RHO GTPases Activate NADPH Oxidases (Homo sapiens)

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1, 5, 11, 12, 23...14, 32, 377, 18, 215, 24, 38, 5011361, 12, 16, 23, 28...4, 45, 5114, 32, 37, 485, 24, 37, 38, 507, 42, 43193512, 13, 15, 28, 377, 18, 31, 34phagocytic vesiclecytosolRAC2 p-T500-PRKCB S100A9 FAD NCF1 NOX2complex:RAC2:GTPRAC1 O2.-NOX1 NOXO1 p-T202,Y204-MAPK3 p-p38 MAPKalpha/betaADPp-T180,Y182-MAPK14 ATPNCF2 ADPClass I MHC mediatedantigen processing& presentationO2p-6S-NCF1 PIK3R4 PIN1 NCF2 heme NCF1 S100A8 p-T233-NCF2 p-T233-NCF2 GTP NCF4 Ca2+ CYBA NOXO1 GTP p-T154,S315-NCF4 p-PKCA,p-PKCB,p-PKCZ,p-PKCDGTP NADPHNCF2 NADPHPIN1:p-S-345-NCF1:NCF2:NCF4NOXA1 NADP+RAC2 S100A8:S100A9:AA:Ca2+NADPHNOX2 complexGTP NCF2 NOXA1 O2.-NCF2 Signaling by VEGFCYBA NOX1 PIN1:p-S-6S-NCF1:NCF2:NCF4AA RAC1:GTPNCF4 PIK3C3 NOX3complex:RAC1:GTPCYBA NCF1 NCF2 NOXA1 ROS and RNSproduction inphagocytesADPO2PIN1 O2.-CYBB NOX1 ComplexNCF4 S100A8 NADP+heme p-T154,S315-NCF4 PIK3C3:PIK3R4CYBA p-6S-NCF1 PIS100A9 p-T410-PRKCZ H+p-6S-NCF1 NCF1 NCF1:NCF2:NCF4AA p-T154,S315-NCF4 NOX3 GTP NCF4 O2p-T,Y MAPK dimersCYBB Ca2+ RAC2:GTPp-T233-NCF2 NADP+CYBA NOXA1 O2.-p-T497-PRKCA NCF2 p-S-345-NCF1:NCF2:NCF4NCF2 CYBA NOX2complex:RAC1:GTPp-6S-NCF1 NOX2complex:S100A8:S100A9:Ca2+CYBB NOX2 complexp-T507-PRKCD FAD p-S345-NCF1 NCF4 PI3PCYBA p-S345-NCF1 RAC1 NOX1complex:RAC1:GTPRAC1 NOX3 RAC2 CYBA CYBA CYBB H+O2NCF4 CYBB NOX3 ComplexATPRAC1 ATPp-T180,Y182-MAPK11 NCF1 GTP H+GTP p-T185,Y187-MAPK1 PIN14949398, 254917, 229, 10, 29, 334124, 50393, 40, 474114, 32, 37, 48462, 6, 20, 26, 30...12, 28, 373914, 32, 485, 384141


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>


Pathway is converted from Reactome ID: 5668599
Reactome version: 73
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

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  1. Roberts AW, Kim C, Zhen L, Lowe JB, Kapur R, Petryniak B, Spaetti A, Pollock JD, Borneo JB, Bradford GB, Atkinson SJ, Dinauer MC, Williams DA.; ''Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense.''; PubMed Europe PMC Scholia
  2. Vyas JM, Van der Veen AG, Ploegh HL.; ''The known unknowns of antigen processing and presentation.''; PubMed Europe PMC Scholia
  3. Korndörfer IP, Brueckner F, Skerra A.; ''The crystal structure of the human (S100A8/S100A9)2 heterotetramer, calprotectin, illustrates how conformational changes of interacting alpha-helices can determine specific association of two EF-hand proteins.''; PubMed Europe PMC Scholia
  4. Steinckwich N, Schenten V, Melchior C, Bréchard S, Tschirhart EJ.; ''An essential role of STIM1, Orai1, and S100A8-A9 proteins for Ca2+ signaling and FcγR-mediated phagosomal oxidative activity.''; PubMed Europe PMC Scholia
  5. Cheng G, Diebold BA, Hughes Y, Lambeth JD.; ''Nox1-dependent reactive oxygen generation is regulated by Rac1.''; PubMed Europe PMC Scholia
  6. Elliott T, Neefjes J.; ''The complex route to MHC class I-peptide complexes.''; PubMed Europe PMC Scholia
  7. El-Benna J, Hurtado-Nedelec M, Marzaioli V, Marie JC, Gougerot-Pocidalo MA, Dang PM.; ''Priming of the neutrophil respiratory burst: role in host defense and inflammation.''; PubMed Europe PMC Scholia
  8. Dutil EM, Toker A, Newton AC.; ''Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1).''; PubMed Europe PMC Scholia
  9. Matsumoto T, Mugishima H.; ''Signal transduction via vascular endothelial growth factor (VEGF) receptors and their roles in atherogenesis.''; PubMed Europe PMC Scholia
  10. Hicklin DJ, Ellis LM.; ''Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis.''; PubMed Europe PMC Scholia
  11. Bedard K, Krause KH.; ''The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology.''; PubMed Europe PMC Scholia
  12. Knaus UG, Heyworth PG, Evans T, Curnutte JT, Bokoch GM.; ''Regulation of phagocyte oxygen radical production by the GTP-binding protein Rac 2.''; PubMed Europe PMC Scholia
