RHO GTPases activate WASPs and WAVEs (Homo sapiens)

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8193-5, 10, 26...1, 207, 12, 14, 17, 21...18, 3319, 23, 253, 104, 159, 11, 24, 28-3113, 34cytosolWIPF2 GTP G-actinCYFIP1 PI(4,5)P2 GTP GTP GTP RAC1:GTPNCK1 NCK1 CDC42:GTPACTR2 ACTB(1-375) ATPN-WASP Motherfilament:branchingcomplex:daughterfilamentARPC1A RAC1 ARPC1A ARPC2 BRK1 CYFIP2 ACTB(1-375) ACTB(1-375) ACTR3 RAC1 SH3 domain proteinsCDC42 GTP PI(3,4,5)P3 p-Y291-WAS WAVE RegulatoryComplexWIPF2 NCK1 CDC42 WIP family proteinsBRK1 p-Y,S,T-WRC:IRSp53/58:RAC1:GTP:PIP3BRK1 GTP ACTB(1-375) NCKAP1L N-WASP ARPC3 WIPF3 NCKAP1L CDC42 ATP ABL1PI(3,4,5)P3 ARPC4 WASP/N-WASPCYFIP1 ARPC3 WIPF2 WAS Actin:ADPActivated WAVE2 andWASP/N-WASP:ARP2/3complex:G-actinCYFIP2 ARPC1A WIPF2 ADPNCKAP1L CDC42 ARPC2 BAIAP2 p-Y256-WASL CYFIP2 WIPF1 GRB2-1 WAS NCKAP1L Fcgamma receptor(FCGR) dependentphagocytosisATP CYFIP2 WIPF1 NCKIPSD ARP2/3 complex (ATPbound)CYFIP2 PiCDC42:GTP:WASP/N-WASPACTR2 GTP CDC42 NCKAP1L p-T,Y MAPK dimersGTP ATP BAIAP2 RAC1 PI(4,5)P2 CYFIP2 RAC1 NCKIPSD GTP ACTB(1-375) ARPC4 Motherfilament:ARP2/3:actin:GDPARPC5 ACTR2 Motherfilament:branchingcomplexADP CYFIP1 CDC42 WIPF1 RAC1 ARPC4 ACTG1 BAIAP2 BRK1 NCK1 NCKAP1 ACTR3 ACTR3 CDC42:GTP:WASP/N-WASP:WIP:SH3 proteinsWIPF2 PI(4,5)P2 RAC1 ARPC1A ARPC3 ARPC3 NCKAP1 NCKAP1L p-Y256-WASL WIPF3 NCKIPSD BAIAP2 GRB2-1 ARPC5 BAIAP2 ACTG1 p-Y291-WAS RAC1 CYFIP1 ACTG1 GRB2-1 WIPF3 p-Y256-WASL PI(3,4,5)P3 ACTG1 Src-kinasesBRK1 WIPF1 GTP ACTR2 ACTR2 BRK1 p-Y256-WASL BAIAP2NCKAP1L PI(3,4,5)P3 p-Y291-WAS WIPF3 WIPF1 GRB2-1 CYFIP1 ATP ATP NCKAP1 ARPC5 ARPC3 ARPC2 PI(3,4,5)P3 p-Y-WRC:IRSp53/58:RAC1:GTP:PIP3WRC:IRSp53/58:RAC1:GTP:PIP3PI(3,4,5)P3ATPNCK1 ACTR3 ADPACTR3 ARPC4 ATPActivated WAVE2 andWASP/N-WASPNCKAP1 ARPC2 GTP ACTB(1-375) GTP ARPC2 CYFIP1 ARPC1A CYFIP2 CYFIP1 p-Y291-WAS ARPC5 CDC42:GTP:p-Y-WASP/p-Y-WASL:WIP:SH3 proteinsNCKIPSD GTP ARPC4 PI(4,5)P2 ADPPI(4,5)P2 F-actinATP ACTG1 PI(3,4,5)P3 ACTG1 ADP BAIAP2 NCKIPSD ARPC5 NCKAP1 PI(4,5)P2 GRB2-1 GTP PI(4,5)P2CDC42 NCKAP1 NCKAP1 BRK1 WIPF3 2, 6, 16, 32


