IKK2

IKK-β also known as inhibitor of nuclear factor kappa-B kinase subunit beta is a protein that in humans is encoded by the IKBKB (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta) gene.

IKBKB
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4KIK, 3BRT, 3BRV, 4E3C
Identifiers
Aliases	IKBKB, IKK-beta, IKK2, IKKB, IMD15, NFKBIKB, inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta, inhibitor of nuclear factor kappa B kinase subunit beta, IMD15A, IMD15B
External IDs	OMIM: 603258 MGI: 1338071 HomoloGene: 7782 GeneCards: IKBKB
Gene location (Human) Chr. Chromosome 8 (human)[1] Band 8p11.21 Start 42,271,302 bp[1] End 42,332,653 bp[1]
Gene location (Mouse) Chr. Chromosome 8 (mouse)[2] Band 8|8 A2 Start 22,659,212 bp[2] End 22,706,589 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • transferase activity • protein kinase activity • IkappaB kinase activity • nucleotide binding • protein homodimerization activity • scaffold protein binding • kinase activity • GO:0001948 protein binding • ATP binding • protein kinase binding • protein heterodimerization activity • protein serine/threonine kinase activity • identical protein binding Cellular component • membrane • membrane raft • CD40 receptor complex • cytoplasmic side of plasma membrane • cell nucleus • IkappaB kinase complex • cytoplasm • cytosol Biological process • phosphorylation • regulation of tumor necrosis factor-mediated signaling pathway • cellular response to tumor necrosis factor • response to virus • regulation of phosphorylation • negative regulation of apoptotic process • stimulatory C-type lectin receptor signaling pathway • T cell receptor signaling pathway • TRIF-dependent toll-like receptor signaling pathway • Fc-epsilon receptor signaling pathway • positive regulation of transcription, DNA-templated • protein phosphorylation • negative regulation of bicellular tight junction assembly • stress-activated MAPK cascade • positive regulation of I-kappaB kinase/NF-kappaB signaling • negative regulation of myosin-light-chain-phosphatase activity • innate immune system • inflammatory response • I-kappaB kinase/NF-kappaB signaling • GO:0033109 cortical actin cytoskeleton organization • positive regulation of transcription from RNA polymerase II promoter • regulation of establishment of endothelial barrier • I-kappaB phosphorylation • tumor necrosis factor-mediated signaling pathway • positive regulation of NF-kappaB transcription factor activity • antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent • anatomical structure morphogenesis • protein localization to plasma membrane • MyD88-independent toll-like receptor signaling pathway • peptidyl-serine phosphorylation • interleukin-1-mediated signaling pathway • GO:0022415 viral process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	3551	16150
Ensembl	ENSG00000104365	ENSMUSG00000031537
UniProt	O14920	O88351
RefSeq (mRNA)	NM_001190720 NM_001190721 NM_001190722 NM_001242778 NM_001556	NM_001159774 NM_010546
RefSeq (protein)	NP_001177649 NP_001229707 NP_001547	NP_001153246 NP_034676
Location (UCSC)	Chr 8: 42.27 – 42.33 Mb	Chr 8: 22.66 – 22.71 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

Main article: IκB kinase

IKK-β is an enzyme that serves as a protein subunit of IκB kinase, which is a component of the cytokine-activated intracellular signaling pathway involved in triggering immune responses. IKK's activity causes activation of a transcription factor known as Nuclear Transcription factor kappa-B or NF-κB. Activated IKK-β phosphorylates a protein called the inhibitor of NF-κB, IκB (IκBα), which binds NF-κB to inhibit its function. Phosphorylated IκB is degraded via the ubiquitination pathway, freeing NF-κB, and allowing its entry into the nucleus of the cell where it activates various genes involved in inflammation and other immune responses.

