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Gene Review

NCF2  -  neutrophil cytosolic factor 2

Homo sapiens

Synonyms: 67 kDa neutrophil oxidase factor, NADPH oxidase activator 2, NCF-2, NOXA2, Neutrophil NADPH oxidase factor 2, ...
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Disease relevance of NCF2


Psychiatry related information on NCF2


High impact information on NCF2

  • Rac1 interacted directly with p67phox in a GTP-dependent manner [6].
  • Interaction of Rac with p67phox and regulation of phagocytic NADPH oxidase activity [6].
  • Oxidase activity was reconstituted in vitro with only the purified oxidase proteins p47phox, p67phox, Rac-related guanine nucleotide (GTP)-binding proteins, and membrane-bound cytochrome b558 [7].
  • A 65-kilodalton factor, NCF-2, restored activity to defective neutrophil cytosol from one patient with autosomal CGD [8].
  • NCF-1, NCF-2, and a third cytosol fraction, NCF-3, were inactive alone or in pairs, but together replaced unfractionated cytosol in cell-free O2.- generation [8].

Chemical compound and disease context of NCF2


Biological context of NCF2

  • p67(phox) and gp91(phox) are components of the phagocyte-specific respiratory burst oxidase that are encoded by the NCF2 and CYBB genes, respectively [13].
  • In contrast, RNA decay assays demonstrated that there was no significant difference between stability of NCF2 intron 1 transcripts and the exon 1 5'-UTR variant in HL-60, MonoMac 6, and U937 cells [14].
  • Haplotype analyses and homozygosity mapping with microsatellite markers around known CGD genes assigned the genetic defect to NCF1 in four patients, to NCF2 in four patients and to CYBA in two patients [15].
  • Two are cytosolic components (p47-phox and p67-phox) that contain Src homology 3 (SH3) domains and associate with a transmembrane cytochrome b558 upon activation [16].
  • Approximately 5% of CGD patients have an autosomal recessive form of disease caused by a severe deficiency of p67-phox, a 526-amino acid subunit of the oxidase that appears to regulate electron transport within the enzyme [10].

Anatomical context of NCF2


Associations of NCF2 with chemical compounds

  • These results provide the first demonstration that p40phox is practically involved in the activation of NADPH oxidase through the association of its COOH-terminal, but not its NH2-terminal, with p67phox [1].
  • However, these accumulations of Rac in the membrane, as well as that of p47phox and p67phox, were also regulated by Src tyrosine kinases [20].
  • We previously reported that p67phox is essential for adventitial fibroblast NADPH oxidase O2- production [2].
  • These results suggest that neither p47-phox nor p67-phox is a flavoprotein and that neither, therefore, is the oxidase component which accepts electrons from NADPH [21].
  • However, neither FAD nor FMN was localized in the precipitates, even though substantial amounts of p47-phox and p67-phox precipitated [21].

Physical interactions of NCF2

  • The protein p51nox as well as p67phox can form a complex with p47phox and with p41nox via the C-terminal SH3 domain and binds to GTP-bound Rac via the N-terminal domain containing four tetratricopeptide repeat motifs [22].
  • We identify a sequence in the NCF2 promoter that is homologous to the HoxA10-binding CYBB cis element [13].
  • We hypothesize that Rac-GTP binds the p67phox N-terminal domain encompassing amino acids 170-199 that transmits a conformational change which causes p40phox to dissociate from its binding site in the p67phox C-terminus [23].
  • Assembly of the human neutrophil NADPH oxidase involves binding of p67phox and flavocytochrome b to a common functional domain in p47phox [24].