Description

WASP and WAVE proteins belong to the Wiskott-Aldrich Syndrome protein family, with recessive mutations in the founding member WASP being responsible for the X-linked recessive immunodeficieny known as the Wiskott-Aldrich Syndrome. WASP proteins include WASP and WASL (N-WASP). WAVE proteins include WASF1 (WAVE1), WASF2 (WAVE2) and WASF3 (WAVE3). WASPs and WAVEs contain a VCA domain (consisting of WH2 and CA subdomains) at the C-terminus, responsible for binding to G-actin (WH2 subdomain) and the actin-associated ARP2/3 complex (CA subdomain). WASPs contain a WH1 (WASP homology 1) domain at the N-terminus, responsible for binding to WIPs (WASP-interacting proteins). A RHO GTPase binding domain (GBD) is located in the N-terminal half of WASPs and C-terminally located in WAVEs. RHO GTPases activate WASPs by disrupting the autoinhibitory interaction between the GBD and VCA domains, which allows WASPs to bind actin and the ARP2/3 complex and act as nucleation promoting factors in actin polymerization. WAVEs have the WAVE/SCAR homology domain (WHD/SHD) at the N-terminus, which binds ABI, NCKAP1, CYFIP2 and BRK1 to form the WAVE regulatory complex (WRC). Binding of the RAC1:GTP to the GBD of WAVEs most likely induces a conformational change in the WRC that allows activating phosphorylation of WAVEs by ABL1, thus enabling them to function as nucleation promoting factors in actin polymerization through binding G-actin and the ARP2/3 complex (Reviewed by Lane et al. 2014). Source:Reactome.

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Bibliography

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History

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CompareRevisionActionTimeUserComment
116653view11:43, 9 May 2021EweitzModified title
114741view16:22, 25 January 2021ReactomeTeamReactome version 75
113185view11:25, 2 November 2020ReactomeTeamReactome version 74
112413view15:35, 9 October 2020ReactomeTeamReactome version 73
101317view11:20, 1 November 2018ReactomeTeamreactome version 66
100854view20:52, 31 October 2018ReactomeTeamreactome version 65
100395view19:26, 31 October 2018ReactomeTeamreactome version 64
99943view16:11, 31 October 2018ReactomeTeamreactome version 63
99499view14:44, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
94008view13:51, 16 August 2017ReactomeTeamreactome version 61
93623view11:29, 9 August 2017ReactomeTeamreactome version 61
89090view08:05, 22 August 2016EgonwOntology Term : 'signaling pathway' added !
86733view09:25, 11 July 2016ReactomeTeamreactome version 56
83387view11:04, 18 November 2015ReactomeTeamVersion54
81572view13:06, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ABL1ProteinP00519 (Uniprot-TrEMBL)
ACTB(1-375) ProteinP60709 (Uniprot-TrEMBL)
ACTG1 ProteinP63261 (Uniprot-TrEMBL)
ACTR2 ProteinP61160 (Uniprot-TrEMBL)
ACTR3 ProteinP61158 (Uniprot-TrEMBL)
ADP MetaboliteCHEBI:16761 (ChEBI)
ADPMetaboliteCHEBI:16761 (ChEBI)
ARP2/3 complex (ATP bound)ComplexR-HSA-1861670 (Reactome)
ARPC1A ProteinQ92747 (Uniprot-TrEMBL)
ARPC2 ProteinO15144 (Uniprot-TrEMBL)
ARPC3 ProteinO15145 (Uniprot-TrEMBL)
ARPC4 ProteinP59998 (Uniprot-TrEMBL)
ARPC5 ProteinO15511 (Uniprot-TrEMBL)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Actin:ADPComplexR-HSA-202994 (Reactome)
Activated WAVE2 and

