Inhibitor of nuclear factor kappa-B kinase subunit alpha
Details
- Name
- Inhibitor of nuclear factor kappa-B kinase subunit alpha
- Kind
- protein
- Synonyms
- 2.7.11.10
- Conserved helix-loop-helix ubiquitous kinase
- I-kappa-B kinase 1
- I-kappa-B kinase alpha
- IkappaB kinase
- IkBKA
- IKK-1
- IKK-A
- IKK-alpha
- IKK1
- IKKA
- NFKBIKA
- Nuclear factor NF-kappa-B inhibitor kinase alpha
- TCF-16
- TCF16
- Transcription factor 16
- Gene Name
- CHUK
- UniProtKB Entry
- O15111Swiss-Prot
- Organism
- Humans
- NCBI Taxonomy ID
- 9606
- Amino acid sequence
>lcl|BSEQ0013242|Inhibitor of nuclear factor kappa-B kinase subunit alpha MERPPGLRPGAGGPWEMRERLGTGGFGNVCLYQHRELDLKIAIKSCRLELSTKNRERWCH EIQIMKKLNHANVVKACDVPEELNILIHDVPLLAMEYCSGGDLRKLLNKPENCCGLKESQ ILSLLSDIGSGIRYLHENKIIHRDLKPENIVLQDVGGKIIHKIIDLGYAKDVDQGSLCTS FVGTLQYLAPELFENKPYTATVDYWSFGTMVFECIAGYRPFLHHLQPFTWHEKIKKKDPK CIFACEEMSGEVRFSSHLPQPNSLCSLVVEPMENWLQLMLNWDPQQRGGPVDLTLKQPRC FVLMDHILNLKIVHILNMTSAKIISFLLPPDESLHSLQSRIERETGINTGSQELLSETGI SLDPRKPASQCVLDGVRGCDSYMVYLFDKSKTVYEGPFASRSLSDCVNYIVQDSKIQLPI IQLRKVWAEAVHYVSGLKEDYSRLFQGQRAAMLSLLRYNANLTKMKNTLISASQQLKAKL EFFHKSIQLDLERYSEQMTYGISSEKMLKAWKEMEEKAIHYAEVGVIGYLEDQIMSLHAE IMELQKSPYGRRQGDLMESLEQRAIDLYKQLKHRPSDHSYSDSTEMVKIIVHTVQSQDRV LKELFGHLSKLLGCKQKIIDLLPKVEVALSNIKEADNTVMFMQGKRQKEIWHLLKIACTQ SSARSLVGSSLEGAVTPQTSAWLPPTSAEHDHSLSCVVTPQDGETSAQMIEENLNCLGHL STIIHEANEEQGNSMMNLDWSWLTE
- Number of residues
- 745
- Molecular Weight
- 84638.88
- Theoretical pI
- Not Available
- GO Classification
- Functionsprotein serine/threonine kinase activity / protein-containing complex binding / transferrin receptor bindingProcessescanonical NF-kappaB signal transduction / cellular response to cadmium ion / cellular response to reactive oxygen species / cellular response to virus / negative regulation of NF-kappaB transcription factor activity / non-canonical NF-kappaB signal transduction / positive regulation of canonical NF-kappaB signal transduction / positive regulation of DNA-templated transcription / positive regulation of interferon-alpha production / positive regulation of transcription by RNA polymerase II / response to cholecystokinin / response to xenobiotic stimulus
- General Function
- Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses (PubMed:18626576, PubMed:9244310, PubMed:9252186, PubMed:9346484). Acts as a part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on serine residues (PubMed:18626576, PubMed:35952808, PubMed:9244310, PubMed:9252186, PubMed:9346484). These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome (PubMed:18626576, PubMed:9244310, PubMed:9252186, PubMed:9346484). In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis (PubMed:18626576, PubMed:9244310, PubMed:9252186, PubMed:9346484). Negatively regulates the pathway by phosphorylating the scaffold protein TAXBP1 and thus promoting the assembly of the A20/TNFAIP3 ubiquitin-editing complex (composed of A20/TNFAIP3, TAX1BP1, and the E3 ligases ITCH and RNF11) (PubMed:21765415). Therefore, CHUK plays a key role in the negative feedback of NF-kappa-B canonical signaling to limit inflammatory gene activation. As part of the non-canonical pathway of NF-kappa-B