NADPH oxidase 4

NameNADPH oxidase 4
Synonyms
  • 1.6.3.-
  • Kidney oxidase-1
  • Kidney superoxide-producing NADPH oxidase
  • KOX-1
  • Renal NAD(P)H-oxidase
  • RENOX
Gene NameNOX4
OrganismHuman
Amino acid sequence
>lcl|BSEQ0009326|NADPH oxidase 4
MAVSWRSWLANEGVKHLCLFIWLSMNVLLFWKTFLLYNQGPEYHYLHQMLGLGLCLSRAS
ASVLNLNCSLILLPMCRTLLAYLRGSQKVPSRRTRRLLDKSRTFHITCGVTICIFSGVHV
AAHLVNALNFSVNYSEDFVELNAARYRDEDPRKLLFTTVPGLTGVCMVVVLFLMITASTY
AIRVSNYDIFWYTHNLFFVFYMLLTLHVSGGLLKYQTNLDTHPPGCISLNRTSSQNISLP
EYFSEHFHEPFPEGFSKPAEFTQHKFVKICMEEPRFQANFPQTWLWISGPLCLYCAERLY
RYIRSNKPVTIISVMSHPSDVMEIRMVKENFKARPGQYITLHCPSVSALENHPFTLTMCP
TETKATFGVHLKIVGDWTERFRDLLLPPSSQDSEILPFIQSRNYPKLYIDGPFGSPFEES
LNYEVSLCVAGGIGVTPFASILNTLLDDWKPYKLRRLYFIWVCRDIQSFRWFADLLCMLH
NKFWQENRPDYVNIQLYLSQTDGIQKIIGEKYHALNSRLFIGRPRWKLLFDEIAKYNRGK
TVGVFCCGPNSLSKTLHKLSNQNNSYGTRFEYNKESFS
Number of residues578
Molecular Weight66930.995
Theoretical pINot Available
GO Classification
Functions
  • superoxide-generating NADPH oxidase activity
  • electron carrier activity
  • NAD(P)H oxidase activity
  • modified amino acid binding
  • oxygen sensor activity
  • nucleotide binding
  • heme binding
  • flavin adenine dinucleotide binding
Processes
  • positive regulation of MAP kinase activity
  • inflammatory response
  • positive regulation of DNA biosynthetic process
  • superoxide anion generation
  • positive regulation of ERK1 and ERK2 cascade
  • positive regulation of smooth muscle cell migration
  • gene expression
  • reactive oxygen species metabolic process
  • homocysteine metabolic process
  • cell aging
  • cellular response to cAMP
  • positive regulation of protein kinase B signaling
  • positive regulation of apoptotic process
  • cellular response to glucose stimulus
  • cellular response to transforming growth factor beta stimulus
  • cell morphogenesis
  • oxidation-reduction process
  • bone resorption
  • negative regulation of cell proliferation
  • positive regulation of stress fiber assembly
  • response to hypoxia
  • cardiac muscle cell differentiation
  • positive regulation of reactive oxygen species metabolic process
  • superoxide metabolic process
  • cellular response to gamma radiation
Components
  • endoplasmic reticulum membrane
  • NADPH oxidase complex
  • focal adhesion
  • integral component of membrane
  • stress fiber
  • nucleolus
  • perinuclear region of cytoplasm
  • apical plasma membrane
  • mitochondrion
General FunctionSuperoxide-generating nadph oxidase activity
Specific FunctionConstitutive 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 5 and isoform 6 display reduced activity.Isoform 4: Involved in redox signaling in vascular cells. Constitutively and NADPH-dependently generates reactive oxygen species (ROS). Modulates the nuclear activation of ERK1/2 and the ELK1 transcription factor, and is capable of inducing nuclear DNA damage. Displays an increased activity relative to isoform 1.
