IKK2

Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta
Rendering based on PDB 3BRT.
Available structures PDB 3BRT, 3BRV
Identifiers
Symbols	IKBKB; FLJ33771; FLJ36218; FLJ38368; FLJ40509; IKK-beta; IKK2; IKKB; MGC131801; NFKBIKB
External IDs	OMIM: 603258 MGI: 1338071 HomoloGene: 7782 GeneCards: IKBKB Gene
EC number	2.7.11.10
Gene Ontology Molecular function • nucleotide binding • protein kinase activity • protein serine/threonine kinase activity • protein binding • ATP binding • IkappaB kinase activity • identical protein binding Cellular component • cytoplasm • cytosol • cytosol • internal side of plasma membrane • membrane • CD40 receptor complex • membrane raft Biological process • toll-like receptor signaling pathway • MyD88-dependent toll-like receptor signaling pathway • MyD88-dependent toll-like receptor signaling pathway • MyD88-independent toll-like receptor signaling pathway • MyD88-independent toll-like receptor signaling pathway • protein phosphorylation • protein phosphorylation • anti-apoptosis • Toll signaling pathway • toll-like receptor 1 signaling pathway • toll-like receptor 2 signaling pathway • toll-like receptor 3 signaling pathway • toll-like receptor 4 signaling pathway • positive regulation of I-kappaB kinase/NF-kappaB cascade • innate immune response • positive regulation of transcription, DNA-dependent • nerve growth factor receptor signaling pathway • T cell receptor signaling pathway • positive regulation of NF-kappaB transcription factor activity • positive regulation of NF-kappaB transcription factor activity Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3551	16150
Ensembl	ENSG00000104365	ENSMUSG00000031537
UniProt	O14920	Q05DR8
RefSeq (mRNA)	NM_001190720.1	NM_010546
RefSeq (protein)	NP_001177649.1	NP_034676
Location (UCSC)	Chr 8: 42.13 – 42.19 Mb	Chr 8: 23.77 – 23.82 Mb
PubMed search	[1]	[2]

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

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. Its 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. citation needed, Oct 2011. If NF-κB inhibition 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.^[1] The size of the infarct, or tissue killed or damaged by ischemia, is reduced in mice in which IKK-β has been blocked.^[2] Additionally, experimental mice with an overactive form of IKK-β experience loss of many more neurons than normal mice after a stroke-simulating event.^[1] Researchers found a molecule that could block the signaling of IKK-β for up to four and a half hours.^[3] 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.^[4]

Interactions

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

• CDC37,^[5]
• CHUK^{[5][6][7][8][9][10][11]}
• CTNNB1,^[12]
• FANCA,^[7]
• IKBKG^{[5][10][13][14][15]}
• IRAK1,^[16][17]
• NFKBIA,^[9][18][19]
• MAP3K14,^[9][20]
• NFKB1,^[21][22]
• NFKBIB,^[9]
• NCOA3,^[14]
• PPM1B,^[23]
• TNFRSF1A,^[24][25] and
• TRAF2.^[26][27]