  13. Lapouge K, Smith SJ, Walker PA, Gamblin SJ, Smerdon SJ, Rittinger K.; ''Structure of the TPR domain of p67phox in complex with Rac.GTP.''; PubMed Europe PMC Scholia
  14. Miyano K, Sumimoto H.; ''Role of the small GTPase Rac in p22phox-dependent NADPH oxidases.''; PubMed Europe PMC Scholia
  15. Koga H, Terasawa H, Nunoi H, Takeshige K, Inagaki F, Sumimoto H.; ''Tetratricopeptide repeat (TPR) motifs of p67(phox) participate in interaction with the small GTPase Rac and activation of the phagocyte NADPH oxidase.''; PubMed Europe PMC Scholia
  16. Anderson KE, Chessa TA, Davidson K, Henderson RB, Walker S, Tolmachova T, Grys K, Rausch O, Seabra MC, Tybulewicz VL, Stephens LR, Hawkins PT.; ''PtdIns3P and Rac direct the assembly of the NADPH oxidase on a novel, pre-phagosomal compartment during FcR-mediated phagocytosis in primary mouse neutrophils.''; PubMed Europe PMC Scholia
  17. Flannagan RS, Cosío G, Grinstein S.; ''Antimicrobial mechanisms of phagocytes and bacterial evasion strategies.''; PubMed Europe PMC Scholia
  18. Dang PM, Stensballe A, Boussetta T, Raad H, Dewas C, Kroviarski Y, Hayem G, Jensen ON, Gougerot-Pocidalo MA, El-Benna J.; ''A specific p47phox -serine phosphorylated by convergent MAPKs mediates neutrophil NADPH oxidase priming at inflammatory sites.''; PubMed Europe PMC Scholia
  19. Boussetta T, Gougerot-Pocidalo MA, Hayem G, Ciappelloni S, Raad H, Arabi Derkawi R, Bournier O, Kroviarski Y, Zhou XZ, Malter JS, Lu PK, Bartegi A, Dang PM, El-Benna J.; ''The prolyl isomerase Pin1 acts as a novel molecular switch for TNF-alpha-induced priming of the NADPH oxidase in human neutrophils.''; PubMed Europe PMC Scholia
  20. Antoniou AN, Powis SJ, Elliott T.; ''Assembly and export of MHC class I peptide ligands.''; PubMed Europe PMC Scholia
  21. Dang PM, Dewas C, Gaudry M, Fay M, Pedruzzi E, Gougerot-Pocidalo MA, El Benna J.; ''Priming of human neutrophil respiratory burst by granulocyte/macrophage colony-stimulating factor (GM-CSF) involves partial phosphorylation of p47(phox).''; PubMed Europe PMC Scholia
  22. Yang Y, Bazhin AV, Werner J, Karakhanova S.; ''Reactive oxygen species in the immune system.''; PubMed Europe PMC Scholia
  23. Jyoti A, Singh AK, Dubey M, Kumar S, Saluja R, Keshari RS, Verma A, Chandra T, Kumar A, Bajpai VK, Barthwal MK, Dikshit M.; ''Interaction of inducible nitric oxide synthase with rac2 regulates reactive oxygen and nitrogen species generation in the human neutrophil phagosomes: implication in microbial killing.''; PubMed Europe PMC Scholia
  24. Takeya R, Ueno N, Kami K, Taura M, Kohjima M, Izaki T, Nunoi H, Sumimoto H.; ''Novel human homologues of p47phox and p67phox participate in activation of superoxide-producing NADPH oxidases.''; PubMed Europe PMC Scholia
  25. Keranen LM, Dutil EM, Newton AC.; ''Protein kinase C is regulated in vivo by three functionally distinct phosphorylations.''; PubMed Europe PMC Scholia
  26. York IA, Rock KL.; ''Antigen processing and presentation by the class I major histocompatibility complex.''; PubMed Europe PMC Scholia
  27. Brown DI, Griendling KK.; ''Nox proteins in signal transduction.''; PubMed Europe PMC Scholia
  28. Kim C, Dinauer MC.; ''Rac2 is an essential regulator of neutrophil nicotinamide adenine dinucleotide phosphate oxidase activation in response to specific signaling pathways.''; PubMed Europe PMC Scholia
  29. Shibuya M, Claesson-Welsh L.; ''Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis.''; PubMed Europe PMC Scholia
  30. Wearsch PA, Cresswell P.; ''The quality control of MHC class I peptide loading.''; PubMed Europe PMC Scholia
  31. Makni-Maalej K, Marzaioli V, Boussetta T, Belambri SA, Gougerot-Pocidalo MA, Hurtado-Nedelec M, Dang PM, El-Benna J.; ''TLR8, but not TLR7, induces the priming of the NADPH oxidase activation in human neutrophils.''; PubMed Europe PMC Scholia