Regulatory relationships of NCF2


Other interactions of NCF2


Analytical, diagnostic and therapeutic context of NCF2


  1. Involvement of p40phox in activation of phagocyte NADPH oxidase through association of its carboxyl-terminal, but not its amino-terminal, with p67phox. Tsunawaki, S., Kagara, S., Yoshikawa, K., Yoshida, L.S., Kuratsuji, T., Namiki, H. J. Exp. Med. (1996) [Pubmed]
  2. Adventitial delivery of dominant-negative p67phox attenuates neointimal hyperplasia of the rat carotid artery. Weaver, M., Liu, J., Pimentel, D., Reddy, D.J., Harding, P., Peterson, E.L., Pagano, P.J. Am. J. Physiol. Heart Circ. Physiol. (2006) [Pubmed]
  3. Partial reconstitution of the respiratory burst oxidase in lymphoblastoid B cell lines lacking p67-phox after transfection with an expression vector containing wild-type and mutant p67 -phox cDNAs: Deletions of the carboxy and amino terminal residues of p67-phox are not required for activity. Chanock, S.J., Faust, L.R., Barrett, D., Christensen, B., Newburger, P.E., Babior, B.M. Exp. Hematol. (1996) [Pubmed]
  4. NADPH oxidase in human lung fibroblasts. Dhaunsi, G.S., Paintlia, M.K., Kaur, J., Turner, R.B. J. Biomed. Sci. (2004) [Pubmed]
  5. Activation of NADPH oxidase in Alzheimer's disease brains. Shimohama, S., Tanino, H., Kawakami, N., Okamura, N., Kodama, H., Yamaguchi, T., Hayakawa, T., Nunomura, A., Chiba, S., Perry, G., Smith, M.A., Fujimoto, S. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  6. Interaction of Rac with p67phox and regulation of phagocytic NADPH oxidase activity. Diekmann, D., Abo, A., Johnston, C., Segal, A.W., Hall, A. Science (1994) [Pubmed]
  7. Cytochrome b558: the flavin-binding component of the phagocyte NADPH oxidase. Rotrosen, D., Yeung, C.L., Leto, T.L., Malech, H.L., Kwong, C.H. Science (1992) [Pubmed]
  8. Two forms of autosomal chronic granulomatous disease lack distinct neutrophil cytosol factors. Nunoi, H., Rotrosen, D., Gallin, J.I., Malech, H.L. Science (1988) [Pubmed]
  9. Role of Src homology 3 domains in assembly and activation of the phagocyte NADPH oxidase. Sumimoto, H., Kage, Y., Nunoi, H., Sasaki, H., Nose, T., Fukumaki, Y., Ohno, M., Minakami, S., Takeshige, K. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  10. Molecular characterization of autosomal recessive chronic granulomatous disease caused by a defect of the nicotinamide adenine dinucleotide phosphate (reduced form) oxidase component p67-phox. Patiño, P.J., Rae, J., Noack, D., Erickson, R., Ding, J., de Olarte, D.G., Curnutte, J.T. Blood (1999) [Pubmed]
  11. The p67-phox cytosolic peptide of the respiratory burst oxidase from human neutrophils. Functional aspects. Okamura, N., Babior, B.M., Mayo, L.A., Peveri, P., Smith, R.M., Curnutte, J.T. J. Clin. Invest. (1990) [Pubmed]
  12. Transient association of the nicotinamide adenine dinucleotide phosphate oxidase subunits p47phox and p67phox with phagosomes in neutrophils from patients with X-linked chronic granulomatous disease. Allen, L.A., DeLeo, F.R., Gallois, A., Toyoshima, S., Suzuki, K., Nauseef, W.M. Blood (1999) [Pubmed]
  13. HoxA10 represses transcription of the gene encoding p67phox in phagocytic cells. Lindsey, S., Zhu, C., Lu, Y.F., Eklund, E.A. J. Immunol. (2005) [Pubmed]
  14. Variants of the 5'-untranslated region of human NCF2: expression and translational efficiency. Gauss, K.A., Bunger, P.L., Crawford, M.A., McDermott, B.E., Swearingen, R., Nelson-Overton, L.K., Siemsen, D.W., Kobayashi, S.D., Deleo, F.R., Quinn, M.T. Gene (2006) [Pubmed]
  15. Genetic and mutational heterogeneity of autosomal recessive chronic granulomatous disease in Tunisia. El Kares, R., Barbouche, M.R., Elloumi-Zghal, H., Bejaoui, M., Chemli, J., Mellouli, F., Tebib, N., Abdelmoula, M.S., Boukthir, S., Fitouri, Z., M'rad, S., Bouslama, K., Touiri, H., Abdelhak, S., Dellagi, M.K. J. Hum. Genet. (2006) [Pubmed]
  16. Assembly of the phagocyte NADPH oxidase: binding of Src homology 3 domains to proline-rich targets. Leto, T.L., Adams, A.G., de Mendez, I. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  17. Genes for two autosomal recessive forms of chronic granulomatous disease assigned to 1q25 (NCF2) and 7q11.23 (NCF1). Francke, U., Hsieh, C.L., Foellmer, B.E., Lomax, K.J., Malech, H.L., Leto, T.L. Am. J. Hum. Genet. (1990) [Pubmed]
  18. SHP1 protein-tyrosine phosphatase inhibits gp91PHOX and p67PHOX expression by inhibiting interaction of PU.1, IRF1, interferon consensus sequence-binding protein, and CREB-binding protein with homologous Cis elements in the CYBB and NCF2 genes. Kautz, B., Kakar, R., David, E., Eklund, E.A. J. Biol. Chem. (2001) [Pubmed]
