RHO GTPases activate NADPH oxidases (Homo sapiens)

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1, 5, 8, 9, 15...1, 2, 6, 8, 11...2, 3, 9, 28, 312, 7, 8, 14, 305332, 15, 343, 9, 28, 312, 15, 23, 344phagocytic vesiclecytosolH+GTP NOX2complex:RAC1:GTPNCF4 NADP+Signaling by VEGFCYBB NCF1 CYBA NOX3 ComplexGTP ATPGTP RAC1:GTPFAD RAC1 NCF2 NCF1 RAC2:GTPRAC2 Class I MHC mediatedantigen processing& presentationheme PIK3C3:PIK3R4CYBA p-6S-NCF1 PIK3R4 CYBA PIRAC1 O2.-NOX1 ComplexNOX1 CYBB CYBA NOXO1 NCF4 NOXA1 NOX2 complexGTP NOXA1 NOX2 complexNOX1complex:RAC1:GTPCYBA NADPHNCF2 RAC1:GTPp-T233-NCF2 NOXA1 RAC1 NCF2 p-T154,S315-NCF4 NADPHp-6S-NCF1 PIK3C3 NCF1 GTP NCF1 CYBA heme NOX3 CYBB O2NCF2 FAD O2GTP RAC1 NOX1 RAC2 PI3Pp-T154,S315-NCF4 p-T233-NCF2 NOX3 H+NOXA1 CYBA NOXO1 O2.-NADP+NOX3complex:RAC1:GTPRAC1 GTP ADPCYBA NOX2complex:RAC2:GTPCYBB 612, 13, 16, 21, 22, 24...181810, 17, 20, 2561115, 23, 342, 8, 30113, 312, 15, 23, 349, 28


Description

NADPH oxidases (NOX) are membrane-associated enzymatic complexes that use NADPH as an electon donor to reduce oxygen and produce superoxide (O2-) that serves as a secondary messenger (Brown and Griendling 2009).

NOX2 complex consists of CYBB (NOX2), CYBA (p22phox), NCF1 (p47phox), NCF2 (p67phox) and NCF4 (p40ohox). RAC1:GTP binds NOX2 complex in response to VEGF signaling by directly interracting with CYBB and NCF2, leading to enhancement of VEGF-signaling through VEGF receptor VEGFR2, which plays a role in angiogenesis (Ushio-Fukai et al. 2002, Bedard and Krause 2007). RAC2:GTP can also activate the NOX2 complex by binding to CYBB and NCF2, leading to production of superoxide in phagosomes of neutrophils which is necessary fo the microbicidal activity of neutrophils (Knaus et al. 1991, Roberts et al. 1999, Kim and Dinauer 2001, Jyoti et al. 2014).<p>NOX1 complex (composed of NOX1, NOXA1, NOXO1 and CYBA) and NOX3 complex (composed of NOX3, CYBA, NCF1 amd NCF2 or NOXA1) can also be activated by binding to RAC1:GTP to produce superoxide (Cheng et al. 2006, Miyano et al. 2006, Ueyama et al. 2006). View original pathway at:Reactome.</div>

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Bibliography

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History

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CompareRevisionActionTimeUserComment
116651view11:41, 9 May 2021EweitzModified title
114720view16:20, 25 January 2021ReactomeTeamReactome version 75
113165view11:23, 2 November 2020ReactomeTeamReactome version 74
112393view15:32, 9 October 2020ReactomeTeamReactome version 73
101297view11:18, 1 November 2018ReactomeTeamreactome version 66
100834view20:49, 31 October 2018ReactomeTeamreactome version 65
100375view19:24, 31 October 2018ReactomeTeamreactome version 64
99922view16:07, 31 October 2018ReactomeTeamreactome version 63
99477view14:40, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99131view12:40, 31 October 2018ReactomeTeamreactome version 62
93750view13:33, 16 August 2017ReactomeTeamreactome version 61
93269view11:18, 9 August 2017ReactomeTeamreactome version 61
89085view08:02, 22 August 2016EgonwOntology Term : 'signaling pathway' added !
86346view09:15, 11 July 2016ReactomeTeamreactome version 56
83210view10:22, 18 November 2015ReactomeTeamVersion54
81596view13:08, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
CYBA ProteinP13498 (Uniprot-TrEMBL)
CYBB ProteinP04839 (Uniprot-TrEMBL)
Class I MHC mediated