WASP/N-WASP:ARP2/3

complex:G-actin		ComplexR-HSA-442565 (Reactome)
Activated WAVE2 and WASP/N-WASPR-HSA-2197675 (Reactome)
BAIAP2 ProteinQ9UQB8 (Uniprot-TrEMBL)
BAIAP2ProteinQ9UQB8 (Uniprot-TrEMBL)
BRK1 ProteinQ8WUW1 (Uniprot-TrEMBL)
CDC42 ProteinP60953 (Uniprot-TrEMBL)
CDC42:GTP:WASP/N-WASP:WIP:SH3 proteinsComplexR-HSA-2197683 (Reactome)
CDC42:GTP:WASP/N-WASPComplexR-HSA-442584 (Reactome)
CDC42:GTP:p-Y-WASP/p-Y-WASL:WIP:SH3 proteinsComplexR-HSA-2197680 (Reactome)
CDC42:GTPComplexR-HSA-182921 (Reactome)
CYFIP1 ProteinQ7L576 (Uniprot-TrEMBL)
CYFIP2 ProteinQ96F07 (Uniprot-TrEMBL)
F-actinR-HSA-201877 (Reactome)
Fcgamma receptor

(FCGR) dependent

phagocytosis		PathwayR-HSA-2029480 (Reactome) Phagocytosis is one of the important innate immune responses that function to eliminate invading infectious agents. Monocytes, macrophages, and neutrophils are the professional phagocytic cells. Phagocytosis is a complex process involving the recognition of invading foreign particles by specific types of phagocytic receptors and the subsequent internalization of the particles. Fc gamma receptors (FCGRs) are among the best studied phagocytic receptors that bind to Fc portion of immunoglobulin G (IgG). Through their antigen binding F(ab) end, antibodies bind to specific antigen while their constant (Fc) region binds to FCGRs on phagocytes. The clustering of FCGRs by IgG antibodies on the phagocyte initiates a variety of signals, which lead, through the reorganisation of actin cytoskeleton and membrane remodelling, to the formation of pseudopod and phagosome. Fc gamma receptors are classified into three classes: FCGRI, FCGRII and FCGRIII. Each class of these FCGRs consists of several individual isoforms. Among all these isoforms FCGRI, FCGRIIA and FCGRIIIA, are able to mediate phagocytosis (Joshi et al. 2006, Garcia Garcia & Rosales 2002, Nimmerjahn & Ravetch 2006).
G-actinComplexR-HSA-201857 (Reactome)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
Mother filament:ARP2/3:actin:GDPComplexR-HSA-2197686 (Reactome)
Mother

filament:branching complex:daughter

filament		ComplexR-HSA-1861699 (Reactome)
Mother

filament:branching

complex		ComplexR-HSA-2029140 (Reactome)
N-WASP ProteinO00401 (Uniprot-TrEMBL)
NCK1 ProteinP16333 (Uniprot-TrEMBL)
NCKAP1 ProteinQ9Y2A7 (Uniprot-TrEMBL)
NCKAP1L ProteinP55160 (Uniprot-TrEMBL)
NCKIPSD ProteinQ9NZQ3 (Uniprot-TrEMBL)
PI(3,4,5)P3 MetaboliteCHEBI:16618 (ChEBI)
PI(3,4,5)P3MetaboliteCHEBI:16618 (ChEBI)
PI(4,5)P2 MetaboliteCHEBI:18348 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PiMetaboliteCHEBI:18367 (ChEBI)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC1:GTPComplexR-HSA-442641 (Reactome)
SH3 domain proteinsR-HSA-2197679 (Reactome)
Src-kinasesR-HSA-2197681 (Reactome)
WAS ProteinP42768 (Uniprot-TrEMBL)
WASP/N-WASPR-HSA-201892 (Reactome)
WAVE Regulatory ComplexComplexR-HSA-2029154 (Reactome)
WIP family proteinsR-HSA-2197678 (Reactome)
WIPF1 ProteinO43516 (Uniprot-TrEMBL)
WIPF2 ProteinQ8TF74 (Uniprot-TrEMBL)
WIPF3 ProteinA6NGB9 (Uniprot-TrEMBL)
WRC:IRSp53/58:RAC1:GTP:PIP3ComplexR-HSA-2029147 (Reactome)
p-T,Y MAPK dimersR-HSA-1268261 (Reactome)
p-Y,S,T-WRC:IRSp53/58:RAC1:GTP:PIP3ComplexR-HSA-2029148 (Reactome)
p-Y-WRC:IRSp53/58:RAC1:GTP:PIP3ComplexR-HSA-2130182 (Reactome)
p-Y256-WASL ProteinO00401 (Uniprot-TrEMBL)
p-Y291-WAS ProteinP42768 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ABL1mim-catalysisR-HSA-2130194 (Reactome)
ADPArrowR-HSA-2029469 (Reactome)
ADPArrowR-HSA-2130194 (Reactome)
ADPArrowR-HSA-2197698 (Reactome)
ARP2/3 complex (ATP bound)R-HSA-442592 (Reactome)
ATPR-HSA-2029469 (Reactome)
ATPR-HSA-2130194 (Reactome)
ATPR-HSA-2197698 (Reactome)
Actin:ADPArrowR-HSA-2029473 (Reactome)
Activated WAVE2 and

