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Identification
HMDB Protein ID HMDBP08280
Secondary Accession Numbers
  • 13992
Name NADPH oxidase 4
Synonyms
  1. KOX-1
  2. Kidney oxidase-1
  3. Kidney superoxide-producing NADPH oxidase
  4. Renal NAD(P)H-oxidase
Gene Name NOX4
Protein Type Unknown
Biological Properties
General Function Involved in oxidoreductase activity
Specific Function Constitutive NADPH oxidase which generates superoxide intracellularly upon formation of a complex with CYBA/p22phox. Regulates signaling cascades probably through phosphatases inhibition. May function as an oxygen sensor regulating the KCNK3/TASK-1 potassium channel and HIF1A activity. May regulate insulin signaling cascade. May play a role in apoptosis, bone resorption and lipolysaccharide-mediated activation of NFKB. May produce superoxide in the nucleus and play a role in regulating gene expression upon cell stimulation. Isoform 3 is not functional. Isoform 4 displays an increased activity. Isoform 5 and isoform 6 display reduced activity
Pathways
  • Thyroid hormone synthesis
  • Tyrosine Metabolism
Reactions Not Available
GO Classification
Component
membrane
cell part
membrane part
intrinsic to membrane
integral to membrane
Function
ion binding
cation binding
metal ion binding
binding
catalytic activity
transition metal ion binding
nucleoside binding
purine nucleoside binding
adenyl nucleotide binding
electron carrier activity
iron ion binding
oxidoreductase activity
fad or fadh2 binding
Process
metabolic process
oxidation reduction
Cellular Location
  1. Cell membrane
  2. Endoplasmic reticulum membrane
  3. Multi-pass membrane protein
  4. Multi-pass membrane protein (Probable)
  5. Nucleus (Probable)
  6. Cell junction
  7. focal adhesion (Probable)
Gene Properties
Chromosome Location Chromosome:1
Locus 11q14.2-q21
SNPs NOX4
Gene Sequence
>1737 bp
ATGGCTGTGTCCTGGAGGAGCTGGCTCGCCAACGAAGGGGTTAAACACCTCTGCCTGTTC
ATCTGGCTCTCCATGAATGTCCTGCTTTTCTGGAAAACCTTCTTGCTGTATAACCAAGGG
CCAGAGTATCACTACCTCCACCAGATGTTGGGGCTAGGATTGTGTCTAAGCAGAGCCTCA
GCATCTGTTCTTAACCTCAACTGCAGCCTTATCCTTTTACCCATGTGCCGAACACTCTTG
GCTTACCTCCGAGGATCACAGAAGGTTCCAAGCAGGAGAACCAGGAGATTGTTGGATAAA
AGCAGAACATTCCATATTACCTGTGGTGTTACTATCTGTATTTTCTCAGGCGTGCATGTG
GCTGCCCATCTGGTGAATGCCCTCAACTTCTCAGTGAATTACAGTGAAGACTTTGTTGAA
CTGAATGCAGCAAGATACCGAGATGAGGATCCTAGAAAACTTCTCTTCACAACTGTTCCT
GGCCTGACAGGGGTCTGCATGGTGGTGGTGCTATTCCTCATGATCACAGCCTCTACATAT
GCAATAAGAGTTTCTAACTATGATATCTTCTGGTATACTCATAACCTCTTCTTTGTCTTC
TACATGCTGCTGACGTTGCATGTTTCAGGAGGGCTGCTGAAGTATCAAACTAATTTAGAT
ACCCACCCTCCCGGCTGCATCAGTCTTAACCGAACCAGCTCTCAGAATATTTCCTTACCA
GAGTATTTCTCAGAACATTTTCATGAACCTTTCCCTGAAGGATTTTCAAAACCGGCAGAG
TTTACCCAGCACAAATTTGTGAAGATTTGTATGGAAGAGCCCAGATTCCAAGCTAATTTT
CCACAGACTTGGCTTTGGATTTCTGGACCTTTGTGCCTGTACTGTGCCGAAAGACTTTAC
