IKK2

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; OMA:IKBKB - orthologs
Gene location (Human)
Chr.	Chromosome 8 (human)
End	42,332,460 bp
Gene location (Mouse)
Chr.	Chromosome 8 (mouse)
End	23,196,605 bp
RNA expression pattern
	Top expressed in
	spleen; ; granulocyte; ; right lobe of thyroid gland; ; right uterine tube; ; skin of leg; ; skin of abdomen; ; minor salivary glands; ; left lobe of thyroid gland; ; tonsil; ; vagina;
	Top expressed in
	mesenteric lymph nodes; ; blood; ; Paneth cell; ; crypt of lieberkuhn of small intestine; ; hair follicle; ; molar; ; medullary collecting duct; ; superior cervical ganglion; ; stroma of bone marrow; ; spleen;
	More reference expression data
	; ; ; ;
	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; 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; 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 response; inflammatory response; I-kappaB kinase/NF-kappaB signaling; cortical actin cytoskeleton organization; positive regulation of transcription by RNA polymerase II; 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; viral process;
	Sources:Amigo / QuickGO
Orthologs
	3551
	16150
	ENSG00000104365
	ENSMUSG00000031537
	O14920
	O88351
	NM_001190720; NM_001190721; NM_001190722; NM_001242778; NM_001556
	NM_001159774; NM_010546
	NP_001177649; NP_001229707; NP_001547
	NP_001153246; NP_034676
	Wikidata
View/Edit Human	View/Edit Mouse

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.

Function

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.^[5] 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.^[6]

Inhibition of IKK and IKK-related kinases has been investigated as a therapeutic option for the treatment of inflammatory diseases and cancer.^[7] The small-molecule inhibitor of IKK2 SAR113945, developed by Sanofi-Aventis, was evaluated in patients with knee osteoarthritis.^[8]