activation, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes (PubMed:20501937). In turn, these complexes regulate genes encoding molecules involved in B-cell survival and lymphoid organogenesis. Participates also in the negative feedback of the non-canonical NF-kappa-B signaling pathway by phosphorylating and destabilizing MAP3K14/NIK. Within the nucleus, phosphorylates CREBBP and consequently increases both its transcriptional and histone acetyltransferase activities (PubMed:17434128). Modulates chromatin accessibility at NF-kappa-B-responsive promoters by phosphorylating histones H3 at 'Ser-10' that are subsequently acetylated at 'Lys-14' by CREBBP (PubMed:12789342). Additionally, phosphorylates the CREBBP-interacting protein NCOA3. Also phosphorylates FOXO3 and may regulate this pro-apoptotic transcription factor (PubMed:15084260). Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (By similarity). Phosphorylates AMBRA1 following mitophagy induction, promoting AMBRA1 interaction with ATG8 family proteins and its mitophagic activity (PubMed:30217973)
- Specific Function
- ATP binding
- Pfam Domain Function
- Signal Regions
- Not Available
- Transmembrane Regions
- Not Available
- Cellular Location
- Cytoplasm
- Gene sequence
>lcl|BSEQ0013243|Inhibitor of nuclear factor kappa-B kinase subunit alpha (CHUK) ATGGAGCGGCCCCCGGGGCTGCGGCCGGGCGCGGGCGGGCCCTGGGAGATGCGGGAGCGG CTGGGCACCGGCGGCTTCGGGAACGTCTGTCTGTACCAGCATCGGGAACTTGATCTCAAA ATAGCAATTAAGTCTTGTCGCCTAGAGCTAAGTACCAAAAACAGAGAACGATGGTGCCAT GAAATCCAGATTATGAAGAAGTTGAACCATGCCAATGTTGTAAAGGCCTGTGATGTTCCT GAAGAATTGAATATTTTGATTCATGATGTGCCTCTTCTAGCAATGGAATACTGTTCTGGA GGAGATCTCCGAAAGCTGCTCAACAAACCAGAAAATTGTTGTGGACTTAAAGAAAGCCAG ATACTTTCTTTACTAAGTGATATAGGGTCTGGGATTCGATATTTGCATGAAAACAAAATT ATACATCGAGATCTAAAACCTGAAAACATAGTTCTTCAGGATGTTGGTGGAAAGATAATA CATAAAATAATTGATCTGGGATATGCCAAAGATGTTGATCAAGGAAGTCTGTGTACATCT TTTGTGGGAACACTGCAGTATCTGGCCCCAGAGCTCTTTGAGAATAAGCCTTACACAGCC ACTGTTGATTATTGGAGCTTTGGGACCATGGTATTTGAATGTATTGCTGGATATAGGCCT TTTTTGCATCATCTGCAGCCATTTACCTGGCATGAGAAGATTAAGAAGAAGGATCCAAAG TGTATATTTGCATGTGAAGAGATGTCAGGAGAAGTTCGGTTTAGTAGCCATTTACCTCAA CCAAATAGCCTTTGTAGTTTAGTAGTAGAACCCATGGAAAACTGGCTACAGTTGATGTTG AATTGGGACCCTCAGCAGAGAGGAGGACCTGTTGACCTTACTTTGAAGCAGCCAAGATGT TTTGTATTAATGGATCACATTTTGAATTTGAAGATAGTACACATCCTAAATATGACTTCT GCAAAGATAATTTCTTTTCTGTTACCACCTGATGAAAGTCTTCATTCACTACAGTCTCGT ATTGAGCGTGAAACTGGAATAAATACTGGTTCTCAAGAACTTCTTTCAGAGACAGGAATT TCTCTGGATCCTCGGAAACCAGCCTCTCAATGTGTTCTAGATGGAGTTAGAGGCTGTGAT AGCTATATGGTTTATTTGTTTGATAAAAGTAAAACTGTATATGAAGGGCCATTTGCTTCC AGAAGTTTATCTGATTGTGTAAATTATATTGTACAGGACAGCAAAATACAGCTTCCAATT ATACAGCTGCGTAAAGTGTGGGCTGAAGCAGTGCACTATGTGTCTGGACTAAAAGAAGAC TATAGCAGGCTCTTTCAGGGACAAAGGGCAGCAATGTTAAGTCTTCTTAGATATAATGCT AACTTAACAAAAATGAAGAACACTTTGATCTCAGCATCACAACAACTGAAAGCTAAATTG GAGTTTTTTCACAAAAGCATTCAGCTTGACTTGGAGAGATACAGCGAGCAGATGACGTAT GGGATATCTTCAGAAAAAATGCTAAAAGCATGGAAAGAAATGGAAGAAAAGGCCATCCAC TATGCTGAGGTTGGTGTCATTGGATACCTGGAGGATCAGATTATGTCTTTGCATGCTGAA ATCATGGAGCTACAGAAGAGCCCCTATGGAAGACGTCAGGGAGACTTGATGGAATCTCTG GAACAGCGTGCCATTGATCTATATAAGCAGTTAAAACACAGACCTTCAGATCACTCCTAC AGTGACAGCACAGAGATGGTGAAAATCATTGTGCACACTGTGCAGAGTCAGGACCGTGTG CTCAAGGAGCTGTTTGGTCATTTGAGCAAGTTGTTGGGCTGTAAGCAGAAGATTATTGAT CTACTCCCTAAGGTGGAAGTGGCCCTCAGTAATATCAAAGAAGCTGACAATACTGTCATG TTCATGCAGGGAAAAAGGCAGAAAGAAATATGGCATCTCCTTAAAATTGCCTGTACACAG AGTTCTGCCCGGTCCCTTGTAGGATCCAGTCTAGAAGGTGCAGTAACCCCTCAGACATCA GCATGGCTGCCCCCGACTTCAGCAGAACATGATCATTCTCTGTCATGTGTGGTAACTCCT CAAGATGGGGAGACTTCAGCACAAATGATAGAAGAAAATTTGAACTGCCTTGGCCATTTA AGCACTATTATTCATGAGGCAAATGAGGAACAGGGCAATAGTATGATGAATCTTGATTGG AGTTGGTTAACAGAATGA