AGGTATATCCGGAGCAATAAGCCAGTCACCATCATTTCGGTCATAAGTCATCCCTCAGAT
GTCATGGAAATCCGAATGGTCAAAGAAAATTTTAAAGCAAGACCTGGTCAGTATATTACT
CTACATTGTCCCAGTGTATCTGCATTAGAAAATCATCCATTTACCCTCACAATGTGTCCA
ACTGAAACCAAAGCAACATTTGGGGTTCATCTTAAAATAGTAGGAGACTGGACAGAACGA
TTTCGAGATTTACTACTGCCTCCATCTAGTCAAGACTCCGAAATTCTGCCCTTCATTCAA
TCTAGAAATTATCCCAAGCTGTATATTGATGGTCCTTTTGGAAGTCCATTTGAGGAATCA
CTGAACTATGAGGTCAGCCTCTGCGTGGCTGGAGGCATTGGAGTAACTCCATTTGCATCA
ATACTCAACACCCTGTTGGATGACTGGAAACCATACAAGCTTAGAAGACTATACTTTATT
TGGGTATGCAGAGATATCCAGTCCTTCCGTTGGTTTGCAGATTTACTCTGTATGTTGCAT
AACAAGTTTTGGCAAGAGAACAGACCTGACTATGTCAACATCCAGCTGTACCTCAGTCAA
ACAGATGGGATACAGAAGATAATTGGAGAAAAATATCATGCACTGAATTCAAGACTGTTT
ATAGGACGTCCTCGGTGGAAACTTTTGTTTGATGAAATAGCAAAATATAACAGAGGAAAA
ACAGTTGGTGTTTTCTGTTGTGGACCCAATTCACTATCCAAGACTCTTCATAAACTGAGT
AACCAGAACAACTCATATGGGACAAGATTTGAATACAATAAAGAGTCTTTCAGCTGA
Protein Properties
Number of Residues 578
Molecular Weight 66931.0
Theoretical pI 8.8
Pfam Domain Function
Signals
  • None
Transmembrane Regions
  • 17-37
  • 63-83
  • 104-124
  • 155-175
  • 189-209
  • 425-445
Protein Sequence
>NADPH oxidase 4
MAVSWRSWLANEGVKHLCLFIWLSMNVLLFWKTFLLYNQGPEYHYLHQMLGLGLCLSRAS
ASVLNLNCSLILLPMCRTLLAYLRGSQKVPSRRTRRLLDKSRTFHITCGVTICIFSGVHV
AAHLVNALNFSVNYSEDFVELNAARYRDEDPRKLLFTTVPGLTGVCMVVVLFLMITASTY
AIRVSNYDIFWYTHNLFFVFYMLLTLHVSGGLLKYQTNLDTHPPGCISLNRTSSQNISLP
EYFSEHFHEPFPEGFSKPAEFTQHKFVKICMEEPRFQANFPQTWLWISGPLCLYCAERLY
RYIRSNKPVTIISVMSHPSDVMEIRMVKENFKARPGQYITLHCPSVSALENHPFTLTMCP
TETKATFGVHLKIVGDWTERFRDLLLPPSSQDSEILPFIQSRNYPKLYIDGPFGSPFEES
LNYEVSLCVAGGIGVTPFASILNTLLDDWKPYKLRRLYFIWVCRDIQSFRWFADLLCMLH
NKFWQENRPDYVNIQLYLSQTDGIQKIIGEKYHALNSRLFIGRPRWKLLFDEIAKYNRGK
TVGVFCCGPNSLSKTLHKLSNQNNSYGTRFEYNKESFS
GenBank ID Protein 7939591
UniProtKB/Swiss-Prot ID Q9NPH5
UniProtKB/Swiss-Prot Entry Name NOX4_HUMAN
PDB IDs Not Available
GenBank Gene ID AB041035
GeneCard ID NOX4
GenAtlas ID NOX4
HGNC ID HGNC:7891
References
General References
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  3. Taylor TD, Noguchi H, Totoki Y, Toyoda A, Kuroki Y, Dewar K, Lloyd C, Itoh T, Takeda T, Kim DW, She X, Barlow KF, Bloom T, Bruford E, Chang JL, Cuomo CA, Eichler E, FitzGerald MG, Jaffe DB, LaButti K, Nicol R, Park HS, Seaman C, Sougnez C, Yang X, Zimmer AR, Zody MC, Birren BW, Nusbaum C, Fujiyama A, Hattori M, Rogers J, Lander ES, Sakaki Y: Human chromosome 11 DNA sequence and analysis including novel gene identification. Nature. 2006 Mar 23;440(7083):497-500. [PubMed:16554811 ]
  4. Martyn KD, Frederick LM, von Loehneysen K, Dinauer MC, Knaus UG: Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases. Cell Signal. 2006 Jan;18(1):69-82. Epub 2005 May 31. [PubMed:15927447 ]
  5. Park HS, Jung HY, Park EY, Kim J, Lee WJ, Bae YS: Cutting edge: direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-kappa B. J Immunol. 2004 Sep 15;173(6):3589-93. [PubMed:15356101 ]
