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NCF4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1H6H, 1OEY, 1W6X, 1W70, 1Z9Q, 2DYB
Identifiers
Aliases	NCF4, NCF, P40PHOX, SH3PXD4, Neutrophil cytosolic factor 4, CGD3
External IDs	OMIM: 601488; MGI: 109186; HomoloGene: 525; GeneCards: NCF4; OMA:NCF4 - orthologs
Gene location (Human) Chr. Chromosome 22 (human) Band 22q12.3 Start 36,860,988 bp End 36,878,017 bp
Gene location (Mouse) Chr. Chromosome 15 (mouse) Band 15 E1|15 37.1 cM Start 78,129,001 bp End 78,146,780 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in blood spleen granulocyte bone marrow monocyte bone marrow cells appendix lymph node synovial membrane placenta Top expressed in granulocyte blood tibiofemoral joint spleen mesenteric lymph nodes bone marrow fetal liver hematopoietic progenitor cell stroma of bone marrow embryo internal carotid artery More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein dimerization activity phosphatidylinositol-3-phosphate binding protein binding phosphatidylinositol binding lipid binding superoxide-generating NADPH oxidase activator activity Cellular component cytoplasm cytosol endosome membrane phagolysosome endosome membrane trans-Golgi network NADPH oxidase complex Biological process vascular endothelial growth factor receptor signaling pathway immune response positive regulation of catalytic activity vesicle-mediated transport phagocytosis respiratory burst superoxide metabolic process antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent cellular response to oxidative stress cell redox homeostasis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4689 17972 Ensembl ENSG00000275990 ENSG00000100365 ENSMUSG00000071715 UniProt Q15080 P97369 RefSeq (mRNA) NM_000631 NM_013416 NM_008677 RefSeq (protein) NP_000622 NP_038202 NP_032703 Location (UCSC) Chr 22: 36.86 – 36.88 Mb Chr 15: 78.13 – 78.15 Mb PubMed search
Wikidata
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Neutrophil cytosol factor 4 is a protein that in humans is encoded by the NCF4 gene.

Function

The protein encoded by this gene is a cytosolic regulatory component of the superoxide-producing phagocyte NADPH-oxidase, a multicomponent enzyme system important for host defense. This protein is preferentially expressed in cells of myeloid lineage. It interacts primarily with neutrophil cytosolic factor 2 (NCF2/p67-phox) to form a complex with neutrophil cytosolic factor 1 (NCF1/p47-phox), which further interacts with the small G protein RAC1 and translocates to the membrane upon cell stimulation. This complex then activates flavocytochrome b, the membrane-integrated catalytic core of the enzyme system. The PX domain of this protein can bind phospholipid products of the PI(3) kinase, which suggests its role in PI(3) kinase-mediated signaling events. The phosphorylation of this protein was found to negatively regulate the enzyme activity. Alternatively spliced transcript variants encoding distinct isoforms have been observed.

Clinical significance

GWAS studies showed that Crohn's disease patient with certain SNPs in NCF4 are more susceptible to get Crohn's disease. Crohn's patient with rs4821544 variants showed a decreased reactive oxygen species after stimulation with GM-CSF which is a proinflammtory cytokine.

Interactions

Neutrophil cytosolic factor 4 has been shown to interact with Ku70, Neutrophil cytosolic factor 1 and Moesin.