- Chromosome Location
- 10
- Locus
- 10q24.31
- External Identifiers
Resource Link UniProtKB ID O15111 UniProtKB Entry Name IKKA_HUMAN GeneCard ID CHUK HGNC ID HGNC:1974 PDB ID(s) 3BRT, 5EBZ, 5TQW, 5TQX, 5TQY KEGG ID hsa:1147 IUPHAR/Guide To Pharmacology ID 1989 NCBI Gene ID 1147 - General References
- Regnier CH, Song HY, Gao X, Goeddel DV, Cao Z, Rothe M: Identification and characterization of an IkappaB kinase. Cell. 1997 Jul 25;90(2):373-83. [Article]
- DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M: A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature. 1997 Aug 7;388(6642):548-54. [Article]
- Mercurio F, Zhu H, Murray BW, Shevchenko A, Bennett BL, Li J, Young DB, Barbosa M, Mann M, Manning A, Rao A: IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science. 1997 Oct 31;278(5339):860-6. [Article]
- Hu MC, Wang Y: IkappaB kinase-alpha and -beta genes are coexpressed in adult and embryonic tissues but localized to different human chromosomes. Gene. 1998 Nov 5;222(1):31-40. [Article]
- Deloukas P, Earthrowl ME, Grafham DV, Rubenfield M, French L, Steward CA, Sims SK, Jones MC, Searle S, Scott C, Howe K, Hunt SE, Andrews TD, Gilbert JG, Swarbreck D, Ashurst JL, Taylor A, Battles J, Bird CP, Ainscough R, Almeida JP, Ashwell RI, Ambrose KD, Babbage AK, Bagguley CL, Bailey J, Banerjee R, Bates K, Beasley H, Bray-Allen S, Brown AJ, Brown JY, Burford DC, Burrill W, Burton J, Cahill P, Camire D, Carter NP, Chapman JC, Clark SY, Clarke G, Clee CM, Clegg S, Corby N, Coulson A, Dhami P, Dutta I, Dunn M, Faulkner L, Frankish A, Frankland JA, Garner P, Garnett J, Gribble S, Griffiths C, Grocock R, Gustafson E, Hammond S, Harley JL, Hart E, Heath PD, Ho TP, Hopkins B, Horne J, Howden PJ, Huckle E, Hynds C, Johnson C, Johnson D, Kana A, Kay M, Kimberley AM, Kershaw JK, Kokkinaki M, Laird GK, Lawlor S, Lee HM, Leongamornlert DA, Laird G, Lloyd C, Lloyd DM, Loveland J, Lovell J, McLaren S, McLay KE, McMurray A, Mashreghi-Mohammadi M, Matthews L, Milne S, Nickerson T, Nguyen M, Overton-Larty E, Palmer SA, Pearce AV, Peck AI, Pelan S, Phillimore B, Porter K, Rice CM, Rogosin A, Ross MT, Sarafidou T, Sehra HK, Shownkeen R, Skuce CD, Smith M, Standring L, Sycamore N, Tester J, Thorpe A, Torcasso W, Tracey A, Tromans A, Tsolas J, Wall M, Walsh J, Wang H, Weinstock K, West AP, Willey DL, Whitehead SL, Wilming L, Wray PW, Young L, Chen Y, Lovering RC, Moschonas NK, Siebert R, Fechtel K, Bentley D, Durbin R, Hubbard T, Doucette-Stamm L, Beck S, Smith DR, Rogers J: The DNA sequence and comparative analysis of human chromosome 10. Nature. 2004 May 27;429(6990):375-81. [Article]
- Connelly MA, Marcu KB: CHUK, a new member of the helix-loop-helix and leucine zipper families of interacting proteins, contains a serine-threonine kinase catalytic domain. Cell Mol Biol Res. 1995;41(6):537-49. [Article]