Clinical significance

IKK-β plays a significant role in brain cells following a stroke. If NF-κB activation by IKK-β is blocked, damaged cells within the brain stay alive, and according to a study performed by the University of Heidelberg and the University of Ulm, the cells even appear to make some recovery.[5]

Inhibition of IKK and IKK-related kinases has been investigated as a therapeutic option for the treatment of inflammatory diseases and cancer.[6][6] The small-molecule inhibitor of IKK2 SAR113945, developed by Sanofi-Aventis, was evaluated in patients with knee osteoarthritis.[7]

Model organisms

Model organisms have been used in the study of IKK-β function. The size of an infarct, or tissue killed or damaged by ischemia, is reduced in mice in which IKK-β has been blocked.[8] Additionally, experimental mice with an overactive form of IKK-β experience loss of many more neurons than normal mice after a stroke-simulating event.[5] Researchers found a molecule that could block the signaling of IKK-β for up to four and a half hours.[9] In another study, researchers found that inhibiting IKK-β prevented kidney and wasting diseases in an animal model used to study wasting diseases of human AIDS sufferers.[10]

Ikbkb knockout mouse phenotype

Characteristic	Phenotype
Homozygote viability	Abnormal
Recessive lethal study	Abnormal
Fertility	Normal
Body weight	Normal
Anxiety	Normal
Neurological assessment	Normal
Grip strength	Normal
Hot plate	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Body temperature	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Plasma immunoglobulins	Normal
Haematology	Normal
Peripheral blood lymphocytes	Normal
Micronucleus test	Normal
Heart weight	Normal
Tail epidermis wholemount	Normal
Brain histopathology	Normal
Salmonella infection	Normal[11]
Citrobacter infection	Normal[12]
All tests and analysis from[13][14]

A conditional knockout mouse line, called Ikbkb^{tm1a(EUCOMM)Wtsi}[15][16] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[17][18][19]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[13][20] Twenty six tests were carried out and two phenotypes were reported. A reduced number of homozygous mutant embryos were identified during gestation, and none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice, and no significant abnormalities were observed in these animals.[13]

Interactions

IKK-β (IKBKB) has been shown to interact with

• HDAC9,[21]
• CDC37,[22]
• CHUK[22][23][24][25][26][27][28]
• CTNNB1,[29]
• FANCA,[24]
• IKBKG[22][27][30][31][32]
• IRAK1,[33][34]
• NFKBIA,[26][35][36]
• MAP3K14,[26][37]
• NFKB1,[38][39]
• NFKBIB,[26]
• NCOA3,[31]
• PPM1B,[40]
• TNFRSF1A,[41][42] and
• TRAF2.[43][44]