  6. Schwarzer C, Machen TE, Illek B, Fischer H: NADPH oxidase-dependent acid production in airway epithelial cells. J Biol Chem. 2004 Aug 27;279(35):36454-61. Epub 2004 Jun 21. [PubMed:15210697 ]
  7. Cheng G, Cao Z, Xu X, van Meir EG, Lambeth JD: Homologs of gp91phox: cloning and tissue expression of Nox3, Nox4, and Nox5. Gene. 2001 May 16;269(1-2):131-40. [PubMed:11376945 ]
  8. Cucoranu I, Clempus R, Dikalova A, Phelan PJ, Ariyan S, Dikalov S, Sorescu D: NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circ Res. 2005 Oct 28;97(9):900-7. Epub 2005 Sep 22. [PubMed:16179589 ]
  9. Geiszt M, Kopp JB, Varnai P, Leto TL: Identification of renox, an NAD(P)H oxidase in kidney. Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8010-4. [PubMed:10869423 ]
  10. Shiose A, Kuroda J, Tsuruya K, Hirai M, Hirakata H, Naito S, Hattori M, Sakaki Y, Sumimoto H: A novel superoxide-producing NAD(P)H oxidase in kidney. J Biol Chem. 2001 Jan 12;276(2):1417-23. [PubMed:11032835 ]
  11. Goyal P, Weissmann N, Rose F, Grimminger F, Schafers HJ, Seeger W, Hanze J: Identification of novel Nox4 splice variants with impact on ROS levels in A549 cells. Biochem Biophys Res Commun. 2005 Apr 1;329(1):32-9. [PubMed:15721269 ]
  12. Vaquero EC, Edderkaoui M, Pandol SJ, Gukovsky I, Gukovskaya AS: Reactive oxygen species produced by NAD(P)H oxidase inhibit apoptosis in pancreatic cancer cells. J Biol Chem. 2004 Aug 13;279(33):34643-54. Epub 2004 May 23. [PubMed:15155719 ]
  13. Mahadev K, Motoshima H, Wu X, Ruddy JM, Arnold RS, Cheng G, Lambeth JD, Goldstein BJ: The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of H2O2 and plays an integral role in insulin signal transduction. Mol Cell Biol. 2004 Mar;24(5):1844-54. [PubMed:14966267 ]
  14. Pedruzzi E, Guichard C, Ollivier V, Driss F, Fay M, Prunet C, Marie JC, Pouzet C, Samadi M, Elbim C, O'dowd Y, Bens M, Vandewalle A, Gougerot-Pocidalo MA, Lizard G, Ogier-Denis E: NAD(P)H oxidase Nox-4 mediates 7-ketocholesterol-induced endoplasmic reticulum stress and apoptosis in human aortic smooth muscle cells. Mol Cell Biol. 2004 Dec;24(24):10703-17. [PubMed:15572675 ]
  15. Maranchie JK, Zhan Y: Nox4 is critical for hypoxia-inducible factor 2-alpha transcriptional activity in von Hippel-Lindau-deficient renal cell carcinoma. Cancer Res. 2005 Oct 15;65(20):9190-3. [PubMed:16230378 ]
  16. Kuroda J, Nakagawa K, Yamasaki T, Nakamura K, Takeya R, Kuribayashi F, Imajoh-Ohmi S, Igarashi K, Shibata Y, Sueishi K, Sumimoto H: The superoxide-producing NAD(P)H oxidase Nox4 in the nucleus of human vascular endothelial cells. Genes Cells. 2005 Dec;10(12):1139-51. [PubMed:16324151 ]
  17. Lee YM, Kim BJ, Chun YS, So I, Choi H, Kim MS, Park JW: NOX4 as an oxygen sensor to regulate TASK-1 activity. Cell Signal. 2006 Apr;18(4):499-507. Epub 2005 Jul 14. [PubMed:16019190 ]