Wikipedia

CHUK

"Ikka" redirects here. For the singer, see Ikka Singh.
For the political party Change UK, see Change UK - The Independent Group.

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.[5] IKK-α is part of the IκB kinase complex that plays an important role in regulating the NF-κB transcription factor.[6] However, IKK-α has many additional cellular _targets, and is thought to function independently of the NF-κB pathway to regulate epidermal differentiation.[7][8]

CHUK
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCHUK, IKBKA, IKK-alpha, IKK1, IKKA, NFKBIKA, TCF16, conserved helix-loop-helix ubiquitous kinase, component of inhibitor of nuclear factor kappa B kinase complex, BPS2
External IDsOMIM: 600664; MGI: 99484; HomoloGene: 979; GeneCards: CHUK; OMA:CHUK - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1147

12675

Ensembl

ENSG00000213341

ENSMUSG00000025199

UniProt

O15111

Q60680

RefSeq (mRNA)

NM_001278
NM_001320928

NM_001162410
NM_007700

RefSeq (protein)

NP_001269
NP_001307857

n/a

Location (UCSC)Chr 10: 100.19 – 100.23 MbChr 19: 44.06 – 44.1 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

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NF-κB response

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Main article: IκB kinase

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.[9]

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

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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.[10] 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.[7]

The zebrafish homolog of IKK-α has also been shown to play a role in the differentiation of the embryonic epithelium.[11] 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

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IκB kinase α (IKKα) is a regulator of keratinocyte terminal differentiation and proliferation and plays a role in skin cancer.[12]

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.[13] 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.[14]

Other cellular _targets

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IKK-α has also been reported to regulate the cell cycle protein cyclin D1 in an NF-κB-independent manner.[15][16]

Clinical significance

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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.[17]

Mutations in IKK-α in humans have been linked to lethal fetal malformations.[18] 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.[19]

Interactions

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IKK-α has been shown to interact with:

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000213341 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025199 – 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. ^ Mock BA, Connelly MA, McBride OW, Kozak CA, Marcu KB (May 1995). "CHUK, a conserved helix-loop-helix ubiquitous kinase, maps to human chromosome 10 and mouse chromosome 19". Genomics. 27 (2): 348–51. doi:10.1006/geno.1995.1054. PMID 7558004.
  6. ^ Häcker H, Karin M (October 2006). "Regulation and function of IKK and IKK-related kinases". Sci. STKE. 2006 (357): re13. doi:10.1126/stke.3572006re13. PMID 17047224. S2CID 19617181.
  7. ^ a b Descargues P, Sil AK, Karin M (October 2008). "IKKα, a critical regulator of epidermal differentiation and a suppressor of skin cancer". EMBO J. 27 (20): 2639–47. doi:10.1038/emboj.2008.196. PMC 2556095. PMID 18818691.
  8. ^ Zhu F, Park E, Liu B, Xia X, Fischer SM, Hu Y (February 2009). "Critical role of IkappaB kinase alpha in embryonic skin development and skin carcinogenesis". Histol. Histopathol. 24 (2): 265–71. PMC 7243875. PMID 19085841.
  9. ^ "Entrez Gene: CHUK conserved helix-loop-helix ubiquitous kinase".
  10. ^ 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. PMC 316728. PMID 10346820.
  11. ^ Fukazawa C, Santiago C, Park K, Deery W, Gomez de la Torre Canny S, Holterhoff C, Wagner DS (October 2010). "poky/chuk/ikk1 is required for differentiation of the zebrafish embryonic epidermis". Developmental Biology. 346 (2): 272–83. doi:10.1016/j.ydbio.2010.07.037. PMC 2956273. PMID 20692251.
  12. ^ Xie Y, Xie K, Gou Q, Chen N (2015). "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. doi:10.3892/or.2015.4229. PMID 26323241.
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  30. ^ 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". Mol. Immunol. 45 (6): 1633–45. doi:10.1016/j.molimm.2007.09.036. PMID 18207244.
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  NODES
Association 1
chat 1
Note 1