  19. SHP1 protein-tyrosine phosphatase regulates HoxA10 DNA binding and transcriptional repression activity in undifferentiated myeloid cells. Eklund, E.A., Goldenberg, I., Lu, Y., Andrejic, J., Kakar, R. J. Biol. Chem. (2002) [Pubmed]
  20. Down-regulation of Rac activity during beta 2 integrin-mediated adhesion of human neutrophils. Dib, K., Melander, F., Axelsson, L., Dagher, M.C., Aspenström, P., Andersson, T. J. Biol. Chem. (2003) [Pubmed]
  21. Two cytosolic components of the neutrophil NADPH oxidase, P47-phox and P67-phox, are not flavoproteins. Chiba, T., Kaneda, M., Fujii, H., Clark, R.A., Nauseef, W.M., Kakinuma, K. Biochem. Biophys. Res. Commun. (1990) [Pubmed]
  22. Novel human homologues of p47phox and p67phox participate in activation of superoxide-producing NADPH oxidases. Takeya, R., Ueno, N., Kami, K., Taura, M., Kohjima, M., Izaki, T., Nunoi, H., Sumimoto, H. J. Biol. Chem. (2003) [Pubmed]
  23. Rac1 disrupts p67phox/p40phox binding: a novel role for Rac in NADPH oxidase activation. Rinckel, L.A., Faris, S.L., Hitt, N.D., Kleinberg, M.E. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  24. Assembly of the human neutrophil NADPH oxidase involves binding of p67phox and flavocytochrome b to a common functional domain in p47phox. De Leo, F.R., Ulman, K.V., Davis, A.R., Jutila, K.L., Quinn, M.T. J. Biol. Chem. (1996) [Pubmed]
  25. Expression of a functionally active gp91phox-containing neutrophil-type NAD(P)H oxidase in smooth muscle cells from human resistance arteries: regulation by angiotensin II. Touyz, R.M., Chen, X., Tabet, F., Yao, G., He, G., Quinn, M.T., Pagano, P.J., Schiffrin, E.L. Circ. Res. (2002) [Pubmed]
  26. Recruitment of CREB-binding protein by PU.1, IFN-regulatory factor-1, and the IFN consensus sequence-binding protein is necessary for IFN-gamma-induced p67phox and gp91phox expression. Eklund, E.A., Kakar, R. J. Immunol. (1999) [Pubmed]
  27. A 29-kDa protein associated with p67phox expresses both peroxiredoxin and phospholipase A2 activity and enhances superoxide anion production by a cell-free system of NADPH oxidase activity. Leavey, P.J., Gonzalez-Aller, C., Thurman, G., Kleinberg, M., Rinckel, L., Ambruso, D.W., Freeman, S., Kuypers, F.A., Ambruso, D.R. J. Biol. Chem. (2002) [Pubmed]
  28. Identification of a novel tumor necrosis factor alpha-responsive region in the NCF2 promoter. Gauss, K.A., Bunger, P.L., Larson, T.C., Young, C.J., Nelson-Overton, L.K., Siemsen, D.W., Quinn, M.T. J. Leukoc. Biol. (2005) [Pubmed]
  29. Neutrophil nicotinamide adenine dinucleotide phosphate oxidase assembly. Translocation of p47-phox and p67-phox requires interaction between p47-phox and cytochrome b558. Heyworth, P.G., Curnutte, J.T., Nauseef, W.M., Volpp, B.D., Pearson, D.W., Rosen, H., Clark, R.A. J. Clin. Invest. (1991) [Pubmed]
  30. A point mutation in gp91-phox of cytochrome b558 of the human NADPH oxidase leading to defective translocation of the cytosolic proteins p47-phox and p67-phox. Leusen, J.H., de Boer, M., Bolscher, B.G., Hilarius, P.M., Weening, R.S., Ochs, H.D., Roos, D., Verhoeven, A.J. J. Clin. Invest. (1994) [Pubmed]
  31. Superoxide release and NADPH oxidase components in mature human phagocytes: correlation between functional capacity and amount of functional proteins. Yagisawa, M., Yuo, A., Yonemaru, M., Imajoh-Ohmi, S., Kanegasaki, S., Yazaki, Y., Takaku, F. Biochem. Biophys. Res. Commun. (1996) [Pubmed]
  32. Molecular mechanism for activation of superoxide-producing NADPH oxidases. Takeya, R., Sumimoto, H. Mol. Cells (2003) [Pubmed]
  33. A constitutive NADPH oxidase-like system containing gp91phox homologs in human keratinocytes. Chamulitrat, W., Stremmel, W., Kawahara, T., Rokutan, K., Fujii, H., Wingler, K., Schmidt, H.H., Schmidt, R. J. Invest. Dermatol. (2004) [Pubmed]
  34. P67-phox-mediated NADPH oxidase assembly: imaging of cytochrome b558 liposomes by atomic force microscopy. Paclet, M.H., Coleman, A.W., Vergnaud, S., Morel, F. Biochemistry (2000) [Pubmed]
  35. The functional expression of p47-phox and p67-phox may contribute to the generation of superoxide by an NADPH oxidase-like system in human fibroblasts. Jones, S.A., Wood, J.D., Coffey, M.J., Jones, O.T. FEBS Lett. (1994) [Pubmed]
  36. Activation of NADPH oxidase of human neutrophils involves the phosphorylation and the translocation of cytosolic p67phox. Dusi, S., Rossi, F. Biochem. J. (1993) [Pubmed]
  37. The PC motif: a novel and evolutionarily conserved sequence involved in interaction between p40phox and p67phox, SH3 domain-containing cytosolic factors of the phagocyte NADPH oxidase. Nakamura, R., Sumimoto, H., Mizuki, K., Hata, K., Ago, T., Kitajima, S., Takeshige, K., Sakaki, Y., Ito, T. Eur. J. Biochem. (1998) [Pubmed]
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