Biology:IKK2

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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 page: Biology: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

References

  1. ↑ "IKK mediates ischemia-induced neuronal death". Nature Medicine 11 (12): 1322–9. December 2005. doi:10.1038/nm1323. PMID 16286924. 
  2. ↑ "Stroke 'cell-death trigger' found". BBC News. 14 November 2005. http://news.bbc.co.uk/2/hi/health/4427702.stm. 
  3. ↑ "Small-molecule inhibitors of IκB kinase (IKK) and IKK-related kinases". Pharmaceutical Patent Analyst 2 (4): 481–98. July 2013. doi:10.4155/ppa.13.31. PMID 24237125. 
  4. ↑ "SAR113945 published clinical trials". http://clinicaltrials.gov/ct2/results?term=SAR113945&Search=Search. 
  5. ↑ "Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability". Circulation Research 127 (6): 811–823. August 2020. doi:10.1161/CIRCRESAHA.120.316743. PMID 32546048. https://epub.ub.uni-muenchen.de/72640/. 
  6. ↑ 6.0 6.1 6.2 "TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90". Molecular Cell 9 (2): 401–10. February 2002. doi:10.1016/S1097-2765(02)00450-1. PMID 11864612. 
  7. ↑ "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. doi:10.1016/S0092-8674(00)80406-7. PMID 9346241. 
  8. ↑ 8.0 8.1 "Fanconi anemia protein complex is a novel target of the IKK signalsome". Journal of Cellular Biochemistry 86 (4): 613–23. 2002. doi:10.1002/jcb.10270. PMID 12210728. https://zenodo.org/record/1229210. 
  9. ↑ "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. doi:10.1126/science.289.5484.1550. PMID 10968790. Bibcode: 2000Sci...289.1550M. 
  10. ↑ 10.0 10.1 10.2 10.3 "IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK". Science 278 (5339): 866–9. October 1997. doi:10.1126/science.278.5339.866. PMID 9346485. Bibcode: 1997Sci...278..866W. 
  11. ↑ 11.0 11.1 "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. doi:10.1016/S0092-8674(00)00126-4. PMID 11057907. 
  12. ↑ "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. doi:10.1128/MCB.21.21.7207-7217.2001. PMID 11585904. 
  13. ↑ "Regulation of beta-catenin function by the IkappaB kinases". The Journal of Biological Chemistry 276 (45): 42276–86. November 2001. doi:10.1074/jbc.M104227200. PMID 11527961. 
  14. ↑ "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. doi:10.1074/jbc.M205069200. PMID 12133833. 
  15. ↑ 15.0 15.1 "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. doi:10.1128/MCB.22.10.3549-3561.2002. PMID 11971985. 
  16. ↑ "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. doi:10.1016/j.molimm.2007.09.036. PMID 18207244. 
  17. ↑ "SIMPL is a tumor necrosis factor-specific regulator of nuclear factor-kappaB activity". The Journal of Biological Chemistry 276 (11): 7859–66. March 2001. doi:10.1074/jbc.M010399200. PMID 11096118. 
  18. ↑ "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. doi:10.1128/MCB.02380-06. PMID 18180283. 
  19. ↑ "IkappaB kinase (IKK)-associated protein 1, a common component of the heterogeneous IKK complex". Molecular and Cellular Biology 19 (2): 1526–38. February 1999. doi:10.1128/mcb.19.2.1526. PMID 9891086. 
  20. ↑ "IKAP is a scaffold protein of the IkappaB kinase complex". Nature 395 (6699): 292–6. September 1998. doi:10.1038/26254. PMID 9751059. Bibcode: 1998Natur.395..292C. 
  21. ↑ "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. doi:10.1074/jbc.C100103200. PMID 11278268. 
  22. ↑ "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. doi:10.1128/MCB.21.4.1024-1035.2001. PMID 11158290. 
  23. ↑ "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. doi:10.1093/emboj/18.17.4766. PMID 10469655. 
  24. ↑ "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. doi:10.1074/jbc.M306273200. PMID 14585847. 
  25. ↑ "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. doi:10.1016/S1074-7613(00)80183-1. PMID 10755617. 
  26. ↑ "Activation of the NF-kappaB pathway by caspase 8 and its homologs". Oncogene 19 (39): 4451–60. September 2000. doi:10.1038/sj.onc.1203812. PMID 11002417. 
  27. ↑ "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. doi:10.1128/MCB.21.12.3986-3994.2001. PMID 11359906. 
  28. ↑ "PKC phosphorylation of TRAF2 mediates IKKalpha/beta recruitment and K63-linked polyubiquitination". Molecular Cell 33 (1): 30–42. January 2009. doi:10.1016/j.molcel.2008.11.023. PMID 19150425. 

See also



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