WASP/N-WASP:ARP2/3

complex:G-actin		ArrowR-HSA-442592 (Reactome)
Activated WAVE2 and

WASP/N-WASP:ARP2/3

complex:G-actin		R-HSA-2029466 (Reactome)
Activated WAVE2 and WASP/N-WASPArrowR-HSA-2197690 (Reactome)
Activated WAVE2 and WASP/N-WASPR-HSA-442592 (Reactome)
BAIAP2R-HSA-2029465 (Reactome)
CDC42:GTP:WASP/N-WASP:WIP:SH3 proteinsArrowR-HSA-2197691 (Reactome)
CDC42:GTP:WASP/N-WASP:WIP:SH3 proteinsR-HSA-2197698 (Reactome)
CDC42:GTP:WASP/N-WASPArrowR-HSA-442586 (Reactome)
CDC42:GTP:WASP/N-WASPR-HSA-2197691 (Reactome)
CDC42:GTP:p-Y-WASP/p-Y-WASL:WIP:SH3 proteinsArrowR-HSA-2197698 (Reactome)
CDC42:GTPR-HSA-442586 (Reactome)
F-actinR-HSA-2029466 (Reactome)
G-actinR-HSA-2029473 (Reactome)
G-actinR-HSA-442592 (Reactome)
Mother filament:ARP2/3:actin:GDPArrowR-HSA-2197690 (Reactome)
Mother filament:ARP2/3:actin:GDPR-HSA-2029473 (Reactome)
Mother

