Jump to content

IKK2

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by Monkbot (talk | contribs) at 13:15, 3 December 2020 (Task 18 (cosmetic): eval 40 templates: del empty params (1×);). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

IKBKB
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesIKBKB, 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 IDsOMIM: 603258; MGI: 1338071; HomoloGene: 7782; GeneCards: IKBKB; OMA:IKBKB - orthologs
Orthologs
SpeciesHumanMouse
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 MbChr 8: 23.15 – 23.2 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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

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.[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]

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.[9] Additionally, experimental mice with an overactive form of IKK-β experience loss of many more neurons than normal mice after a stroke-simulating event.[6] Researchers found a molecule that could block the signaling of IKK-β for up to four and a half hours.[10] 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.[11]

A conditional knockout mouse line, called Ikbkbtm1a(EUCOMM)Wtsi[16][17] 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.[18][19][20]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[14][21] 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.[14]

Interactions

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

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000104365 – Ensembl, May 2017
  2. ^ a b c 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. ^ 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.
  6. ^ a b "Stroke 'cell-death trigger' found". BBC News. 14 November 2005. Retrieved June 28, 2007.
  7. ^ 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.
  8. ^ "SAR113945 published clinical trials".
  9. ^ Schwaninger M, Inta I, Herrmann O (December 2006). "NF-kappaB signalling in cerebral ischaemia". Biochemical Society Transactions. 34 (Pt 6): 1291–4. doi:10.1042/BST0341291. PMID 17073804.
  10. ^ 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.
  11. ^ Heckmann A, Waltzinger C, Jolicoeur P, Dreano M, Kosco-Vilbois MH, Sagot Y (April 2004). "IKK2 inhibitor alleviates kidney and wasting diseases in a murine model of human AIDS". The American Journal of Pathology. 164 (4): 1253–62. doi:10.1016/S0002-9440(10)63213-0. PMC 1615343. PMID 15039214.
  12. ^ "Salmonella infection data for Ikbkb". Wellcome Trust Sanger Institute.
  13. ^ "Citrobacter infection data for Ikbkb". Wellcome Trust Sanger Institute.
  14. ^ a b c 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. S2CID 85911512.
  15. ^ Mouse Resources Portal, Wellcome Trust Sanger Institute.
  16. ^ "International Knockout Mouse Consortium".
  17. ^ "Mouse Genome Informatics".
  18. ^ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, et al. (June 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
  19. ^ Dolgin E (June 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  20. ^ Collins FS, Rossant J, Wurst W (January 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247. S2CID 18872015.
  21. ^ van der Weyden L, White JK, Adams DJ, Logan DW (June 2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  22. ^ 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.
  23. ^ 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.
  24. ^ 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.
  25. ^ 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.
  26. ^ 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. PMID 10968790.
  27. ^ 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. doi:10.1126/science.278.5339.866. PMID 9346485.
  28. ^ 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.
  29. ^ 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.
  30. ^ 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.
  31. ^ 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.
  32. ^ 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.
  33. ^ 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.
  34. ^ 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.
  35. ^ 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.
  36. ^ 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.
  37. ^ 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. PMID 9751059. S2CID 4327300.
  38. ^ 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.
  39. ^ 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.
  40. ^ 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.
  41. ^ 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.
  42. ^ 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.
  43. ^ 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.
  44. ^ 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.
  45. ^ 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

Retrieved from "https://en.wikipedia.org/w/index.php?title=IKK2&oldid=992091409"