  32. Ueyama T, Geiszt M, Leto TL.; ''Involvement of Rac1 in activation of multicomponent Nox1- and Nox3-based NADPH oxidases.''; PubMed Europe PMC Scholia
  33. Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L.; ''VEGF-receptor signal transduction.''; PubMed Europe PMC Scholia
  34. Dewas C, Dang PM, Gougerot-Pocidalo MA, El-Benna J.; ''TNF-alpha induces phosphorylation of p47(phox) in human neutrophils: partial phosphorylation of p47phox is a common event of priming of human neutrophils by TNF-alpha and granulocyte-macrophage colony-stimulating factor.''; PubMed Europe PMC Scholia
  35. Raiborg C, Schink KO, Stenmark H.; ''Class III phosphatidylinositol 3-kinase and its catalytic product PtdIns3P in regulation of endocytic membrane traffic.''; PubMed Europe PMC Scholia
  36. Ushio-Fukai M, Tang Y, Fukai T, Dikalov SI, Ma Y, Fujimoto M, Quinn MT, Pagano PJ, Johnson C, Alexander RW.; ''Novel role of gp91(phox)-containing NAD(P)H oxidase in vascular endothelial growth factor-induced signaling and angiogenesis.''; PubMed Europe PMC Scholia
  37. Kao YY, Gianni D, Bohl B, Taylor RM, Bokoch GM.; ''Identification of a conserved Rac-binding site on NADPH oxidases supports a direct GTPase regulatory mechanism.''; PubMed Europe PMC Scholia
  38. Park HS, Park D, Bae YS.; ''Molecular interaction of NADPH oxidase 1 with betaPix and Nox Organizer 1.''; PubMed Europe PMC Scholia
  39. Bouin AP, Grandvaux N, Vignais PV, Fuchs A.; ''p40(phox) is phosphorylated on threonine 154 and serine 315 during activation of the phagocyte NADPH oxidase. Implication of a protein kinase c-type kinase in the phosphorylation process.''; PubMed Europe PMC Scholia
  40. Strupat K, Rogniaux H, Van Dorsselaer A, Roth J, Vogl T.; ''Calcium-induced noncovalently linked tetramers of MRP8 and MRP14 are confirmed by electrospray ionization-mass analysis.''; PubMed Europe PMC Scholia
  41. el Benna J, Faust LP, Babior BM.; ''The phosphorylation of the respiratory burst oxidase component p47phox during neutrophil activation. Phosphorylation of sites recognized by protein kinase C and by proline-directed kinases.''; PubMed Europe PMC Scholia
  42. Fontayne A, Dang PM, Gougerot-Pocidalo MA, El-Benna J.; ''Phosphorylation of p47phox sites by PKC alpha, beta II, delta, and zeta: effect on binding to p22phox and on NADPH oxidase activation.''; PubMed Europe PMC Scholia
  43. El-Benna J, Dang PM, Gougerot-Pocidalo MA, Marie JC, Braut-Boucher F.; ''p47phox, the phagocyte NADPH oxidase/NOX2 organizer: structure, phosphorylation and implication in diseases.''; PubMed Europe PMC Scholia
  44. Loureiro J, Ploegh HL.; ''Antigen presentation and the ubiquitin-proteasome system in host-pathogen interactions.''; PubMed Europe PMC Scholia
  45. Nunes P, Demaurex N, Dinauer MC.; ''Regulation of the NADPH oxidase and associated ion fluxes during phagocytosis.''; PubMed Europe PMC Scholia
  46. Lapouge K, Smith SJ, Groemping Y, Rittinger K.; ''Architecture of the p40-p47-p67phox complex in the resting state of the NADPH oxidase. A central role for p67phox.''; PubMed Europe PMC Scholia
  47. Leukert N, Vogl T, Strupat K, Reichelt R, Sorg C, Roth J.; ''Calcium-dependent tetramer formation of S100A8 and S100A9 is essential for biological activity.''; PubMed Europe PMC Scholia
  48. Ueno N, Takeya R, Miyano K, Kikuchi H, Sumimoto H.; ''The NADPH oxidase Nox3 constitutively produces superoxide in a p22phox-dependent manner: its regulation by oxidase organizers and activators.''; PubMed Europe PMC Scholia
  49. Zhao X, Xu B, Bhattacharjee A, Oldfield CM, Wientjes FB, Feldman GM, Cathcart MK.; ''Protein kinase Cdelta regulates p67phox phosphorylation in human monocytes.''; PubMed Europe PMC Scholia
  50. Miyano K, Ueno N, Takeya R, Sumimoto H.; ''Direct involvement of the small GTPase Rac in activation of the superoxide-producing NADPH oxidase Nox1.''; PubMed Europe PMC Scholia