- Mittal R, Peak-Chew SY, McMahon HT: Acetylation of MEK2 and I kappa B kinase (IKK) activation loop residues by YopJ inhibits signaling. Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18574-9. Epub 2006 Nov 20. [Article]
- Cohen L, Henzel WJ, Baeuerle PA: IKAP is a scaffold protein of the IkappaB kinase complex. Nature. 1998 Sep 17;395(6699):292-6. [Article]
- Ling L, Cao Z, Goeddel DV: NF-kappaB-inducing kinase activates IKK-alpha by phosphorylation of Ser-176. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3792-7. [Article]
- Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB: NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature. 1999 Sep 2;401(6748):82-5. [Article]
- Delhase M, Hayakawa M, Chen Y, Karin M: Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation. Science. 1999 Apr 9;284(5412):309-13. [Article]
- Nemoto S, DiDonato JA, Lin A: Coordinate regulation of IkappaB kinases by mitogen-activated protein kinase kinase kinase 1 and NF-kappaB-inducing kinase. Mol Cell Biol. 1998 Dec;18(12):7336-43. [Article]
- Jobin C, Sartor RB: The I kappa B/NF-kappa B system: a key determinant of mucosalinflammation and protection. Am J Physiol Cell Physiol. 2000 Mar;278(3):C451-62. [Article]
- Wu RC, Qin J, Hashimoto Y, Wong J, Xu J, Tsai SY, Tsai MJ, O'Malley BW: Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator activity by I kappa B kinase. Mol Cell Biol. 2002 May;22(10):3549-61. [Article]
- Tegethoff S, Behlke J, Scheidereit C: Tetrameric oligomerization of IkappaB kinase gamma (IKKgamma) is obligatory for IKK complex activity and NF-kappaB activation. Mol Cell Biol. 2003 Mar;23(6):2029-41. [Article]
- Yamamoto Y, Verma UN, Prajapati S, Kwak YT, Gaynor RB: Histone H3 phosphorylation by IKK-alpha is critical for cytokine-induced gene expression. Nature. 2003 Jun 5;423(6940):655-9. [Article]
- Hu MC, Lee DF, Xia W, Golfman LS, Ou-Yang F, Yang JY, Zou Y, Bao S, Hanada N, Saso H, Kobayashi R, Hung MC: IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell. 2004 Apr 16;117(2):225-37. [Article]
- Bruey JM, Bruey-Sedano N, Newman R, Chandler S, Stehlik C, Reed JC: PAN1/NALP2/PYPAF2, an inducible inflammatory mediator that regulates NF-kappaB and caspase-1 activation in macrophages. J Biol Chem. 2004 Dec 10;279(50):51897-907. Epub 2004 Sep 28. [Article]
- Witherow DS, Garrison TR, Miller WE, Lefkowitz RJ: beta-Arrestin inhibits NF-kappaB activity by means of its interaction with the NF-kappaB inhibitor IkappaBalpha. Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8603-7. Epub 2004 Jun 1. [Article]
- Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp J: Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature. 2005 Oct 20;437(7062):1167-72. Epub 2005 Sep 21. [Article]
- Liu B, Yang Y, Chernishof V, Loo RR, Jang H, Tahk S, Yang R, Mink S, Shultz D, Bellone CJ, Loo JA, Shuai K: Proinflammatory stimuli induce IKKalpha-mediated phosphorylation of PIAS1 to restrict inflammation and immunity. Cell. 2007 Jun 1;129(5):903-14. [Article]