Interactions

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

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000104365 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000031537 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Herrmann O, Baumann B, de Lorenzi R, Muhammad S, Zhang W, Kleesiek J, et al. (December 2005). "IKK mediates ischemia-induced neuronal death". Nature Medicine. 11 (12): 1322–9. doi:10.1038/nm1323. PMID 16286924. S2CID 28490303.
^ "Stroke 'cell-death trigger' found". BBC News. 14 November 2005. Retrieved June 28, 2007.
^ Llona-Minguez S, Baiget J, Mackay SP (July 2013). "Small-molecule inhibitors of IκB kinase (IKK) and IKK-related kinases". Pharmaceutical Patent Analyst. 2 (4): 481–98. doi:10.4155/ppa.13.31. PMID 24237125.
^ "SAR113945 published clinical trials".
^ Asare Y, Campbell-James TA, Bokov Y, Yu LL, Prestel M, El Bounkari O, et al. (August 2020). "Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability". Circulation Research. 127 (6): 811–823. doi:10.1161/CIRCRESAHA.120.316743. PMID 32546048. S2CID 219726725.
^ ^a ^b ^c Chen G, Cao P, Goeddel DV (February 2002). "TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90". Molecular Cell. 9 (2): 401–10. doi:10.1016/S1097-2765(02)00450-1. PMID 11864612.
^ 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. PMID 9346241. S2CID 6399108.
^ ^a ^b Otsuki T, Young DB, Sasaki DT, Pando MP, Li J, Manning A, et al. (2002). "Fanconi anemia protein complex is a novel target of the IKK signalsome". Journal of Cellular Biochemistry. 86 (4): 613–23. doi:10.1002/jcb.10270. PMID 12210728. S2CID 42471384.
^ 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. Bibcode:2000Sci...289.1550M. doi:10.1126/science.289.5484.1550. PMID 10968790.
^ ^a ^b ^c ^d 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. Bibcode:1997Sci...278..866W. doi:10.1126/science.278.5339.866. PMID 9346485.
^ ^a ^b Deng L, Wang C, Spencer E, Yang L, Braun A, You J, et al. (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. PMID 11057907. S2CID 18154645.
^ Yeung KC, Rose DW, Dhillon AS, Yaros D, Gustafsson M, Chatterjee D, et al. (November 2001). "Raf kinase inhibitor protein interacts with NF-kappaB-inducing kinase and TAK1 and inhibits NF-kappaB activation". Molecular and Cellular Biology. 21 (21): 7207–17. doi:10.1128/MCB.21.21.7207-7217.2001. PMC 99896. PMID 11585904.
^ 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". The Journal of Biological Chemistry. 276 (45): 42276–86. doi:10.1074/jbc.M104227200. PMID 11527961.
^ 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". The Journal of Biological Chemistry. 277 (40): 37029–36. doi:10.1074/jbc.M205069200. PMID 12133833.
^ ^a ^b Wu RC, Qin J, Hashimoto Y, Wong J, Xu J, Tsai SY, et al. (May 2002). "Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator activity by I kappa B kinase". Molecular and Cellular Biology. 22 (10): 3549–61. doi:10.1128/MCB.22.10.3549-3561.2002. PMC 133790. PMID 11971985.
^ 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". Molecular Immunology. 45 (6): 1633–45. doi:10.1016/j.molimm.2007.09.036. PMID 18207244.
^ Vig E, Green M, Liu Y, Yu KY, Kwon HJ, Tian J, et al. (March 2001). "SIMPL is a tumor necrosis factor-specific regulator of nuclear factor-kappaB activity". The Journal of Biological Chemistry. 276 (11): 7859–66. doi:10.1074/jbc.M010399200. PMID 11096118.
^ 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 IkappaBalpha kinase". Molecular and Cellular Biology. 28 (5): 1783–91. doi:10.1128/MCB.02380-06. PMC 2258775. PMID 18180283.
^ Mercurio F, Murray BW, Shevchenko A, Bennett BL, Young DB, Li JW, et al. (February 1999). "IkappaB kinase (IKK)-associated protein 1, a common component of the heterogeneous IKK complex". Molecular and Cellular Biology. 19 (2): 1526–38. doi:10.1128/mcb.19.2.1526. PMC 116081. PMID 9891086.
^ Cohen L, Henzel WJ, Baeuerle PA (September 1998). "IKAP is a scaffold protein of the IkappaB kinase complex". Nature. 395 (6699): 292–6. Bibcode:1998Natur.395..292C. doi:10.1038/26254. PMID 9751059. S2CID 4327300.
^ 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". The Journal of Biological Chemistry. 276 (18): 14602–6. doi:10.1074/jbc.C100103200. PMID 11278268.
^ Heissmeyer V, Krappmann D, Hatada EN, Scheidereit C (February 2001). "Shared pathways of IkappaB kinase-induced SCF(betaTrCP)-mediated ubiquitination and degradation for the NF-kappaB precursor p105 and IkappaBalpha". Molecular and Cellular Biology. 21 (4): 1024–35. doi:10.1128/MCB.21.4.1024-1035.2001. PMC 99557. PMID 11158290.
^ 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". The EMBO Journal. 18 (17): 4766–78. doi:10.1093/emboj/18.17.4766. PMC 1171549. PMID 10469655.
^ 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". The Journal of Biological Chemistry. 279 (3): 1739–46. doi:10.1074/jbc.M306273200. PMID 14585847.
^ 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. PMID 10755617.
^ 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. PMID 11002417.
^ Devin A, Lin Y, Yamaoka S, Li Z, Karin M (June 2001). "The alpha and beta subunits of IkappaB kinase (IKK) mediate TRAF2-dependent IKK recruitment to tumor necrosis factor (TNF) receptor 1 in response to TNF". Molecular and Cellular Biology. 21 (12): 3986–94. doi:10.1128/MCB.21.12.3986-3994.2001. PMC 87061. PMID 11359906.
^ Li S, Wang L, Dorf ME (January 2009). "PKC phosphorylation of TRAF2 mediates IKKalpha/beta recruitment and K63-linked polyubiquitination". Molecular Cell. 33 (1): 30–42. doi:10.1016/j.molcel.2008.11.023. PMC 2643372. PMID 19150425.

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

IKK2

Function

Clinical significance

Interactions

References

See also

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