  51. Berthier S, Nguyen MV, Baillet A, Hograindleur MA, Paclet MH, Polack B, Morel F.; ''Molecular interface of S100A8 with cytochrome b558 and NADPH oxidase activation.''; PubMed Europe PMC Scholia
  52. Purcell AW, Elliott T.; ''Molecular machinations of the MHC-I peptide loading complex.''; PubMed Europe PMC Scholia


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112393view15:32, 9 October 2020ReactomeTeamReactome version 73
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93750view13:33, 16 August 2017ReactomeTeamreactome version 61
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89085view08:02, 22 August 2016EgonwOntology Term : 'signaling pathway' added !
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83210view10:22, 18 November 2015ReactomeTeamVersion54
81596view13:08, 21 August 2015ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
AA MetaboliteCHEBI:15843 (ChEBI)
ADPMetaboliteCHEBI:456216 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
CYBA ProteinP13498 (Uniprot-TrEMBL)
CYBB ProteinP04839 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
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)
NCF1:NCF2:NCF4ComplexR-HSA-9626870 (Reactome)
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 complex:S100A8:S100A9:Ca2+ComplexR-HSA-9626792 (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)
PIN1 ProteinQ13526 (Uniprot-TrEMBL)
PIN1:p-S-345-NCF1:NCF2:NCF4ComplexR-HSA-9626778 (Reactome)
PIN1:p-S-6S-NCF1:NCF2:NCF4ComplexR-HSA-9626814 (Reactome)
PIN1ProteinQ13526 (Uniprot-TrEMBL)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC1:GTPComplexR-HSA-442641 (Reactome)
RAC2 ProteinP15153 (Uniprot-TrEMBL)
RAC2:GTPComplexR-HSA-5668609 (Reactome)

production in

PathwayR-HSA-1222556 (Reactome) The first line of defense against infectious agents involves an active recruitment of phagocytes to the site of infection. Recruited cells include polymorhonuclear (PMN) leukocytes (i.e., neutrophils) and monocytes/macrophages, which function together as innate immunity sentinels (Underhill DM & Ozinsky A 2002; Stuart LM & Ezekowitz RA 2005; Flannagan RS et al. 2012). Dendritic cells are also present, serving as important players in antigen presentation for ensuing adaptive responses (Savina A & Amigorena S 2007). These cell types are able to bind and engulf invading microbes into a membrane-enclosed vacuole - the phagosome, in a process termed phagocytosis. Phagocytosis can be defined as the receptor-mediated engulfment of particles greater than 0.5 micron in diameter. It is initiated by the cross-linking of host cell membrane receptors following engagement with their cognate ligands on the target surface (Underhill DM & Ozinsky A 2002; Stuart LM & Ezekowitz RA 2005; Flannagan RS et al. 2012). When engulfed by phagocytes, microorganisms are exposed to a number of host defense microbicidal events within the resulting phagosome. These include the production of reactive oxygen and nitrogen species (ROS and RNS, RONS) by specialized enzymes (Fang FC et al. 2004; Kohchi C et al. 2009; Gostner JM et al. 2013; Vatansever F et al. 2013). NADPH oxidase (NOX) complex consume oxygen to produce superoxide radical anion (O2.-) and hydrogen peroxide (H2O2) (Robinson et al. 2004). Induced NO synthase (iNOS) is involved in the production of NO, which is the primary source of all RNS in biological systems (Evans TG et al. 1996). The phagocyte NADPH oxidase and iNOS are expressed in both PMN and mononuclear phagocytes and both cell types have the capacity for phagosomal burst activity. However, the magnitude of ROS generation in neutrophils far exceeds that observed in macrophages (VanderVen BC et al. 2009). Macrophages are thought to produce considerably more RNS than neutrophils (Fang FC et al. 2004; Nathan & Shiloh 2000).