References

1. ^ ENSG00000100365 GRCh38: Ensembl release 89: ENSG00000275990, ENSG00000100365 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000071715 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Zhan S, Vazquez N, Zhan S, Wientjes FB, Budarf ML, Schrock E, Ried T, Green ED, Chanock SJ (Nov 1996). "Genomic structure, chromosomal localization, start of transcription, and tissue expression of the human p40-phox, a new component of the nicotinamide adenine dinucleotide phosphate-oxidase complex". Blood. 88 (7): 2714–21. doi:10.1182/blood.V88.7.2714.bloodjournal8872714. PMID 8839867.
6. "Entrez Gene: NCF4 neutrophil cytosolic factor 4, 40kDa".
7. Muise AM, Xu W, Guo CH, Walters TD, Wolters VM, Fattouh R, Lam GY, Hu P, Murchie R, Sherlock M, Gana JC, Russell RK, Glogauer M, Duerr RH, Cho JH, Lees CW, Satsangi J, Wilson DC, Paterson AD, Griffiths AM, Silverberg MS, Brumell JH (2012). "NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2". Gut. 61 (7): 1028–35. doi:10.1136/gutjnl-2011-300078. PMC 3806486. PMID 21900546.
8. Somasundaram R, Deuring JJ, van der Woude CJ, Peppelenbosch MP, Fuhler GM (2012). "Linking risk conferring mutations in NCF4 to functional consequences in Crohn's disease". Gut. 61 (7): 1097, author reply 1097–8. doi:10.1136/gutjnl-2011-301344. PMID 22027479. S2CID 5315006.
9. Grandvaux N, Grizot S, Vignais PV, Dagher MC (Feb 1999). "The Ku70 autoantigen interacts with p40phox in B lymphocytes". J. Cell Sci. 112 ( Pt 4) (4): 503–13. doi:10.1242/jcs.112.4.503. PMID 9914162.
10. Lapouge K, Smith SJ, Groemping Y, Rittinger K (Mar 2002). "Architecture of the p40-p47-p67phox complex in the resting state of the NADPH oxidase. A central role for p67phox". J. Biol. Chem. 277 (12): 10121–8. doi:10.1074/jbc.M112065200. PMID 11796733.
11. Grizot S, Grandvaux N, Fieschi F, Fauré J, Massenet C, Andrieu JP, Fuchs A, Vignais PV, Timmins PA, Dagher MC, Pebay-Peyroula E (Mar 2001). "Small angle neutron scattering and gel filtration analyses of neutrophil NADPH oxidase cytosolic factors highlight the role of the C-terminal end of p47phox in the association with p40phox". Biochemistry. 40 (10): 3127–33. doi:10.1021/bi0028439. PMID 11258927.
12. Sathyamoorthy M, de Mendez I, Adams AG, Leto TL (Apr 1997). "p40(phox) down-regulates NADPH oxidase activity through interactions with its SH3 domain". J. Biol. Chem. 272 (14): 9141–6. doi:10.1074/jbc.272.14.9141. PMID 9083043.
13. Wientjes FB, Reeves EP, Soskic V, Furthmayr H, Segal AW (Nov 2001). "The NADPH oxidase components p47(phox) and p40(phox) bind to moesin through their PX domain". Biochem. Biophys. Res. Commun. 289 (2): 382–8. doi:10.1006/bbrc.2001.5982. PMID 11716484.

