteinP30622 (Uniprot-TrEMBL)
CTNNA1 ProteinP35221 (Uniprot-TrEMBL)
CTNNB1 ProteinP35222 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
F-actin R-HSA-201877 (Reactome)
F-actinR-HSA-201877 (Reactome)
GTP MetaboliteCHEBI:15996 (ChEBI)
IQGAP1 ProteinP46940 (Uniprot-TrEMBL)
IQGAP1 dimerComplexR-HSA-5626540 (Reactome)
IQGAP2 ProteinQ13576 (Uniprot-TrEMBL)
IQGAP3 ProteinQ86VI3 (Uniprot-TrEMBL)
IQGAPComplexR-HSA-5626373 (Reactome)
MEN1 ProteinO00255 (Uniprot-TrEMBL)
MEN1ProteinO00255 (Uniprot-TrEMBL)
Microtubule protofilament R-HSA-8982424 (Reactome)
MicrotubuleComplexR-HSA-190599 (Reactome)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC1,CDC42:GTP:IQGAP1:CLIP1:microtubuleComplexR-HSA-5672333 (Reactome)
RAC1,CDC42:GTP:IQGAP1ComplexR-HSA-5672334 (Reactome)
RAC1,CDC42:GTP:IQGAP:F-actinComplexR-HSA-5626510 (Reactome)
RAC1,CDC42:GTP:IQGAPsComplexR-HSA-5626465 (Reactome)
RAC1:GTP,CDC42:GTP:IQGAPs:CALM1:4Ca2+ComplexR-HSA-5626551 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
CALM1:4Ca2+R-HSA-5626549 (Reactome)
CDC42:GTP, RAC1:GTPR-HSA-5626469 (Reactome)
CDH1 dimer:CTNNB1:CTNNA1R-HSA-5672304 (Reactome)
CDH1 dimer:CTTNB1:CTTNA1:IQGAP1:MEN1ArrowR-HSA-5672304 (Reactome)
CLIP1R-HSA-5672329 (Reactome)
F-actinR-HSA-5626507 (Reactome)
IQGAP1 dimerR-HSA-5672304 (Reactome)
IQGAPR-HSA-5626469 (Reactome)
MEN1R-HSA-5672304 (Reactome)
MicrotubuleR-HSA-5672329 (Reactome)
R-HSA-5626469 (Reactome) IQGAP proteins IQGAP1, IQGAP2 and IQGAP3, bind Rho GTPases RAC1 and CDC42 via the RAS GTPase-activating protein-related domain (GRD) of IQGAPs. Although the GRDs are homologous to the RAS-specific GAP (GTPase activating protein) domains, they do not possess GAP activity. Instead, they increase the amount of activated CDC42 and RAC1 in the cell by stabilizing them in the GTP-bound state (Kuroda et al. 1996, Swart-Mataraza et al. 2002, Wang et al. 2007, Pelikan-Conchaudron et al. 2011).
R-HSA-5626507 (Reactome) IQGAP proteins IQGAP1, IQGAP2 and IQGAP3 bind F-actin filaments through their calponin homology (CH) domain (Pelikan-Conchaudron et al. 2011, Wang et al. 2007, Bashour et al. 1997, Fukata et al. 1997, Brill et al. 1996). Human IQGAP1 is implicated in cell migration, through regulation of actin filaments (Pelikan-Conchaudron et al. 2011). The regulation of actin filaments by IQGAP2 and IQGAP3 is implicated in axon outgrowth in hippocampal neurons (Wang et al. 2007).

Binding of calmodulin to IQ repeats (isoleucine- and glutamine-rich motifs) of IQGAPs inhibits binding of IQGAPs to F-actin (Bashour et al. 1997, Pelikan-Conchaudron et al. 2011).

R-HSA-5626549 (Reactome) IQGAP proteins IQGAP1, IQGAP2 and IQGAP3 possess IQ repeats (isoleucine- and glutamine-rich motifs) that bind CALM1 (calmodulin) in the presence of calcium ions (Atcheson et al. 2011, Andrews et al. 2012). IQGAP1 also binds the calmodulin-related proteins myosin essential light chain (MLCS1A) and S100B (Atcheson et al. 2011). Calmodulin binding inhibits the association of IQGAPs with the F-actin (Bashour et al. 1997, Pelikan-Conchaudron et al. 2011).
R-HSA-5672304 (Reactome) IQGAP1 binds the complex of E-cadherin (CDH1), beta-catenin (CTTNB1) and alpha-catenin (CTTNA1) at adherens junctions (Kuroda et al. 1998, Hage et al. 2009) and this interaction is corroborated by menin (MEN1) (Yan et al. 2009). It is implicated that IQGAP1 binding to CTTNB1 causes CTTNA1 to dissociate from the E-cadherin:catenin complex (Kuroda et al. 1998, Fukata et al. 1999). Binding of IQGAP1 to activated RAC1 or CDC42 competes with IQGAP1 association with the CDH1 dimer:CTTNB1:CTTNA1 complex (Kuroda et al. 1998, Fukata et al. 1999, Yan et al. 2009, Hage et al. 2009). Studies done in pancreatic cell lines found that the binding of IQGAP1 to E-cadherin:catenin complex at adherens junctions increases cell adhesion and decreases cell motility (Yan et al. 2009, Hage et al. 2009). On the contrary, studies done in mouse fibroblasts reported that IQGAP1 binding to E-cadherin:catenin complex and the concomitant displacement of CTTNA1 causes dissociation of adherens junctions (Kuroda et al. 1998, Fukata et al. 1999).
R-HSA-5672329 (Reactome) Once bound to activated RAC1 (RAC1:GTP) or CDC42 (CDC42:GTP), IQGAP1 binds CLIP1 (CLIP-170) via the C-terminus of IQGAP1 and the N-terminus of CLIP1. CLIP1 simultaneously interacts with IQGAP1 and the positive end of microtubules. Formation of the RAC1 or CDC42 complex with IQGAP1, CLIP1 and microtubules determines the orientation of microtubules and results in a polarized cellular morphology (Fukata et al. 2002). The RAC1:GTP:IQGAP1:CLIP1 complex is also involved in the regulation of lamellipodia formation and cell invasion in human breast cancer cells (Suzuki and Takahashi 2008).
RAC1,CDC42:GTP:IQGAP1:CLIP1:microtubuleArrowR-HSA-5672329 (Reactome)
RAC1,CDC42:GTP:IQGAP1R-HSA-5672329 (Reactome)
RAC1,CDC42:GTP:IQGAP:F-actinArrowR-HSA-5626507 (Reactome)
RAC1,CDC42:GTP:IQGAPsArrowR-HSA-5626469 (Reactome)
RAC1,CDC42:GTP:IQGAPsR-HSA-5626507 (Reactome)
RAC1,CDC42:GTP:IQGAPsR-HSA-5626549 (Reactome)
RAC1:GTP,CDC42:GTP:IQGAPs:CALM1:4Ca2+ArrowR-HSA-5626549 (Reactome)
RAC1:GTP,CDC42:GTP:IQGAPs:CALM1:4Ca2+TBarR-HSA-5626507 (Reactome)

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