The presence of RONS characterized by a relatively low reactivity, such as H2O2, O2˙− or NO, has no deleterious effect on biological environment (Attia SM 2010; Weidinger A & and Kozlov AV 2015). Their activity is controlled by endogenous antioxidants (both enzymatic and non-enzymatic) that are induced by oxidative stress. However the relatively low reactive species can initiate a cascade of reactions to generate more damaging “secondary� species such as hydroxyl radical (•OH), singlet oxygen or peroxinitrite (Robinson JM 2008; Fang FC et al. 2004). These "secondary" RONS are extremely toxic causing irreversible damage to all classes of biomolecules (Weidinger A & and Kozlov AV 2015; Fang FC et al. 2004; Kohchi C et al. 2009; Gostner JM et al. 2013; Vatansever F et al. 2013).

Although macrophages and neutrophils use similar mechanisms for the internalization of targets, there are differences in how they perform phagocytosis and in the final outcome of the process (Tapper H & Grinstein S 1997; Vierira OV et al. 2002). Once formed, the phagosome undergoes an extensive maturation process whereby it develops into a microbicidal organelle able to eliminate the invading pathogen. Maturation involves re-modeling both the membrane of the phagosome and its luminal contents (Vierira OV et al. 2002). In macrophages, phagosome formation and maturation follows a series of strictly coordinated membrane fission/fusion events between the phagosome and compartments of the endo/lysosomal network gradually transforming the nascent phagosome into a phagolysosome, a degradative organelle endowed with potent microbicidal properties (Zimmerli S et al. 1996; Vierira OV et al. 2002). Neutrophils instead contain a large number of preformed granules such as azurophilic and specific granules that can rapidly fuse with phagosomes delivering antimicrobial substances (Karlsson A & Dahlgren C 2002; Naucler C et al. 2002; Nordenfelt P and Tapper H 2011). Phagosomal pH dynamics may also contribute to the maturation process by regulating membrane traffic events. The microbicidal activity of macrophages is characterized by progressive acidification of the lumen (down to pH 4–5) by the proton pumping vATPase. A low pH is a prerequisite for optimal enzymatic activity of most late endosomal/lysosomal hydrolases reported in macrophages. Neutrophil phagosome pH regulation differs significantly from what is observed in macrophages (Nordenfelt P and Tapper H 2011; Winterbourn CC et al. 2016). The massive activation of the oxidative burst is thought to result in early alkalization of neutrophil phagosomes which is linked to proton consumption during the generation of hydrogen peroxide (Segal AW et al. 1981; Levine AP et al. 2015). Other studies showed that neutrophil phagosome maintained neutral pH values before the pH gradually decreased (Jankowski A et al. 2002). Neutrophil phagosomes also exhibited a high proton leak, which was initiated upon activation of the NADPH oxidase, and this activation counteracted phagosomal acidification (Jankowski A et al. 2002).

The Reactome module describes ROS and RNS production by phagocytic cells. The module includes cell-type specific events, for example, myeloperoxidase (MPO)-mediated production of hypochlorous acid in neutrophils. It also highlights differences between phagosomal pH dynamics in neutrophils and macrophages. The module describes microbicidal activity of selective RONS such as hydroxyl radical or peroxynitrite. However, detection of any of these species in the phagosomal environment is subject to many uncertainties (Nüsse O 2011; Erard M et al. 2018). The mechanisms by which reactive oxygen/nitrogen species kill pathogens in phagocytic immune cells are still not fully understood.