- Huang WC, Ju TK, Hung MC, Chen CC: Phosphorylation of CBP by IKKalpha promotes cell growth by switching the binding preference of CBP from p53 to NF-kappaB. Mol Cell. 2007 Apr 13;26(1):75-87. [Article]
- Solt LA, May MJ: The IkappaB kinase complex: master regulator of NF-kappaB signaling. Immunol Res. 2008;42(1-3):3-18. doi: 10.1007/s12026-008-8025-1. [Article]
- Tai DJ, Su CC, Ma YL, Lee EH: SGK1 phosphorylation of IkappaB Kinase alpha and p300 Up-regulates NF-kappaB activity and increases N-Methyl-D-aspartate receptor NR2A and NR2B expression. J Biol Chem. 2009 Feb 13;284(7):4073-89. doi: 10.1074/jbc.M805055200. Epub 2008 Dec 16. [Article]
- Li S, Wang L, Dorf ME: PKC phosphorylation of TRAF2 mediates IKKalpha/beta recruitment and K63-linked polyubiquitination. Mol Cell. 2009 Jan 16;33(1):30-42. doi: 10.1016/j.molcel.2008.11.023. [Article]
- Cui J, Zhu L, Xia X, Wang HY, Legras X, Hong J, Ji J, Shen P, Zheng S, Chen ZJ, Wang RF: NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways. Cell. 2010 Apr 30;141(3):483-96. doi: 10.1016/j.cell.2010.03.040. [Article]
- Lahtela J, Nousiainen HO, Stefanovic V, Tallila J, Viskari H, Karikoski R, Gentile M, Saloranta C, Varilo T, Salonen R, Kestila M: Mutant CHUK and severe fetal encasement malformation. N Engl J Med. 2010 Oct 21;363(17):1631-7. doi: 10.1056/NEJMoa0911698. [Article]
- Razani B, Zarnegar B, Ytterberg AJ, Shiba T, Dempsey PW, Ware CF, Loo JA, Cheng G: Negative feedback in noncanonical NF-kappaB signaling modulates NIK stability through IKKalpha-mediated phosphorylation. Sci Signal. 2010 May 25;3(123):ra41. doi: 10.1126/scisignal.2000778. [Article]
- Burkard TR, Planyavsky M, Kaupe I, Breitwieser FP, Burckstummer T, Bennett KL, Superti-Furga G, Colinge J: Initial characterization of the human central proteome. BMC Syst Biol. 2011 Jan 26;5:17. doi: 10.1186/1752-0509-5-17. [Article]
- Shembade N, Pujari R, Harhaj NS, Abbott DW, Harhaj EW: The kinase IKKalpha inhibits activation of the transcription factor NF-kappaB by phosphorylating the regulatory molecule TAX1BP1. Nat Immunol. 2011 Jul 17;12(9):834-43. doi: 10.1038/ni.2066. [Article]
- Wang W, Guo M, Hu L, Cai J, Zeng Y, Luo J, Shu Z, Li W, Huang Z: The zinc finger protein ZNF268 is overexpressed in human cervical cancer and contributes to tumorigenesis via enhancing NF-kappaB signaling. J Biol Chem. 2012 Dec 14;287(51):42856-66. doi: 10.1074/jbc.M112.399923. Epub 2012 Oct 22. [Article]
- Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O'Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR: Patterns of somatic mutation in human cancer genomes. Nature. 2007 Mar 8;446(7132):153-8. [Article]
- Rushe M, Silvian L, Bixler S, Chen LL, Cheung A, Bowes S, Cuervo H, Berkowitz S, Zheng T, Guckian K, Pellegrini M, Lugovskoy A: Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site. Structure. 2008 May;16(5):798-808. doi: 10.1016/j.str.2008.02.012. [Article]
Associated Data
- Drug Relations
Drug Drug group Pharmacological action? Type Actions Details Mesalazine approved unknown target inhibitor Details Aminosalicylic acid approved unknown target inhibitor Details Acetylcysteine approved, investigational unknown target inhibitor Details Sulfasalazine approved unknown target Details