Biology:CHUK
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Inhibitor of nuclear factor kappa-B kinase subunit alpha (IKK-α) also known as IKK1 or conserved helix-loop-helix ubiquitous kinase (CHUK) is a protein kinase that in humans is encoded by the CHUK gene.[1] IKK-α is part of the IκB kinase complex that plays an important role in regulating the NF-κB transcription factor.[2] However, IKK-α has many additional cellular targets, and is thought to function independently of the NF-κB pathway to regulate epidermal differentiation.[3][4]
Function
NF-κB response
IKK-α is a member of the serine/threonine protein kinase family and forms a complex in the cell with IKK-β and NEMO. NF-κB transcription factors are normally held in an inactive state by the inhibitory proteins IκBs. IKK-α and IKK-β phosphorylate the IκB proteins, marking them for degradation via ubiquitination and allowing NF-κB transcription factors to go into the nucleus.[5]
Once activated, NF-κB transcription factors regulate genes that are implicated in many important cellular processes, including immune response, inflammation, cell death, and cell proliferation.
Epidermal differentiation
IKK-α has been shown to function in epidermal differentiation independently of the NF-κB pathway. In the mouse, IKK-α is required for cell cycle exit and differentiation of the embryonic keratinocytes. IKK-α null mice have a truncated snout and limbs, shiny skin, and die shortly after birth due to dehydration.[6] Their epidermis retains a proliferative precursor cell population and lacks the outer two most differentiated cell layers. This function of IKK-α has been shown to be independent of the protein's kinase activity and of the NF-κB pathway. Instead it is thought that IKK-α regulates skin differentiation by acting as a cofactor in the TGF-β / Smad2/3 signaling pathway.[3]
The zebrafish homolog of IKK-α has also been shown to play a role in the differentiation of the embryonic epithelium.[7] Zebrafish embryos born from mothers that are mutant in IKK-α do not produce a differentiated outer epithelial monolayer. Instead, the outermost cells in these embryos are hyperproliferative and fail to turn on critical epidermal genes. Different domains of the protein are required for this function of IKK-α in zebrafish than in mice, but in neither case does the NF-κB pathway seem to be implicated.
Keratinocyte migration
IκB kinase α (IKKα) is a regulator of keratinocyte terminal differentiation and proliferation and plays a role in skin cancer.[8]
Activation of three major hydrogen peroxide-dependent pathways, EGF, FOXO1, and IKK-α occur during injury-induced epidermal keratinocyte migration, adhesion, cytoprotection and wound healing.[9] IKKα regulates human keratinocyte migration by surveillance of the redox environment after wounding. IKK-α is sulfenylated at a conserved cysteine residue in the kinase domain, which correlated with derepression of EGF promoter activity and increased EGF expression, indicating that IKK-α stimulates migration through dynamic interactions with the EGF promoter depending on the redox state within cells.[10]
Other cellular targets
IKK-α has also been reported to regulate the cell cycle protein cyclin D1 in an NF-κB-independent manner.[11][12]
Clinical significance
Inhibition of IκB kinase (IKK) and IKK-related kinases, IKBKE (IKKε) and TANK-binding kinase 1 (TBK1), has been investigated as a therapeutic option for the treatment of inflammatory diseases and cancer.[13]
Mutations in IKK-α in humans have been linked to lethal fetal malformations.[14] The phenotype of these mutant fetuses is similar to the mouse IKK-α null phenotype, and is characterized by shiny, thickened skin and truncated limbs.
Decreased IKK-α activity has been reported in a large percentage of human squamous cell carcinomas, and restoring IKK-α in mouse models of skin cancer has been shown to have an anti-tumorigenic effect.[15]
Interactions
IKK-α has been shown to interact with:
- HDAC9,[16]
- AKT1,[17][18]
- AKT2,[19]
- CTNNB1,[20]
- FANCA,[21][22]
- IKBKG[23][24][25][26]
- IKK2,[22][24][25][27][28][29][30]
- IRAK1,[31][32]
- MAP3K14,[33][34][35][36]
- MAP3K7,[36][37]
- MAP3K8,[38]
- NFKBIA,[29][36][39][40]
- NCOA3,[41]
- PPM1B,[42]
- PRKDC,[43] and
- TRAF2.[33][44][45]
References
- ↑ "CHUK, a conserved helix-loop-helix ubiquitous kinase, maps to human chromosome 10 and mouse chromosome 19". Genomics 27 (2): 348–51. May 1995. doi:10.1006/geno.1995.1054. PMID 7558004.
- ↑ "Regulation and function of IKK and IKK-related kinases". Sci. STKE 2006 (357): re13. October 2006. doi:10.1126/stke.3572006re13. PMID 17047224.