S100A8 ProteinP05109 (Uniprot-TrEMBL)
S100A8:S100A9:AA:Ca2+ComplexR-HSA-9626862 (Reactome)
S100A9 ProteinP06702 (Uniprot-TrEMBL)
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.
heme MetaboliteCHEBI:17627 (ChEBI)
p-6S-NCF1 ProteinP14598 (Uniprot-TrEMBL)
p-PKCA,p-PKCB,p-PKCZ,p-PKCDComplexR-HSA-5218754 (Reactome)
p-S-345-NCF1:NCF2:NCF4ComplexR-HSA-9626850 (Reactome)
p-S345-NCF1 ProteinP14598 (Uniprot-TrEMBL)
p-T,Y MAPK dimersComplexR-HSA-1268261 (Reactome)
p-T154,S315-NCF4 ProteinQ15080 (Uniprot-TrEMBL)
p-T180,Y182-MAPK11 ProteinQ15759 (Uniprot-TrEMBL)
p-T180,Y182-MAPK14 ProteinQ16539 (Uniprot-TrEMBL)
p-T185,Y187-MAPK1 ProteinP28482 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3 ProteinP27361 (Uniprot-TrEMBL)
p-T233-NCF2 ProteinP19878 (Uniprot-TrEMBL)
p-T410-PRKCZ ProteinQ05513 (Uniprot-TrEMBL)
p-T497-PRKCA ProteinP17252 (Uniprot-TrEMBL)
p-T500-PRKCB ProteinP05771 (Uniprot-TrEMBL)
p-T507-PRKCD ProteinQ05655 (Uniprot-TrEMBL)
p-p38 MAPK alpha/betaComplexR-HSA-170997 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-6798174 (Reactome)
ADPArrowR-HSA-9626817 (Reactome)
ADPArrowR-HSA-9626832 (Reactome)
ADPArrowR-HSA-9626880 (Reactome)
ATPR-HSA-6798174 (Reactome)
ATPR-HSA-9626817 (Reactome)
ATPR-HSA-9626832 (Reactome)
ATPR-HSA-9626880 (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)
NCF1:NCF2:NCF4R-HSA-9626832 (Reactome)
NCF1:NCF2:NCF4R-HSA-9626880 (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:GTPR-HSA-9626848 (Reactome)
NOX2 complex:RAC2:GTPmim-catalysisR-HSA-5668629 (Reactome)
NOX2 complex:S100A8:S100A9:Ca2+ArrowR-HSA-5668629 (Reactome)
NOX2 complex:S100A8:S100A9:Ca2+ArrowR-HSA-9626848 (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)
PIN1:p-S-345-NCF1:NCF2:NCF4ArrowR-HSA-9626816 (Reactome)
PIN1:p-S-345-NCF1:NCF2:NCF4R-HSA-9626817 (Reactome)
PIN1:p-S-6S-NCF1:NCF2:NCF4ArrowR-HSA-9626817 (Reactome)
PIN1R-HSA-9626816 (Reactome)
PIN1mim-catalysisR-HSA-9626816 (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. PI3P controls ROS production by regulating the presence of NCF4 and NCF2 (p67phox) at the phagosomal membrane (Song ZM et al. 2017).
R-HSA-9626816 (Reactome) Priming agents such as tumor necrosis factor-α (TNFα) and toll like receptor 7 (TLR7)/TLR8 agonists induced the activation of the peptidyl-prolyl cis/trans isomerase PIN1 in human neutrophils (Boussetta T et al. 2010; Makni-Maalej K et al. 2015). PIN1 is an enzyme that binds to phosphorylated Ser�Pro or Thr�Pro sequences, and subsequently catalyzes their conformational changes (Liou YC et al. 2011). In intact neutrophils, PIN1 was found to bind to the neutrophil cytosol factor 1 (NCF1 or p47phox) via the phosphorylated residue of Ser345 (Boussetta T et al. 2010). PIN1 then catalyzed a conformational change of NCF1 that facilitated subsequent phosphorylation of the protein on other sites by protein kinase C (PKC) (Boussetta T et al. 2010; El-Benna J et al. 2016). Extensive phosphorylation of the subunit NCF1 (p47phox) occurs during the activation of the NADPH oxidase (NOX2) in intact cells.