Pfam Domain Function
Transmembrane Regions17-37 63-83 104-124 155-175 189-209 425-445
GenBank Protein IDNot Available
UniProtKB IDQ9NPH5
UniProtKB Entry NameNOX4_HUMAN
Cellular LocationEndoplasmic reticulum membrane
Gene sequence
>lcl|BSEQ0013803|NADPH oxidase 4 (NOX4)
ATGGCTGTGTCCTGGAGGAGCTGGCTCGCCAACGAAGGGGTTAAACACCTCTGCCTGTTC
ATCTGGCTCTCCATGAATGTCCTGCTTTTCTGGAAAACCTTCTTGCTGTATAACCAAGGG
CCAGAGTATCACTACCTCCACCAGATGTTGGGGCTAGGATTGTGTCTAAGCAGAGCCTCA
GCATCTGTTCTTAACCTCAACTGCAGCCTTATCCTTTTACCCATGTGCCGAACACTCTTG
GCTTACCTCCGAGGATCACAGAAGGTTCCAAGCAGGAGAACCAGGAGATTGTTGGATAAA
AGCAGAACATTCCATATTACCTGTGGTGTTACTATCTGTATTTTCTCAGGCGTGCATGTG
GCTGCCCATCTGGTGAATGCCCTCAACTTCTCAGTGAATTACAGTGAAGACTTTGTTGAA
CTGAATGCAGCAAGATACCGAGATGAGGATCCTAGAAAACTTCTCTTCACAACTGTTCCT
GGCCTGACAGGGGTCTGCATGGTGGTGGTGCTATTCCTCATGATCACAGCCTCTACATAT
GCAATAAGAGTTTCTAACTATGATATCTTCTGGTATACTCATAACCTCTTCTTTGTCTTC
TACATGCTGCTGACGTTGCATGTTTCAGGAGGGCTGCTGAAGTATCAAACTAATTTAGAT
ACCCACCCTCCCGGCTGCATCAGTCTTAACCGAACCAGCTCTCAGAATATTTCCTTACCA
GAGTATTTCTCAGAACATTTTCATGAACCTTTCCCTGAAGGATTTTCAAAACCGGCAGAG
TTTACCCAGCACAAATTTGTGAAGATTTGTATGGAAGAGCCCAGATTCCAAGCTAATTTT
CCACAGACTTGGCTTTGGATTTCTGGACCTTTGTGCCTGTACTGTGCCGAAAGACTTTAC
AGGTATATCCGGAGCAATAAGCCAGTCACCATCATTTCGGTCATAAGTCATCCCTCAGAT
GTCATGGAAATCCGAATGGTCAAAGAAAATTTTAAAGCAAGACCTGGTCAGTATATTACT
CTACATTGTCCCAGTGTATCTGCATTAGAAAATCATCCATTTACCCTCACAATGTGTCCA
ACTGAAACCAAAGCAACATTTGGGGTTCATCTTAAAATAGTAGGAGACTGGACAGAACGA
TTTCGAGATTTACTACTGCCTCCATCTAGTCAAGACTCCGAAATTCTGCCCTTCATTCAA
TCTAGAAATTATCCCAAGGATGACTGGAAACCATACAAGCTTAGAAGACTATACTTTATT
TGGGTATGCAGAGATATCCAGTCCTTCCGTTGGTTTGCAGATTTACTCTGTATGTTGCAT
AACAAGTTTTGGCAAGAGAACAGACCTGACTATGTCAACATCCAGCTGTACCTCAGTCAA
ACAGATGGGATACAGAAGATAATTGGAGAAAAATATCATGCACTGAATTCAAGACTGTTT
ATAGGACGTCCTCGGTGGAAACTTTTGTTTGATGAAATAGCAAAATATAACAGAGGAAAA
ACAGTTGGTGTTTTCTGTTGTGGACCCAATTCACTATCCAAGACTCTTCATAAACTGAGT
AACCAGAACAACTCATATGGGACAAGATTTGAATACAATAAAGAGTCTTTCAGCTGA
GenBank Gene IDNot Available
GeneCard IDNot Available
GenAtlas IDNot Available
HGNC IDHGNC:7891
Chromosome Location11
LocusNot Available
References
  1. 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. 10869423
  2. 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. 11376945
  3. 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. 11032835
  4. 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. 15210697
  5. 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. 15721269
  6. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. 14702039
  7. 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. 16554811
  8. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. 15489334
  9. 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. 15155719
  10. 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. 15356101
  11. 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. 14966267
  12. 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. 15572675
  13. 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. 16230378
  14. 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. 16179589
  15. 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. 16324151
  16. 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. 15927447
  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. 16019190
  18. Anilkumar N, San Jose G, Sawyer I, Santos CX, Sand C, Brewer AC, Warren D, Shah AM: A 28-kDa splice variant of NADPH oxidase-4 is nuclear-localized and involved in redox signaling in vascular cells. Arterioscler Thromb Vasc Biol. 2013 Apr;33(4):e104-12. doi: 10.1161/ATVBAHA.112.300956. Epub 2013 Feb 7. 23393389