References

1. ^ ^{a b} BBC News. 14 November 2005. Stroke 'cell-death trigger' found. Retrieved on June 28, 2007.
2. ^ 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. 
3. ^ Herrmann, O; Baumann, B; De Lorenzi, R; Muhammad, S; Zhang, W; Kleesiek, J; Malfertheiner, M; Köhrmann, M et al. (2005). "IKK mediates ischemia-induced neuronal death". Nature medicine 11 (12): 1322–9. doi:10.1038/nm1323. PMID 16286924. 
4. ^ Heckmann A, Waltzinger C, Jolicoeur P, Dreano M, Kosco-Vilbois MH, and Sagot Y. 2004. IKK-β Inhibitor Alleviates Kidney and Wasting Diseases in a Murine Model of Human AIDS. American Journal of Pathology. Volume 164, Pages 1253-1262. Retrieved on June 30, 2007.
5. ^ ^{a b c} Chen, Guoqing; Cao Ping, Goeddel David V (Feb. 2002). "TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90". Mol. Cell (United States) 9 (2): 401–10. doi:10.1016/S1097-2765(02)00450-1. ISSN 1097-2765. PMID 11864612. 
6. ^ Zandi, E; Rothwarf D M, Delhase M, Hayakawa M, Karin M (Oct. 1997). "The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation". Cell (UNITED STATES) 91 (2): 243–52. doi:10.1016/S0092-8674(00)80406-7. ISSN 0092-8674. PMID 9346241. 
7. ^ ^{a b} Otsuki, Tetsuya; Young David B, Sasaki Dennis T, Pando Matthew P, Li Jianwu, Manning Anthony, Hoekstra Merl, Hoatlin Maureen E, Mercurio Frank, Liu Johnson M (2002). "Fanconi anemia protein complex is a novel target of the IKK signalsome". J. Cell. Biochem. (United States) 86 (4): 613–23. doi:10.1002/jcb.10270. ISSN 0730-2312. PMID 12210728. 
8. ^ May, M J; D'Acquisto F, Madge L A, Glöckner J, Pober J S, Ghosh S (Sep. 2000). "Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex". Science (UNITED STATES) 289 (5484): 1550–4. doi:10.1126/science.289.5484.1550. ISSN 0036-8075. PMID 10968790. 
9. ^ ^{a b c d} Woronicz, J D; Gao X, Cao Z, Rothe M, Goeddel D V (Oct. 1997). "IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK". Science (UNITED STATES) 278 (5339): 866–9. doi:10.1126/science.278.5339.866. ISSN 0036-8075. PMID 9346485. 
10. ^ ^{a b} Deng, L; Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen Z J (Oct. 2000). "Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain". Cell (UNITED STATES) 103 (2): 351–61. doi:10.1016/S0092-8674(00)00126-4. ISSN 0092-8674. PMID 11057907. 
11. ^ Yeung, K C; Rose D W, Dhillon A S, Yaros D, Gustafsson M, Chatterjee D, McFerran B, Wyche J, Kolch W, Sedivy J M (Nov. 2001). "Raf kinase inhibitor protein interacts with NF-kappaB-inducing kinase and TAK1 and inhibits NF-kappaB activation". Mol. Cell. Biol. (United States) 21 (21): 7207–17. doi:10.1128/MCB.21.21.7207-7217.2001. ISSN 0270-7306. PMC 99896. PMID 11585904. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=99896. 
12. ^ Lamberti, C; Lin K M, Yamamoto Y, Verma U, Verma I M, Byers S, Gaynor R B (Nov. 2001). "Regulation of beta-catenin function by the IkappaB kinases". J. Biol. Chem. (United States) 276 (45): 42276–86. doi:10.1074/jbc.M104227200. ISSN 0021-9258. PMID 11527961. 
13. ^ Chariot, Alain; Leonardi Antonio, Muller Jurgen, Bonif Marianne, Brown Keith, Siebenlist Ulrich (Oct. 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. (United States) 277 (40): 37029–36. doi:10.1074/jbc.M205069200. ISSN 0021-9258. PMID 12133833. 
14. ^ ^{a b} Wu, Ray-Chang; Qin Jun, Hashimoto Yoshihiro, Wong Jiemin, Xu Jianming, Tsai Sophia Y, Tsai Ming-Jer, O'Malley Bert W (May. 2002). "Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator activity by I kappa B kinase". Mol. Cell. Biol. (United States) 22 (10): 3549–61. doi:10.1128/MCB.22.10.3549-3561.2002. ISSN 0270-7306. PMC 133790. PMID 11971985. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=133790. 