- ↑ 3.0 3.1 "IKKα, a critical regulator of epidermal differentiation and a suppressor of skin cancer". EMBO J. 27 (20): 2639–47. October 2008. doi:10.1038/emboj.2008.196. PMID 18818691.
- ↑ "Critical role of IkappaB kinase alpha in embryonic skin development and skin carcinogenesis". Histol. Histopathol. 24 (2): 265–71. February 2009. PMID 19085841.
- ↑ "Entrez Gene: CHUK conserved helix-loop-helix ubiquitous kinase". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1147.
- ↑ Qiutang Li; Qingxian Lu; Jason Y. Hwang; Dirk Büscher; Kuo-Fen Lee; Juan Carlos Izpisua-Belmonte; Inder M. Verma (May 1999). "IKK1-deficient mice exhibit abnormal development of skin and skeleton". Genes Dev. 13 (10): 1322–8. doi:10.1101/gad.13.10.1322. PMID 10346820.
- ↑ "poky/chuk/ikk1 is required for differentiation of the zebrafish embryonic epidermis". Developmental Biology 346 (2): 272–83. October 2010. doi:10.1016/j.ydbio.2010.07.037. PMID 20692251.
- ↑ "IκB kinase α functions as a tumor suppressor in epithelial-derived tumors through an NF-κB-independent pathway (Review)". Oncology Reports 34 (5): 2225–32. 2015. doi:10.3892/or.2015.4229. PMID 26323241.
- ↑ "Comparative transcriptomic profiling of hydrogen peroxide signaling networks in zebrafish and human keratinocytes: Implications toward conservation, migration and wound healing". Scientific Reports 6: 20328. February 2016. doi:10.1038/srep20328. PMID 26846883. Bibcode: 2016NatSR...620328L.
- ↑ "IKKα regulates human keratinocyte migration through surveillance of the redox environment". Journal of Cell Science 130 (5): 975–988. March 2017. doi:10.1242/jcs.197343. PMID 28122935.
- ↑ "IkappaB kinase alpha regulates subcellular distribution and turnover of cyclin D1 by phosphorylation". J Biol Chem 280 (40): 33945–52. August 2005. doi:10.1074/jbc.M506206200. PMID 16103118.
- ↑ "A novel role of IKKα in the mediation of UVB-induced G0/G1 cell cycle arrest response by suppressing Cyclin D1 expression". Biochim Biophys Acta 1803 (2): 323–32. February 2010. doi:10.1016/j.bbamcr.2010.01.006. PMID 20080131.
- ↑ "Small-molecule inhibitors of IκB kinase (IKK) and IKK-related kinases". Pharm. Pat. Anal. 2 (4): 481–498. 2013. doi:10.4155/ppa.13.31. PMID 24237125.
- ↑ "Mutant CHUK and severe fetal encasement malformation". New England Journal of Medicine 363 (17): 1631–1637. October 2010. doi:10.1056/NEJMoa0911698. PMID 20961246.
- ↑ "A critical role for IκB kinase α in the development of human and mouse squamous cell carcinomas". Proc. Natl. Acad. Sci. U.S.A. 103 (46): 17202–7. November 2006. doi:10.1073/pnas.0604481103. PMID 17079494. Bibcode: 2006PNAS..10317202L.
- ↑ "Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability". Circulation Research 127 (6): 811–823. June 2020. doi:10.1161/CIRCRESAHA.120.316743. PMID 32546048. https://epub.ub.uni-muenchen.de/72640/.
- ↑ "NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase". Nature 401 (6748): 82–5. September 1999. doi:10.1038/43466. PMID 10485710. Bibcode: 1999Natur.401...82N.
- ↑ "NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling". Nature 401 (6748): 86–90. September 1999. doi:10.1038/43474. PMID 10485711. Bibcode: 1999Natur.401...86R.
- ↑ "Inhibition of JNK by cellular stress- and tumor necrosis factor alpha-induced AKT2 through activation of the NF kappa B pathway in human epithelial Cells". J. Biol. Chem. 277 (33): 29973–82. August 2002. doi:10.1074/jbc.M203636200. PMID 12048203.
- ↑ "Regulation of beta-catenin function by the IkappaB kinases". J. Biol. Chem. 276 (45): 42276–86. November 2001. doi:10.1074/jbc.M104227200. PMID 11527961.
- ↑ "Yeast two-hybrid screens imply involvement of Fanconi anemia proteins in transcription regulation, cell signaling, oxidative metabolism, and cellular transport". Exp. Cell Res. 289 (2): 211–21. October 2003. doi:10.1016/S0014-4827(03)00261-1. PMID 14499622.
- ↑ 22.0 22.1 "Fanconi anemia protein complex is a novel target of the IKK signalsome". J. Cell. Biochem. 86 (4): 613–23. 2002. doi:10.1002/jcb.10270. PMID 12210728. https://zenodo.org/record/1229210.