References

1. GRCh38: Ensembl release 89: ENSG00000104365 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000031537 - 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. BBC News. 14 November 2005. Stroke 'cell-death trigger' found. Retrieved on June 28, 2007.
6. Llona-Minguez S, Baiget J, Mackay SP (2013). "Small-molecule inhibitors of IκB kinase (IKK) and IKK-related kinases". Pharm. Pat. Anal. 2 (4): 481–498. doi:10.4155/ppa.13.31. PMID 24237125.
7. "SAR113945 published clinical trials".
8. Schwaninger M, Inta I, Herrmann O (2006). "NF-kappaB signalling in cerebral ischaemia". Biochemical Society Transactions. 34 (Pt 6): 1291–4. doi:10.1042/BST0341291. PMID 17073804.
9. Herrmann O, Baumann B, de Lorenzi R, Muhammad S, Zhang W, Kleesiek J, Malfertheiner M, Köhrmann M, Potrovita I, Maegele I, Beyer C, Burke JR, Hasan MT, Bujard H, Wirth T, Pasparakis M, Schwaninger M (2005). "IKK mediates ischemia-induced neuronal death". Nature Medicine. 11 (12): 1322–9. doi:10.1038/nm1323. PMID 16286924.
10. Heckmann A, Waltzinger C, Jolicoeur P, Dreano M, Kosco-Vilbois MH, Sagot Y (2004). "IKK2 inhibitor alleviates kidney and wasting diseases in a murine model of human AIDS". Am. J. Pathol. 164 (4): 1253–62. doi:10.1016/S0002-9440(10)63213-0. PMC 1615343. PMID 15039214.
11. "Salmonella infection data for Ikbkb". Wellcome Trust Sanger Institute.
12. "Citrobacter infection data for Ikbkb". Wellcome Trust Sanger Institute.
13. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88 (S248): 0. doi:10.1111/j.1755-3768.2010.4142.x.
14. Mouse Resources Portal, Wellcome Trust Sanger Institute.
15. "International Knockout Mouse Consortium".
16. "Mouse Genome Informatics".
17. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–342. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
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20. van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biol. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
21. Asare Y, Campbell-James TA, Bokov Y, Yu LL, Prestel M, El Bounkari O, Roth S, Megens RT, Straub T, Thomas K, Yan G, Schneider M, Ziesch N, Tiedt S, Silvestre-Roig C, Braster Q, Huang Y, Schneider M, Malik R, Haffner C, Liesz A, Soehnlein O, Bernhagen J, Dichgans M (June 2020). "Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability". Circulation Research. doi:10.1161/CIRCRESAHA.120.316743. PMID 32546048.
22. Chen G, Cao P, Goeddel DV (February 2002). "TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90". Mol. Cell. 9 (2): 401–10. doi:10.1016/S1097-2765(02)00450-1. ISSN 1097-2765. PMID 11864612.
23. Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M (October 1997). "The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation". Cell. 91 (2): 243–52. doi:10.1016/S0092-8674(00)80406-7. ISSN 0092-8674. PMID 9346241.
24. Otsuki T, Young DB, Sasaki DT, Pando MP, Li J, Manning A, Hoekstra M, Hoatlin ME, Mercurio F, Liu JM (2002). "Fanconi anemia protein complex is a novel target of the IKK signalsome". J. Cell. Biochem. 86 (4): 613–23. doi:10.1002/jcb.10270. ISSN 0730-2312. PMID 12210728.
25. May MJ, D'Acquisto F, Madge LA, Glöckner J, Pober JS, Ghosh S (September 2000). "Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex". Science. 289 (5484): 1550–4. doi:10.1126/science.289.5484.1550. ISSN 0036-8075. PMID 10968790.
26. Woronicz JD, Gao X, Cao Z, Rothe M, Goeddel DV (October 1997). "IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK". Science. 278 (5339): 866–9. doi:10.1126/science.278.5339.866. ISSN 0036-8075. PMID 9346485.
27. Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ (October 2000). "Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain". Cell. 103 (2): 351–61. doi:10.1016/S0092-8674(00)00126-4. ISSN 0092-8674. PMID 11057907.
28. Yeung KC, Rose DW, Dhillon AS, Yaros D, Gustafsson M, Chatterjee D, McFerran B, Wyche J, Kolch W, Sedivy JM (November 2001). "Raf Kinase Inhibitor Protein Interacts with NF-κB-Inducing Kinase and TAK1 and Inhibits NF-κB Activation". Mol. Cell. Biol. 21 (21): 7207–17. doi:10.1128/MCB.21.21.7207-7217.2001. ISSN 0270-7306. PMC 99896. PMID 11585904.
29. Lamberti C, Lin KM, Yamamoto Y, Verma U, Verma IM, Byers S, Gaynor RB (November 2001). "Regulation of beta-catenin function by the IkappaB kinases". J. Biol. Chem. 276 (45): 42276–86. doi:10.1074/jbc.M104227200. ISSN 0021-9258. PMID 11527961.
