IKK2 explained

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

See 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.^[1] 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.^[2]

Inhibition of IKK and IKK-related kinases has been investigated as a therapeutic option for the treatment of inflammatory diseases and cancer.^[3] The small-molecule inhibitor of IKK2 SAR113945, developed by Sanofi-Aventis, was evaluated in patients with knee osteoarthritis.^[4]

Interactions

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

• HDAC9,^[5]
• CDC37,^[6]
• CHUK^{[6] [7] [8] [9]}
• CTNNB1,^[10]
• FANCA,^[11]
• IKBKG^{[6] [12] [13] [14]}
• IRAK1,^{[15] [16]}
• NFKBIA,^{[17] [18]}
• MAP3K14,^[19]
• NFKB1,^{[20] [21]}
• NFKBIB,^[22]
• NCOA3,^[23]
• PPM1B,^[24]
• TNFRSF1A,^{[25] [26]} and
• TRAF2.^{[27] [28]}

See also

• IκB kinase

Notes and References

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2. Web site: BBC News . 14 November 2005 . Stroke 'cell-death trigger' found . June 28, 2007 .
3. Llona-Minguez S, Baiget J, Mackay SP . Small-molecule inhibitors of IκB kinase (IKK) and IKK-related kinases . Pharmaceutical Patent Analyst . 2 . 4 . 481–98 . July 2013 . 24237125 . 10.4155/ppa.13.31 .
4. Web site: SAR113945 published clinical trials.
5. 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 . 6 . Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability . Circulation Research . 127 . 6 . 811–823 . August 2020 . 32546048 . 10.1161/CIRCRESAHA.120.316743 . 219726725 . free .
6. Chen G, Cao P, Goeddel DV . TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90 . Molecular Cell . 9 . 2 . 401–10 . February 2002 . 11864612 . 10.1016/S1097-2765(02)00450-1 . free .
7. Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M . 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 . October 1997 . 9346241 . 10.1016/S0092-8674(00)80406-7 . 6399108 . free .
8. May MJ, D'Acquisto F, Madge LA, Glöckner J, Pober JS, Ghosh S . 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 . September 2000 . 10968790 . 10.1126/science.289.5484.1550 . 2000Sci...289.1550M .
9. Yeung KC, Rose DW, Dhillon AS, Yaros D, Gustafsson M, Chatterjee D, McFerran B, Wyche J, Kolch W, Sedivy JM . 6 . 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 . November 2001 . 11585904 . 99896 . 10.1128/MCB.21.21.7207-7217.2001 .
10. Richard Gaynor . Lamberti C, Lin KM, Yamamoto Y, Verma U, Verma IM, Byers S, Gaynor RB . Regulation of beta-catenin function by the IkappaB kinases . The Journal of Biological Chemistry . 276 . 45 . 42276–86 . November 2001 . 11527961 . 10.1074/jbc.M104227200 . free .
11. Otsuki T, Young DB, Sasaki DT, Pando MP, Li J, Manning A, Hoekstra M, Hoatlin ME, Mercurio F, Liu JM . 6 . Fanconi anemia protein complex is a novel target of the IKK signalsome . Journal of Cellular Biochemistry . 86 . 4 . 613–23 . 2002 . 12210728 . 10.1002/jcb.10270 . 42471384 .
12. Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ . 6 . 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 . October 2000 . 11057907 . 10.1016/S0092-8674(00)00126-4 . 18154645 . free .
13. Chariot A, Leonardi A, Muller J, Bonif M, Brown K, Siebenlist U . 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 . October 2002 . 12133833 . 10.1074/jbc.M205069200 . free .
14. Shifera AS, Horwitz MS . 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 . March 2008 . 18207244 . 10.1016/j.molimm.2007.09.036 .
15. Vig E, Green M, Liu Y, Yu KY, Kwon HJ, Tian J, Goebl MG, Harrington MA . 6 . SIMPL is a tumor necrosis factor-specific regulator of nuclear factor-kappaB activity . The Journal of Biological Chemistry . 276 . 11 . 7859–66 . March 2001 . 11096118 . 10.1074/jbc.M010399200 . free .
16. Windheim M, Stafford M, Peggie M, Cohen P . 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 . March 2008 . 18180283 . 2258775 . 10.1128/MCB.02380-06 .
17. Mercurio F, Murray BW, Shevchenko A, Bennett BL, Young DB, Li JW, Pascual G, Motiwala A, Zhu H, Mann M, Manning AM . 6 . IkappaB kinase (IKK)-associated protein 1, a common component of the heterogeneous IKK complex . Molecular and Cellular Biology . 19 . 2 . 1526–38 . February 1999 . 9891086 . 116081 . 10.1128/mcb.19.2.1526 .
18. Cohen L, Henzel WJ, Baeuerle PA . IKAP is a scaffold protein of the IkappaB kinase complex . Nature . 395 . 6699 . 292–6 . September 1998 . 9751059 . 10.1038/26254 . 1998Natur.395..292C . 4327300 .
19. Luftig MA, Cahir-McFarland E, Mosialos G, Kieff E . 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 . May 2001 . 11278268 . 10.1074/jbc.C100103200 . free .
20. Heissmeyer V, Krappmann D, Hatada EN, Scheidereit C . 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 . February 2001 . 11158290 . 99557 . 10.1128/MCB.21.4.1024-1035.2001 .
21. Heissmeyer V, Krappmann D, Wulczyn FG, Scheidereit C . 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 . September 1999 . 10469655 . 1171549 . 10.1093/emboj/18.17.4766 .
22. Woronicz JD, Gao X, Cao Z, Rothe M, Goeddel DV . IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK . Science . 278 . 5339 . 866–9 . October 1997 . 9346485 . 10.1126/science.278.5339.866 . 1997Sci...278..866W .
23. Wu RC, Qin J, Hashimoto Y, Wong J, Xu J, Tsai SY, Tsai MJ, O'Malley BW . 6 . 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 . May 2002 . 11971985 . 133790 . 10.1128/MCB.22.10.3549-3561.2002 .
24. Prajapati S, Verma U, Yamamoto Y, Kwak YT, Gaynor RB . 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 . January 2004 . 14585847 . 10.1074/jbc.M306273200 . free .
25. Zhang SQ, Kovalenko A, Cantarella G, Wallach D . 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 . March 2000 . 10755617 . 10.1016/S1074-7613(00)80183-1 . free .
26. Chaudhary PM, Eby MT, Jasmin A, Kumar A, Liu L, Hood L . Activation of the NF-kappaB pathway by caspase 8 and its homologs . Oncogene . 19 . 39 . 4451–60 . September 2000 . 11002417 . 10.1038/sj.onc.1203812 . free .
27. Devin A, Lin Y, Yamaoka S, Li Z, Karin M . 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 . June 2001 . 11359906 . 87061 . 10.1128/MCB.21.12.3986-3994.2001 .
28. Li S, Wang L, Dorf ME . PKC phosphorylation of TRAF2 mediates IKKalpha/beta recruitment and K63-linked polyubiquitination . Molecular Cell . 33 . 1 . 30–42 . January 2009 . 19150425 . 2643372 . 10.1016/j.molcel.2008.11.023 .