antigen processing

& presentation		PathwayR-HSA-983169 (Reactome) Major histocompatibility complex (MHC) class I molecules play an important role in cell mediated immunity by reporting on intracellular events such as viral infection, the presence of intracellular bacteria or tumor-associated antigens. They bind peptide fragments of these proteins and presenting them to CD8+ T cells at the cell surface. This enables cytotoxic T cells to identify and eliminate cells that are synthesizing abnormal or foreign proteins. MHC class I is a trimeric complex composed of a polymorphic heavy chain (HC or alpha chain) and an invariable light chain, known as beta2-microglobulin (B2M) plus an 8-10 residue peptide ligand. Represented here are the events in the biosynthesis of MHC class I molecules, including generation of antigenic peptides by the ubiquitin/26S-proteasome system, delivery of these peptides to the endoplasmic reticulum (ER), loading of peptides to MHC class I molecules and display of MHC class I complexes on the cell surface.
FAD MetaboliteCHEBI:16238 (ChEBI)
GTP MetaboliteCHEBI:15996 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NCF1 ProteinP14598 (Uniprot-TrEMBL)
NCF2 ProteinP19878 (Uniprot-TrEMBL)
NCF4 ProteinQ15080 (Uniprot-TrEMBL)
NOX1 complex:RAC1:GTPComplexR-HSA-5668712 (Reactome)
NOX1 ComplexComplexR-HSA-5668698 (Reactome)
NOX1 ProteinQ9Y5S8 (Uniprot-TrEMBL)
NOX2 complex:RAC1:GTPComplexR-HSA-5218774 (Reactome)
NOX2 complex:RAC2:GTPComplexR-HSA-5668618 (Reactome)
NOX2 complexComplexR-HSA-1996217 (Reactome)
NOX2 complexComplexR-HSA-5218791 (Reactome)
NOX3 complex:RAC1:GTPComplexR-HSA-5668738 (Reactome)
NOX3 ComplexComplexR-HSA-5668734 (Reactome)
NOX3 ProteinQ9HBY0 (Uniprot-TrEMBL)
NOXA1 ProteinQ86UR1 (Uniprot-TrEMBL)
NOXO1 ProteinQ8NFA2 (Uniprot-TrEMBL)
O2.-MetaboliteCHEBI:18421 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
PI3PMetaboliteCHEBI:17283 (ChEBI)
PIMetaboliteCHEBI:16749 (ChEBI)
PIK3C3 ProteinQ8NEB9 (Uniprot-TrEMBL)
PIK3C3:PIK3R4ComplexR-HSA-6798183 (Reactome)
PIK3R4 ProteinQ99570 (Uniprot-TrEMBL)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC1:GTPComplexR-HSA-372685 (Reactome)
RAC1:GTPComplexR-HSA-442641 (Reactome)
RAC2 ProteinP15153 (Uniprot-TrEMBL)
RAC2:GTPComplexR-HSA-5668609 (Reactome)
Signaling by VEGFPathwayR-HSA-194138 (Reactome) In normal development vascular endothelial growth factors (VEGFs) are crucial regulators of vascular development during embryogenesis (vasculogenesis) and blood-vessel formation in the adult (angiogenesis). In tumor progression, activation of VEGF pathways promotes tumor vascularization, facilitating tumor growth and metastasis. Abnormal VEGF function is also associated with inflammatory diseases including atherosclerosis, and hyperthyroidism. The members of the VEGF and VEGF-receptor protein families have distinct but overlapping ligand-receptor specificities, cell-type expression, and function. VEGF-receptor activation in turn regulates a network of signaling processes in the body that promote endothelial cell growth, migration and survival (Hicklin and Ellis, 2005; Shibuya and Claesson-Welsh, 2006).
