From Wikipedia, the free encyclopedia
Protein-coding gene in the species Homo sapiens
IKBKB
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, IMD15BExternal IDs
OMIM :
603258
MGI :
1338071
HomoloGene :
7782
GeneCards :
IKBKB
Wikidata
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
HDAC9 ,
[9]
CDC37 ,
[10]
CHUK
[10]
[11]
[12]
[13]
[14]
[15]
[16]
CTNNB1 ,
[17]
FANCA ,
[12]
IKBKG
[10]
[15]
[18]
[19]
[20]
IRAK1 ,
[21]
[22]
NFKBIA ,
[14]
[23]
[24]
MAP3K14 ,
[14]
[25]
NFKB1 ,
[26]
[27]
NFKBIB ,
[14]
NCOA3 ,
[19]
PPM1B ,
[28]
TNFRSF1A ,
[29]
[30] and
TRAF2 .
[31]
[32]
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 .
See also
Activity Regulation Classification Kinetics Types