Further reading

• Matute JD, Arias AA, Dinauer MC, Patiño PJ (2006). "p40phox: the last NADPH oxidase subunit". Blood Cells Mol. Dis. 35 (2): 291–302. doi:10.1016/j.bcmd.2005.06.010. PMID 16102984.
• Jones JH (1977). "The essence of operating room nursing. Paramedical personnel". Australas Nurses J. 7 (1): 44–5, 63–4. PMID 243433.
• Leto TL, Adams AG, de Mendez I (1994). "Assembly of the phagocyte NADPH oxidase: binding of Src homology 3 domains to proline-rich targets". Proc. Natl. Acad. Sci. U.S.A. 91 (22): 10650–4. Bibcode:1994PNAS...9110650L. doi:10.1073/pnas.91.22.10650. PMC 45079. PMID 7938008.
• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Tsunawaki S, Mizunari H, Nagata M, Tatsuzawa O, Kuratsuji T (1994). "A novel cytosolic component, p40phox, of respiratory burst oxidase associates with p67phox and is absent in patients with chronic granulomatous disease who lack p67phox". Biochem. Biophys. Res. Commun. 199 (3): 1378–87. doi:10.1006/bbrc.1994.1383. PMID 8147882.
• Wientjes FB, Hsuan JJ, Totty NF, Segal AW (1993). "p40phox, a third cytosolic component of the activation complex of the NADPH oxidase to contain src homology 3 domains". Biochem. J. 296 ( Pt 3) (3): 557–61. doi:10.1042/bj2960557. PMC 1137734. PMID 8280052.
• Dusi S, Donini M, Rossi F (1996). "Mechanisms of NADPH oxidase activation: translocation of p40phox, Rac1 and Rac2 from the cytosol to the membranes in human neutrophils lacking p47phox or p67phox". Biochem. J. 314 ( Pt 2) (2): 409–12. doi:10.1042/bj3140409. PMC 1217064. PMID 8670049.
• Someya A, Nagaoka I, Nunoi H, Yamashita T (1996). "Translocation of guinea pig p40-phox during activation of NADPH oxidase". Biochim. Biophys. Acta. 1277 (3): 217–25. doi:10.1016/s0005-2728(96)00099-0. PMID 8982388.
• Sathyamoorthy M, de Mendez I, Adams AG, Leto TL (1997). "p40(phox) down-regulates NADPH oxidase activity through interactions with its SH3 domain". J. Biol. Chem. 272 (14): 9141–6. doi:10.1074/jbc.272.14.9141. PMID 9083043.
• Grogan A, Reeves E, Keep N, Wientjes F, Totty NF, Burlingame AL, Hsuan JJ, Segal AW (1997). "Cytosolic phox proteins interact with and regulate the assembly of coronin in neutrophils". J. Cell Sci. 110 ( Pt 24) (24): 3071–81. doi:10.1242/jcs.110.24.3071. PMID 9365277.
• Fuchs A, Bouin AP, Rabilloud T, Vignais PV (1997). "The 40-kDa component of the phagocyte NADPH oxidase (p40phox) is phosphorylated during activation in differentiated HL60 cells". Eur. J. Biochem. 249 (2): 531–9. doi:10.1111/j.1432-1033.1997.00531.x. PMID 9370364.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Bouin AP, Grandvaux N, Vignais PV, Fuchs A (1998). "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". J. Biol. Chem. 273 (46): 30097–103. doi:10.1074/jbc.273.46.30097. PMID 9804763.
• Grandvaux N, Grizot S, Vignais PV, Dagher MC (1999). "The Ku70 autoantigen interacts with p40phox in B lymphocytes". J. Cell Sci. 112 ( Pt 4) (4): 503–13. doi:10.1242/jcs.112.4.503. PMID 9914162.
• Nishiyama A, Ohno T, Iwata S, Matsui M, Hirota K, Masutani H, Nakamura H, Yodoi J (1999). "Demonstration of the interaction of thioredoxin with p40phox, a phagocyte oxidase component, using a yeast two-hybrid system". Immunol. Lett. 68 (1): 155–9. doi:10.1016/S0165-2478(99)00045-0. PMID 10397171.
• Hasebe T, Someya A, Nagaoka I (1999). "Identification of a splice variant mRNA of p40phox, an NADPH oxidase component of phagocytes". FEBS Lett. 455 (3): 257–61. doi:10.1016/S0014-5793(99)00905-9. PMID 10437784. S2CID 23509959.
• Dunham I, Shimizu N, Roe BA, Chissoe S, Hunt AR, Collins JE, Bruskiewich R, Beare DM, Clamp M, Smink LJ, Ainscough R, Almeida JP, Babbage A, Bagguley C, Bailey J, Barlow K, Bates KN, Beasley O, Bird CP, Blakey S, Bridgeman AM, Buck D, Burgess J, Burrill WD, O'Brien KP (1999). "The DNA sequence of human chromosome 22". Nature. 402 (6761): 489–95. Bibcode:1999Natur.402..489D. doi:10.1038/990031. PMID 10591208.
• Vergnaud S, Paclet MH, El Benna J, Pocidalo MA, Morel F (2000). "Complementation of NADPH oxidase in p67-phox-deficient CGD patients p67-phox/p40-phox interaction". Eur. J. Biochem. 267 (4): 1059–67. doi:10.1046/j.1432-1327.2000.01097.x. PMID 10672014.
• Grizot S, Grandvaux N, Fieschi F, Fauré J, Massenet C, Andrieu JP, Fuchs A, Vignais PV, Timmins PA, Dagher MC, Pebay-Peyroula E (2001). "Small angle neutron scattering and gel filtration analyses of neutrophil NADPH oxidase cytosolic factors highlight the role of the C-terminal end of p47phox in the association with p40phox". Biochemistry. 40 (10): 3127–33. doi:10.1021/bi0028439. PMID 11258927.

• Genes on human chromosome 22
• Proteins