R-HSA-9626817 (Reactome) Neutrophil cytosolic factor 1 (NCF1, also known as p47phox) is a component of the NADPH oxidase (NOX2) complex, which consists of six subunits (Groemping Y et al. 2003; El-Benna J et al. 2005). Two of these subunits, p22phox and gp91phox, are integral membrane proteins and form a heterodimeric flavocytochrome that constitutes the catalytic core of the enzyme. The remaining oxidase components reside in the cytosol and include the small GTPase Rac, as well as a complex of NCF4 (p40phox), NCF1, and NCF2 (p67phox) (Groemping Y et al. 2003; El-Benna J et al. 2005). In the resting state, the interaction of NCF1 (p47phox) with p22phox, and thereby translocation and NADPH oxidase activation, is prevented by an auto-inhibited conformation of NCF1 (Groemping Y et al. 2003; Yuzawa S et al. 2004). This is believed to arise from an intramolecular interaction of the SH3 domains with the C-terminal auto�inhibitory region (AIR) (amino acids 292�340) of NCF1 to keep the protein ‘locked’ (Groemping Y et al. 2003; El Benna J et al. 2016). Priming induced by TNF-α or GM-CSF induces NCF1 phosphorylation on Ser345, activation of the proline isomerase PIN1, which binds to NCF1 to induce conformational changes (Boussetta T et al. 2010). This process facilitates extensive phosphorylation of NCF1 by PKC on other sites and induces full opening of NCF1 (Boussetta T et al. 2010). Phosphorylation studies showed that p47phox is phosphorylated on serines located between Ser303 and Ser379 (El Benna J et al. 1994; 2009). Most of these sites correspond to PKC consensus phosphorylation sites, and PKCα, -β, -δ and -ζ were all shown to phosphorylate NCF1 (p47phox) in vitro or in human neutrophil�like HL�60 cells (Dang PM et al. 2001; Fontayne A et al. 2002; Belambri SA et al. 2018). In vitro studies also showed that phosphorylation of p47phox induced its binding to the proline rich region (PRR) of p22phox and enhanced the binding of NCF2 (p67phox) to gp91phox (Fontayne A et al. 2002; Dang PMC et al. 2002; Boussetta T et al. 2010).

The Reactome event depicts the PKC-mediated phosphorylation of NCF1 on Ser303, Ser304, Ser320, Ser328, Ser348. However, NCF1 becomes phosphorylated by PKCs on multiple sites and the number of sites is not defined.

R-HSA-9626832 (Reactome) In resting cells, the NADPH oxidase components, NCF1 (p47phox), NCF2 (p67phox), and NCF4 (p40phox) are located in the cytosol where they associate in a trimer complex with a 1:1:1 stoichiometry through specific domains (Groemping Y & Rittinger K 2005; El-Benna J et al. 2005; Park JW et al. 1994; Lapouge K et al. 2002; El-Benna J et al. 2016). However, NCF1 may also exist separately from the trimer (El-Benna J et al. 2016). In the resting state, two SH3 domains of NCF1 (p47phox) bind the auto�inhibitory region (AIR; amino acids 292�340) to keep NCF1 in a closed auto�inhibited state, preventing its binding to p22phox and therefore NOX2 activation (Groemping Y et al. 2003; Yuzawa S et al. 2004; El-Benna J et al. 2016). Priming of neutrophils by several agents such as GM�CSF, TNFα, PAF, LPS and CL097, a TLR7/8 agonist, induces partial phosphorylation of NCF1 (Makni-Maalej K et al. 2015; Dang PM et al. 1999; Dewas C et al. 2003; DeLeo FR et al. 1998). Mass spectrometry analysis of NCF1 identified Ser345 as the phosphorylated site in neutrophils primed by TNFα and GM�CSF, and site�directed mutagenesis of Ser345 and use of a competitive inhibitory peptide containing the Ser345 sequence have demonstrated that this step is critical for the priming of ROS production in human neutrophils (Dang PMC et al. 2006). Further, inhibitors of the MAPK1 and MAPK3 (ERK1/2) pathway abrogated GM-CSF-induced phosphorylation of Ser345 (Dang PMC et al. 2006).