Molecular features of the VGF signaling cascades are outlined in the figure below (from Olsson et al. 2006; Nature Publishing Group). Tyrosine residues in the intracellular domains of VEGF receptors 1, 2,and 3 are indicated by dark blue boxes; residues susceptible to phosphorylation are numbered. A circled R indicates that phosphorylation is regulated by cell state (VEGFR2), by ligand binding (VEGFR1), or by heterodimerization (VEGFR3). Specific phosphorylation sites (boxed numbers) bind signaling molecules (dark blue ovals), whose interaction with other cytosolic signaling molecules (light blue ovals) leads to specific cellular (pale blue boxes) and tissue-level (pink boxes) responses in vivo. Signaling cascades whose molecular details are unclear are indicated by dashed arrows. DAG, diacylglycerol; EC, endothelial cell; eNOS, endothelial nitric oxide synthase; FAK, focal adhesion kinase; HPC, hematopoietic progenitor cell; HSP27, heat-shock protein-27; MAPK, mitogen-activated protein kinase; MEK, MAPK and ERK kinase; PI3K, phosphatidylinositol 3' kinase; PKC, protein kinase C; PLCgamma, phospholipase C-gamma; Shb, SH2 and beta-cells; TSAd, T-cell-specific adaptor.
In the current release, the first events in these cascades - the interactions between VEGF proteins and their receptors - are annotated. Details of signaling events and their biological outcome, concisely illustrated in the image below, will be available in future versions of this pathway.
heme MetaboliteCHEBI:17627 (ChEBI)
p-6S-NCF1 ProteinP14598 (Uniprot-TrEMBL)
p-T154,S315-NCF4 ProteinQ15080 (Uniprot-TrEMBL)
p-T233-NCF2 ProteinP19878 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-6798174 (Reactome)
ATPR-HSA-6798174 (Reactome)
H+ArrowR-HSA-5218841 (Reactome)
H+ArrowR-HSA-5668629 (Reactome)
H+ArrowR-HSA-5668718 (Reactome)
H+ArrowR-HSA-5668731 (Reactome)
NADP+ArrowR-HSA-5218841 (Reactome)
NADP+ArrowR-HSA-5668629 (Reactome)
NADP+ArrowR-HSA-5668718 (Reactome)
NADP+ArrowR-HSA-5668731 (Reactome)
NADPHR-HSA-5218841 (Reactome)
NADPHR-HSA-5668629 (Reactome)
NADPHR-HSA-5668718 (Reactome)
NADPHR-HSA-5668731 (Reactome)
NOX1 complex:RAC1:GTPArrowR-HSA-5668714 (Reactome)
NOX1 complex:RAC1:GTPmim-catalysisR-HSA-5668718 (Reactome)
NOX1 ComplexR-HSA-5668714 (Reactome)
NOX2 complex:RAC1:GTPArrowR-HSA-5218827 (Reactome)
NOX2 complex:RAC1:GTPmim-catalysisR-HSA-5218841 (Reactome)
NOX2 complex:RAC2:GTPArrowR-HSA-5668605 (Reactome)
NOX2 complex:RAC2:GTPmim-catalysisR-HSA-5668629 (Reactome)
NOX2 complexR-HSA-5218827 (Reactome)
NOX2 complexR-HSA-5668605 (Reactome)
NOX3 complex:RAC1:GTPArrowR-HSA-5668735 (Reactome)
NOX3 complex:RAC1:GTPmim-catalysisR-HSA-5668731 (Reactome)
NOX3 ComplexR-HSA-5668735 (Reactome)
O2.-ArrowR-HSA-5218841 (Reactome)
O2.-ArrowR-HSA-5668629 (Reactome)
O2.-ArrowR-HSA-5668718 (Reactome)
O2.-ArrowR-HSA-5668731 (Reactome)
O2R-HSA-5218841 (Reactome)
O2R-HSA-5668629 (Reactome)
O2R-HSA-5668718 (Reactome)
O2R-HSA-5668731 (Reactome)
PI3PArrowR-HSA-5668629 (Reactome)
PI3PArrowR-HSA-6798174 (Reactome)
PIK3C3:PIK3R4mim-catalysisR-HSA-6798174 (Reactome)
PIR-HSA-6798174 (Reactome)
R-HSA-5218827 (Reactome) NADPH oxidase (NOX) proteins are membrane-associated, multiunit enzymes that catalyze the reduction of oxygen using NADPH as an electron donor. NOX proteins produce superoxide (O2.-) via a single electron reduction (Brown & Griendling 2009). Superoxide molecules function as second messengers to stimulate diverse redox signaling pathways linked to various functions including angiogenesis. VEGF specifically stimulates superoxide production via RAC1 dependent activation of NOX2 complex. VEGF rapidly activates RAC1 and promotes translocation of RAC1 from cytosol to the membrane. At the membrane RAC1 interacts with the NOX enzyme complex via a direct interaction with NOX2 (gp91phox or CYBB) followed by subsequent interaction with the NCF2 (Neutrophil cytosol factor 2) or p67phox subunit and this makes the complex active (Bedard & Krause 2007). O2.- derived from Rac1-dependent NOX2 are involved in oxidation and inactivation of protein tyrosine phosphatases (PTPs) which negatively regulate VEGFR2, thereby enhancing VEGFR2 autophosphorylation, and subsequent redox signaling linked to angiogenic responses such as endothelial cell proliferation and migration (Ushio-Fukai 2006, 2007).