- ↑ "NEMO trimerizes through its coiled-coil C-terminal domain". J. Biol. Chem. 277 (20): 17464–75. May 2002. doi:10.1074/jbc.M201964200. PMID 11877453.
- ↑ 24.0 24.1 "TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90". Mol. Cell 9 (2): 401–10. February 2002. doi:10.1016/S1097-2765(02)00450-1. PMID 11864612.
- ↑ 25.0 25.1 "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.
- ↑ "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. 45 (6): 1633–45. March 2008. doi:10.1016/j.molimm.2007.09.036. PMID 18207244.
- ↑ "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.
- ↑ "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.
- ↑ 29.0 29.1 "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.
- ↑ "Raf Kinase Inhibitor Protein Interacts with NF-κB-Inducing Kinase and TAK1 and Inhibits NF-κB Activation". Mol. Cell. Biol. 21 (21): 7207–17. November 2001. doi:10.1128/MCB.21.21.7207-7217.2001. PMID 11585904.
- ↑ "SIMPL is a tumor necrosis factor-specific regulator of nuclear factor-kappaB activity". J. Biol. Chem. 276 (11): 7859–66. March 2001. doi:10.1074/jbc.M010399200. PMID 11096118.
- ↑ "Interleukin-1 (IL-1) Induces the Lys63-Linked Polyubiquitination of IL-1 Receptor-Associated Kinase 1 To Facilitate NEMO Binding and the Activation of IκBα Kinase". Mol. Cell. Biol. 28 (5): 1783–91. March 2008. doi:10.1128/MCB.02380-06. PMID 18180283.
- ↑ 33.0 33.1 "Identification and characterization of an IkappaB kinase". Cell 90 (2): 373–83. July 1997. doi:10.1016/S0092-8674(00)80344-X. PMID 9244310.
- ↑ "Negative regulation of the nuclear factor kappa B-inducing kinase by a cis-acting domain". J. Biol. Chem. 275 (28): 21081–5. July 2000. doi:10.1074/jbc.M002552200. PMID 10887201.
- ↑ "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. 276 (18): 14602–6. May 2001. doi:10.1074/jbc.C100103200. PMID 11278268.
- ↑ 36.0 36.1 36.2 "The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway". Nature 398 (6724): 252–6. March 1999. doi:10.1038/18465. PMID 10094049. Bibcode: 1999Natur.398..252N.
- ↑ "Functional interactions of transforming growth factor beta-activated kinase 1 with IkappaB kinases to stimulate NF-kappaB activation". J. Biol. Chem. 274 (15): 10641–8. April 1999. doi:10.1074/jbc.274.15.10641. PMID 10187861.
- ↑ "The proto-oncogene Cot kinase participates in CD3/CD28 induction of NF-kappaB acting through the NF-kappaB-inducing kinase and IkappaB kinases". Immunity 10 (2): 271–80. February 1999. doi:10.1016/S1074-7613(00)80027-8. PMID 10072079.
- ↑ "A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB". Nature 388 (6642): 548–54. August 1997. doi:10.1038/41493. PMID 9252186. Bibcode: 1997Natur.388..548D.
- ↑ "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.
- ↑ "Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator Activity by IκB Kinase". Mol. Cell. Biol. 22 (10): 3549–61. May 2002. doi:10.1128/MCB.22.10.3549-3561.2002. PMID 11971985.
- ↑ "Protein phosphatase 2Cbeta association with the IkappaB kinase complex is involved in regulating NF-kappaB activity". J. Biol. Chem. 279 (3): 1739–46. January 2004. doi:10.1074/jbc.M306273200. PMID 14585847.
- ↑ "DNA-Dependent Protein Kinase Phosphorylation of IκBα and IκBβ Regulates NF-κB DNA Binding Properties". Mol. Cell. Biol. 18 (7): 4221–34. July 1998. doi:10.1128/MCB.18.7.4221. PMID 9632806.
- ↑ Devin A; Lin Y; Yamaoka S; Li Z; Karin M; Liu Zg (June 2001). "The α and β Subunits of IκB Kinase (IKK) Mediate TRAF2-Dependent IKK Recruitment to Tumor Necrosis Factor (TNF) Receptor 1 in Response to TNF". Mol. Cell. Biol. 21 (12): 3986–94. doi:10.1128/MCB.21.12.3986-3994.2001. PMID 11359906.
- ↑ "PKC phosphorylation of TRAF2 mediates IKKα/β recruitment and K63-linked polyubiquitination". Mol. Cell 33 (1): 30–42. January 2009. doi:10.1016/j.molcel.2008.11.023. PMID 19150425.
External links
- Human CHUK genome location and CHUK gene details page in the UCSC Genome Browser.
![]() | Original source: https://en.wikipedia.org/wiki/CHUK.
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