filament:branching complex:daughter

filament		ArrowR-HSA-2029473 (Reactome)
Mother

filament:branching

complex		ArrowR-HSA-2029466 (Reactome)
Mother

filament:branching

complex		R-HSA-2197690 (Reactome)
PI(3,4,5)P3R-HSA-2029465 (Reactome)
PI(4,5)P2R-HSA-442586 (Reactome)
PiArrowR-HSA-2029473 (Reactome)
R-HSA-2029465 (Reactome) WASP family verprolin-homologous proteins (WAVEs) function downstream of RAC1 and are involved in activation of the ARP2/3 complex. The resulting actin polymerization mediates the projection of the plasma membrane in lamellipodia and membrane ruffles. WAVEs exist as a pentameric hetero-complex called WAVE Regulatory Complex (WRC). The WRC consists of a WAVE family protein (WASF1, WASF2 or WASF3 - commonly known as WAVE1, WAVE2 or WAVE3), ABI (Abelson-interacting protein), NCKAP1 (NAP1, p125NAP1), CYFIP1 (SRA1) or the closely related CYFIP2 (PIR121), and BRK1 (HSPC300, BRICK). Of the three structurally conserved WAVEs in mammals, the importance of WAVE2 in activation of the ARP2/3 complex and the consequent formation of branched actin filaments is best established. WAVEs in the WRC are intrinsically inactive and are stimulated by RAC1 GTPase and phosphatidylinositols (PIP3). The C-terminal VCA domain of WAVE2 (and likely WAVE1 and WAVE3) which can bind both the ARP2/3 complex and actin monomers (G-actin) is masked in the inactive state. After PIP3 binds to the polybasic region of WAVE2 (and likely WAVE1 and WAVE3) and RAC1:GTP binds to the CYFIP1 (or CYFIP2) subunit of the WRC, allosteric changes most likely occur which allow WAVEs to interact with the ARP2/3 complex. The interactions between WAVEs and RAC1 are indirect. BAIAP2/IRSp53, an insulin receptor substrate, acts as a linker, binding both activated RAC1 and the proline-rich region of WAVE2 (and likely WAVE1 and WAVE3) and forming a trimolecular complex. CYFIP1 (or CYFIP2) in the WAVE regulatory complex binds directly to RAC1:GTP and links it to WAVE2 (and likely WAVE1 and WAVE3) (Derivery et al. 2009, Yamazaki et al. 2006, Takenawa & Suetsugu 2007, Chen et al. 2010, Pollard 2007, Lebensohn & Kirschner 2009).
R-HSA-2029466 (Reactome) Once activated, the ARP2/3 complex nucleates new actin filaments that extend from the sides of pre-existing mother actin filaments at a 70-degree angle to form Y-branched networks (Firat-Karalar & Welch 2010). These branched actin filaments push the cell membrane forward to form a pseudopod. The ARP2/3 complex is composed of two Arps (actin-related proteins), ARP2 and ARP3, and five unique proteins ARPC1, ARPC2, ARPC3, ARPC4 and ARPC5 (Gournier et al. 2001). Both ARP2 and ARP3 subunits bind ATP. There are two proposed models to explain the process of actin nucleation by ARP2/3 complex: the barbed-end branching model and the dendritic nucleation/side branching model (Le Clainche & Carlier 2008).
In barbed-end branching model, the branching/ternary complex (G-actin-WASP/WAVE-Arp2/3 complex) binds to the barbed end of the mother filament. G-actin bound to VCA domain or one of the Arp subunits incorporates into the mother filament at the barbed end, thus positioning ARP2/3 complex to initiate the daughter branch on the side of the mother filament. ARP2/3 nucleates the formation of new actin filament branches, which elongate at the barbed ends (Le Clainche & Carlier 2008, Pantaloni et al 2000, Le Clainche et al. 2003, Egile et al. 2005). In side branching model, the branching complex binds to the side of the mother actin filament mimicking an actin nucleus and initiates a lateral branch (Le Clainche & Carlier 2008, Amann & Pollard 2001).
R-HSA-2029469 (Reactome) The ARP2/3 complex shows higher affinity for the phosphorylated VCA domain of WAVE2 than for the unphosphorylated VCA domain. WAVE proteins can be phosphorylated by various kinases. Active ERK (Mitogen activated protein kinase 3) phosphorylates the WAVE regulatory complex (WRC) on multiple serine/threonine sites within the proline-rich domains (PRDs) of WAVE2 and ABI1. Phosphorylation of the PRDs would disrupt their interaction with SH3 and PLP binding domains, potentially altering WRC activation. ERK phosphorylates both S343 and T346 in WAVE2 and S183, S216, S225, S392, and S410 in ABI1. Cumulatively, the phosphorylation of both WAVE2 and ABI in the WAVE regulatory complex (WRC) contributes to the RAC-induced WRC conformational change that exposes the VCA domain, leading to binding and activation of ARP2/3 (Mendoza et al. 2011, Nakanishi et al. 2007). ERK phosphorylation sites in WAVE2 are not strictly conserved in WAVE1 and WAVE3 but, based on the amino acid sequence, other potential ERK phosphorylation sites exist.