R-HSA-5218841 (Reactome) The activated NOX2 complex generates superoxide (O2.-) by transferring an electron from NADPH in the cytosol to oxygen on the luminal or extracellular space (Bedard & Krause 2007).
R-HSA-5668605 (Reactome) In neutrophils, RAC2 regulates NADPH oxidase NOX2 complex (Knaus et al. 1991, Kim et al. 2001) which consists of CYBB (NOX2), CYBA (p22phox), NCF1 (p47phox), NCF2 (p67phox) and NCF4 (p40phox). GTP-bound RAC2 binds to a conserved region of CYBB and tetratricopeptide repeats of NCF2 (Koga et al. 1999, Lapouge et al. 2000, Kao et al. 2008).
R-HSA-5668629 (Reactome) RAC2:GTP-bound NOX2 complex, consisting of CYBB (NOX2), CYBA (p22phox), NCF1 (p47phox), NCF2 (p67phox) and NCF4 (p40phox), acts as an NADPH oxidase to produce superoxide anion O2- in phagosomes of neutorphils, enabling microbicidal activity of neutrophils (Knaus et al. 1991, Kim et al. 2001, Kao et al. 2008, Anderson et al. 2010, Jyoti et al. 2014). Rac2 knockout mice have dramatically reduced NADPH oxidase activity (Roberts et al. 1999). Phosphorylation of NOX2 complex components NCF1 (el Benna et al. 1994), NCF2 (Zhao et al. 2005) and NCF4 (Bouin et al. 1998) contributes to the activation of the phagosomal NADPH oxidase.
R-HSA-5668714 (Reactome) Activated RAC1 (RAC1:GTP) binds NADPH oxidase NOX1 complex composed of NOX1, NOXA1, NOXO1 and CYBA (p22phox). RAC1 directly interacts with a conserved region in NOX1 and with tetratricopeptide repeats in NOXA1 (Takeya et al. 2003, Park et al. 2006, Cheng et al. 2006, Myano et al. 2006, Kao et al. 2008)
R-HSA-5668718 (Reactome) The activity of the non-phagocytic NADPH oxidase 1 (NOX1) complex, composed of NOX1, NOXA1, NOXO1 and CYBA, is greatly enhanced upon RAC1:GTP binding, resulting in production of the superoxide O2- which can serve as a second messenger (Takeya et al. 2003, Miyano et al. 2006, Park et al. 2006, Cheng et al. 2006).
R-HSA-5668731 (Reactome) While NOX3:CYBA complex has constitutive NADPH oxidase activity, the presence of NCF1, NCF2 or NOXA1 and RAC1:GTP enhances the production of superoxide O2- by the NOX3:CYBA complex. When NCF1 is replaced with NOXO1, RAC1:GTP becomes dispensible for the full activation of the NOX3 complex (Ueno et al. 2005, Ueyama et al. 2006, Miyano and Sumimoto 2007, Kao et al. 2008)
R-HSA-5668735 (Reactome) Activated RAC1 (RAC1:GTP) binds to the NADPH oxidase NOX3 complex, consisting of NOX3, CYBA (p22phox), NCF1 (p47phox) and NCF2 (p67phox) or NOXA1. RAC1 directly interacts with a conserved region of NOX3 and with tetratricopeptide repeats of NCF2 or NOXA1 (Ueyama et al. 2006, Miyano and Sumimoto 2007, Kao et al. 2008).
R-HSA-6798174 (Reactome) 1-phosphatidyl-1D-myo-inositol 3-phosphate (PI3P) is generated largely by the Class III PI3 kinase Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3, Vps34), which is found in intracellular membrane complexes with Phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4, Vps150), necessary for catalytic activity, localization and stability (Florey & Overholtzer 2012, Raiborg et al. 2013). These core subunits are frequently associated with other partners such as Rab5, Beclin-1 and UVRAG.

PI3P strongly upregulates phagosomal NADPH oxidase activity (Hawkins et al. 2010). This effect is mediated by PI3P binding to the PX domain of Neutrophil cytosol factor 4 (NCF4, p40phox), a component of the NOX2 complex.
RAC1:GTPR-HSA-5218827 (Reactome)
RAC1:GTPR-HSA-5668714 (Reactome)
RAC1:GTPR-HSA-5668735 (Reactome)
RAC2:GTPR-HSA-5668605 (Reactome)

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