15. ^ Shifera, Amde Selassie; Horwitz Marshall S (Mar. 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. (England) 45 (6): 1633–45. doi:10.1016/j.molimm.2007.09.036. ISSN 0161-5890. PMID 18207244. 
16. ^ Vig, E; Green M, Liu Y, Yu K Y, Kwon H J, Tian J, Goebl M G, Harrington M A (Mar. 2001). "SIMPL is a tumor necrosis factor-specific regulator of nuclear factor-kappaB activity". J. Biol. Chem. (United States) 276 (11): 7859–66. doi:10.1074/jbc.M010399200. ISSN 0021-9258. PMID 11096118. 
17. ^ Windheim, Mark; Stafford Margaret, Peggie Mark, Cohen Philip (Mar. 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". Mol. Cell. Biol. (United States) 28 (5): 1783–91. doi:10.1128/MCB.02380-06. PMC 2258775. PMID 18180283. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2258775. 
18. ^ Mercurio, F; Murray B W, Shevchenko A, Bennett B L, Young D B, Li J W, Pascual G, Motiwala A, Zhu H, Mann M, Manning A M (Feb. 1999). "IkappaB kinase (IKK)-associated protein 1, a common component of the heterogeneous IKK complex". Mol. Cell. Biol. (UNITED STATES) 19 (2): 1526–38. ISSN 0270-7306. PMC 116081. PMID 9891086. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=116081. 
19. ^ Cohen, L; Henzel W J, Baeuerle P A (Sep. 1998). "IKAP is a scaffold protein of the IkappaB kinase complex". Nature (ENGLAND) 395 (6699): 292–6. doi:10.1038/26254. ISSN 0028-0836. PMID 9751059. 
20. ^ Luftig, M A; 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. (United States) 276 (18): 14602–6. doi:10.1074/jbc.C100103200. ISSN 0021-9258. PMID 11278268. 
21. ^ Heissmeyer, V; Krappmann D, Hatada E N, Scheidereit C (Feb. 2001). "Shared pathways of IkappaB kinase-induced SCF(betaTrCP)-mediated ubiquitination and degradation for the NF-kappaB precursor p105 and IkappaBalpha". Mol. Cell. Biol. (United States) 21 (4): 1024–35. doi:10.1128/MCB.21.4.1024-1035.2001. ISSN 0270-7306. PMC 99557. PMID 11158290. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=99557. 
22. ^ Heissmeyer, V; Krappmann D, Wulczyn F G, Scheidereit C (Sep. 1999). "NF-kappaB p105 is a target of IkappaB kinases and controls signal induction of Bcl-3-p50 complexes". EMBO J. (ENGLAND) 18 (17): 4766–78. doi:10.1093/emboj/18.17.4766. ISSN 0261-4189. PMC 1171549. PMID 10469655. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1171549. 
23. ^ Prajapati, Shashi; Verma Udit, Yamamoto Yumi, Kwak Youn Tae, Gaynor Richard B (Jan. 2004). "Protein phosphatase 2Cbeta association with the IkappaB kinase complex is involved in regulating NF-kappaB activity". J. Biol. Chem. (United States) 279 (3): 1739–46. doi:10.1074/jbc.M306273200. ISSN 0021-9258. PMID 14585847. 
24. ^ Zhang, S Q; Kovalenko A, Cantarella G, Wallach D (Mar. 2000). "Recruitment of the IKK signalosome to the p55 TNF receptor: RIP and A20 bind to NEMO (IKKgamma) upon receptor stimulation". Immunity (UNITED STATES) 12 (3): 301–11. doi:10.1016/S1074-7613(00)80183-1. ISSN 1074-7613. PMID 10755617. 
25. ^ Chaudhary, P M; Eby M T, Jasmin A, Kumar A, Liu L, Hood L (Sep. 2000). "Activation of the NF-kappaB pathway by caspase 8 and its homologs". Oncogene (ENGLAND) 19 (39): 4451–60. doi:10.1038/sj.onc.1203812. ISSN 0950-9232. PMID 11002417. 
26. ^ Devin, A; Lin Y, Yamaoka S, Li Z, Karin M, Liu Zg (Jun. 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". Mol. Cell. Biol. (United States) 21 (12): 3986–94. doi:10.1128/MCB.21.12.3986-3994.2001. ISSN 0270-7306. PMC 87061. PMID 11359906. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=87061. 
27. ^ Li, Shitao; Wang Lingyan, Dorf Martin E (Jan. 2009). "PKC phosphorylation of TRAF2 mediates IKKalpha/beta recruitment and K63-linked polyubiquitination". Mol. Cell (United States) 33 (1): 30–42. doi:10.1016/j.molcel.2008.11.023. PMC 2643372. PMID 19150425. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2643372. 

See also

• IκB kinase