R-HSA-2029473 (Reactome) ATP bound G-actin monomers are added to the fast growing barbed ends of both mother and daughter filaments and the polymerization of these filaments drives membrane protrusion. In the process of phagocytosis, pseudopodia extend around the antibody-bound particle to form the phagocytic cup. This elongation continues until the filament reaches steady state equilibrium with free G-actin monomers (Millard et al. 2004, Le Clainche et al. 2008).
R-HSA-2130194 (Reactome) Abelson interactor-1 (ABL) tyrosine kinase phosphorylates the strictly conserved tyrosine 150 in WAVE2 (Y151 in WAVE1 and WAVE3) (Leng et al. 2003, Chen et al. 2010).
R-HSA-2197690 (Reactome) After incorporation at the branch, the actin bound to VCA domain of WASP/WAVE undergoes ATP hydrolysis and this destabilizes its interaction with WASP/WAVE. This dissociates the branched junction from the membrane-bound WASP/WAVE (Kovar 2006).
R-HSA-2197691 (Reactome) WASP interacting proteins (WIP) family includes WIPF1 (WIP), WIPF2 (WIRE,WICH) and WIPF3 (CR16, corticosteroids and regional expression-16). WIPs share a specific proline rich sequence that interacts with the WH1 domain of WASP and N-WASP (WASL). WIPs form heterocomplexes with WASPs and may contribute to the WASP protein stability (Aspenstrom 2002, Kato et al. 2002, Ho et al. 2001, Moreau et al. 2000).
SH3 domain containing adaptor proteins like GRB2 (Carlier et al. 2000), NCK (Rohatgi et al. 2001) and WISH (DIP/SPIN90) (Fukuoka et al. 2001) bind to the proline rich domain in WASPs and activate the ARP2/3 complex. By binding simultaneously to N-WASP and the ARP2/3 complex, GRB2 works synergistically with CDC42 in the activation of ARP2/3 complex-mediated actin assembly (Carlier et al. 2000).
R-HSA-2197698 (Reactome) WASP is phosphorylated on Tyr291 (Cory et al. 2002) and N-WASP (WASL) on Tyr256 (Wu et al. 2004) by Src family of tyrosine kinases and this phosphorylation may release the autoinhibitory intramolecular interactions. The phosphorylation seems to be enhanced by the activation of CDC42. WASP phosphorylation and binding of CDC42 have a synergistic effect on the activation of the ARP2/3 complex (Takenawa & Suetsugu 2007). In N-WASP, the phosphorylation may reduce its nuclear translocation and may sustain it in its functional site in the cytoplasm (Wu et al. 2004).
R-HSA-442586 (Reactome) Wiskott-Aldrich syndrome protein (WASP) and Neural-WASP (N-WASP, WASL) proteins are scaffolds that transduce signals from cell surface receptors to the activation of the ARP2/3 complex and actin polymerization. WASP and N-WASP possess a central GTPase binding domain (GBD) and an NH2-terminal WASP homology domain 1 (WH1) followed by a basic region (B), and a C-terminal VCA region that contains: a V domain (verprolin homology/WASP homology 2), a C domain (connecting), and an A motif (acidic). The VCA region is responsible for binding to and activating the ARP2/3 complex (Bompard & Caron 2004, Callebaut et al 1998). Under resting conditions, WASP and N-WASP are maintained in an autoinhibited state via interaction of the GBD and the VCA domains. This prevents access of the ARP2/3 complex and G-actin to the VCA region. Activated CDC42 binds to the GBD region of WASPs and this interaction releases the VCA region from autoinhibition, enabling binding of the ARP2/3 complex and stimulating actin polymerization (Kim et al 2000, Park & Cox 2009). Phosphoinositides (PtdIns(4,5)P2) interact with the basic (B) region in WASPs and this interaction is important for activation of the WASPs and the ARP2/3 complex (Higgs & Pollard 2000).
R-HSA-442592 (Reactome) Once WASPs (WASP and N-WASP) and WAVEs (WAVE2 and probably WAVE1 and WAVE3) are activated, their VCA region becomes available for binding to the ARP2/3 complex and actin monomer (G-actin). The actin monomer binds to the V domain and ARP2/3 complex binds to the CA domain. The simultaneous binding of G-actin and the ARP2/3 complex to the VCA region contributes to the activation of the ARP2/3-complex-mediated actin polymerization. The VCA module acts as a platform on which an actin monomer binds to the ARP2/3 complex to trigger actin polymerization (Takenawa & Suetsugu 2007).
RAC1:GTPR-HSA-2029465 (Reactome)
SH3 domain proteinsR-HSA-2197691 (Reactome)
Src-kinasesmim-catalysisR-HSA-2197698 (Reactome)
WASP/N-WASPR-HSA-442586 (Reactome)
WAVE Regulatory ComplexR-HSA-2029465 (Reactome)
WIP family proteinsR-HSA-2197691 (Reactome)
WRC:IRSp53/58:RAC1:GTP:PIP3ArrowR-HSA-2029465 (Reactome)
WRC:IRSp53/58:RAC1:GTP:PIP3R-HSA-2130194 (Reactome)
p-T,Y MAPK dimersmim-catalysisR-HSA-2029469 (Reactome)
p-Y,S,T-WRC:IRSp53/58:RAC1:GTP:PIP3ArrowR-HSA-2029469 (Reactome)
p-Y-WRC:IRSp53/58:RAC1:GTP:PIP3ArrowR-HSA-2130194 (Reactome)
p-Y-WRC:IRSp53/58:RAC1:GTP:PIP3R-HSA-2029469 (Reactome)
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