30. Chariot A, Leonardi A, Muller J, Bonif M, Brown K, Siebenlist U (October 2002). "Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases". J. Biol. Chem. 277 (40): 37029–36. doi:10.1074/jbc.M205069200. ISSN 0021-9258. PMID 12133833.
31. Wu RC, Qin J, Hashimoto Y, Wong J, Xu J, Tsai SY, Tsai MJ, O'Malley BW (May 2002). "Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator Activity by IκB Kinase". Mol. Cell. Biol. 22 (10): 3549–61. doi:10.1128/MCB.22.10.3549-3561.2002. ISSN 0270-7306. PMC 133790. PMID 11971985.
32. Shifera AS, Horwitz MS (March 2008). "Mutations in the zinc finger domain of IKK gamma block the activation of NF-kappa B and the induction of IL-2 in stimulated T lymphocytes". Mol. Immunol. 45 (6): 1633–45. doi:10.1016/j.molimm.2007.09.036. ISSN 0161-5890. PMID 18207244.
33. Vig E, Green M, Liu Y, Yu KY, Kwon HJ, Tian J, Goebl MG, Harrington MA (March 2001). "SIMPL is a tumor necrosis factor-specific regulator of nuclear factor-kappaB activity". J. Biol. Chem. 276 (11): 7859–66. doi:10.1074/jbc.M010399200. ISSN 0021-9258. PMID 11096118.
34. Windheim M, Stafford M, Peggie M, Cohen P (March 2008). "Interleukin-1 (IL-1) Induces the Lys63-Linked Polyubiquitination of IL-1 Receptor-Associated Kinase 1 To Facilitate NEMO Binding and the Activation of IκBα Kinase". Mol. Cell. Biol. 28 (5): 1783–91. doi:10.1128/MCB.02380-06. PMC 2258775. PMID 18180283.
35. Mercurio F, Murray BW, Shevchenko A, Bennett BL, Young DB, Li JW, Pascual G, Motiwala A, Zhu H, Mann M, Manning AM (February 1999). "IκB Kinase (IKK)-Associated Protein 1, a Common Component of the Heterogeneous IKK Complex". Mol. Cell. Biol. 19 (2): 1526–38. doi:10.1128/mcb.19.2.1526. ISSN 0270-7306. PMC 116081. PMID 9891086.
36. Cohen L, Henzel WJ, Baeuerle PA (September 1998). "IKAP is a scaffold protein of the IkappaB kinase complex". Nature. 395 (6699): 292–6. doi:10.1038/26254. ISSN 0028-0836. PMID 9751059.
37. Luftig MA, Cahir-McFarland E, Mosialos G, Kieff E (May 2001). "Effects of the NIK aly mutation on NF-kappaB activation by the Epstein-Barr virus latent infection membrane protein, lymphotoxin beta receptor, and CD40". J. Biol. Chem. 276 (18): 14602–6. doi:10.1074/jbc.C100103200. ISSN 0021-9258. PMID 11278268.
38. Heissmeyer V, Krappmann D, Hatada EN, Scheidereit C (February 2001). "Shared Pathways of IκB Kinase-Induced SCFβTrCP-Mediated Ubiquitination and Degradation for the NF-κB Precursor p105 and IκBα". Mol. Cell. Biol. 21 (4): 1024–35. doi:10.1128/MCB.21.4.1024-1035.2001. ISSN 0270-7306. PMC 99557. PMID 11158290.
39. Heissmeyer V, Krappmann D, Wulczyn FG, Scheidereit C (September 1999). "NF-kappaB p105 is a target of IkappaB kinases and controls signal induction of Bcl-3-p50 complexes". EMBO J. 18 (17): 4766–78. doi:10.1093/emboj/18.17.4766. ISSN 0261-4189. PMC 1171549. PMID 10469655.
40. Prajapati S, Verma U, Yamamoto Y, Kwak YT, Gaynor RB (January 2004). "Protein phosphatase 2Cbeta association with the IkappaB kinase complex is involved in regulating NF-kappaB activity". J. Biol. Chem. 279 (3): 1739–46. doi:10.1074/jbc.M306273200. ISSN 0021-9258. PMID 14585847.
41. Zhang SQ, Kovalenko A, Cantarella G, Wallach D (March 2000). "Recruitment of the IKK signalosome to the p55 TNF receptor: RIP and A20 bind to NEMO (IKKgamma) upon receptor stimulation". Immunity. 12 (3): 301–11. doi:10.1016/S1074-7613(00)80183-1. ISSN 1074-7613. PMID 10755617.
42. Chaudhary PM, Eby MT, Jasmin A, Kumar A, Liu L, Hood L (September 2000). "Activation of the NF-kappaB pathway by caspase 8 and its homologs". Oncogene. 19 (39): 4451–60. doi:10.1038/sj.onc.1203812. ISSN 0950-9232. PMID 11002417.
43. Devin A, Lin Y, Yamaoka S, Li Z, Karin M (June 2001). "The α and β Subunits of IκB Kinase (IKK) Mediate TRAF2-Dependent IKK Recruitment to Tumor Necrosis Factor (TNF) Receptor 1 in Response to TNF". Mol. Cell. Biol. 21 (12): 3986–94. doi:10.1128/MCB.21.12.3986-3994.2001. ISSN 0270-7306. PMC 87061. PMID 11359906.
44. Li S, Wang L, Dorf ME (January 2009). "PKC phosphorylation of TRAF2 mediates IKKα/β recruitment and K63-linked polyubiquitination". Mol. Cell. 33 (1): 30–42. doi:10.1016/j.molcel.2008.11.023. PMC 2643372. PMID 19150425.

See also

• IκB kinase