R-HSA-9626848 (Reactome) Ca(2+) flux across the phagosomal membrane influences NADPH oxidase activity and ROS production. Phagocytic engagement of Fc gamma receptor (FcγR) or complement receptor 3 (CR3) activate phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), leading to the formation of PI(3,4,5)P3. This phospholipid participates in the activation of phospholipase γ C (PLCγ) and phospholipase D (PLD)-mediated downstream signaling pathways. The generation of IP3 by PLCγ triggers Ca(2+) release from intracellular stores (endoplasmic reticulum, ER) via the opening of IP3 receptors (IP3-R). PLD is involved in the process of sphingosine kinase-produced sphingosine 1-phosphate (S1P), leading to the depletion of intracellular Ca(2+) stores. The emptying of intracellular Ca2+ stores induces the activation of the Ca(2+) sensor stromal interaction molecule-1 (STIM1), which, in turn, activates calcium release-activated calcium channel protein 1 (ORAI1) at the plasma membrane and extracellular Ca(2+) entry. The resulting elevation of Ca(2+) mediates the recruitment of the cytosolic Ca(2+)-activated regulators S100A8 (also know as migration inhibitory factor-related proteins 8 (MRP8)) and S100A9 (MRP14) to the phagosomal membrane (Berthier S et al. 2003, 2012; Steinckwich N et al. 2011; Bréchard S et al. 2013). The translocation of S100A8:S100A9 allows the transfer of S100A9-binding arachidonic acid (AA) to cytochrome b558, favoring the conformational change of cytochrome b558 and promoting intraphagosomal NADPH oxidase activation and ROS production (Berthier S et al. 2003, 2012; Doussiere J et L. 2002; Kerkhoff C et al. 2005; Steinckwich N et al. 2011; Bréchard S et al. 2013 ). S100A8 & S100A9 exist mainly as a S100A8:S100A9 heterodimer which is termed calprotectin based on its role in innate immunity (Korndorfer IP et al. 2007). Ca(2+) is also known to stimulate formation of higher order oligomers of S100 proteins, including S100A8/S100A9 tetramers (Leukert N et al. 2006; Korndörfer IP et al. 2007). In addition, calprotectin has been shown to inhibit bacterial growth through chelation of extracellular manganese Mn(2+), zinc Zn(2+) and possibly iron Fe(2+) and thus restricting metal-ion availability during infection (Damo SM et al. 2013; Hayden JA et al. 2013; Brophy MB et al. 2013; Gagnon DM et al. 2015).
R-HSA-9626880 (Reactome) In resting cells, the neutrophil cytosolic factor 1 (NCF1, also known as p47phox), NCF2 (p67phox), and NCF4 (p40phox) are located in the cytosol where they associate in a trimer complex with a 1:1:1 stoichiometry through specific domains (Groemping Y & Rittinger K 2005; El-Benna J et al. 2005; Park JW et al. 1994; Lapouge K et al. 2002; El-Benna J et al. 2016). However, NCF1 may also exist separately from the trimer (El-Benna J et al. 2016). In the resting state, two SH3 domains of NCF1 (p47phox) bind the auto�inhibitory region (AIR; amino acids 292�340) to keep NCF1 in a closed auto�inhibited state, preventing its binding to p22phox and therefore NOX2 activation (Groemping Y et al. 2003; Yuzawa S et al. 2004; El-Benna J et al. 2016). Priming of neutrophils by several agents such as GM�CSF, TNFα, PAF, LPS and CL097, a TLR7/8 agonist, induces partial phosphorylation of NCF1 (Makni-Maalej K et al. 2015; Dang PM et al. 1999; Dewas C et al. 2003; DeLeo FR et al. 1998). Mass spectrometry analysis of NCF1 identified Ser345 as the phosphorylated site in human neutrophils primed by TNFα and GM�CSF (Dang PMC et al. 2006). Site�directed mutagenesis of Ser345 and use of a competitive inhibitory peptide containing the Ser345 sequence have demonstrated that this step is critical for the priming of ROS production in human neutrophils (Dang PMC et al. 2006). Further, inhibitors of the p38 MAPK abrogated TNF-alpha- and TLR8 agonist-induced phosphorylation of Ser345 (Dang PMC et al. 2006; Makni-Maalej K et al. 2015).
RAC1:GTPR-HSA-5218827 (Reactome)
RAC1:GTPR-HSA-5668714 (Reactome)
RAC1:GTPR-HSA-5668735 (Reactome)
RAC2:GTPR-HSA-5668605 (Reactome)
S100A8:S100A9:AA:Ca2+R-HSA-9626848 (Reactome)
p-PKCA,p-PKCB,p-PKCZ,p-PKCDmim-catalysisR-HSA-9626817 (Reactome)
p-S-345-NCF1:NCF2:NCF4ArrowR-HSA-9626832 (Reactome)
p-S-345-NCF1:NCF2:NCF4ArrowR-HSA-9626880 (Reactome)
p-S-345-NCF1:NCF2:NCF4R-HSA-9626816 (Reactome)
p-T,Y MAPK dimersmim-catalysisR-HSA-9626832 (Reactome)
p-p38 MAPK alpha/betamim-catalysisR-HSA-9626880 (Reactome)

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