CHUK

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]

"Ikka" redirects here. For the singer, see Ikka Singh.

CHUK
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3BRT
Identifiers
Aliases	CHUK, IKBKA, IKK-alpha, IKK1, IKKA, NFKBIKA, TCF16, conserved helix-loop-helix ubiquitous kinase, component of inhibitor of nuclear factor kappa B kinase complex
External IDs	OMIM: 600664 MGI: 99484 HomoloGene: 979 GeneCards: CHUK
Gene location (Human) Chr. Chromosome 10 (human)[1] Band 10q24.31 Start 100,188,300 bp[1] End 100,229,596 bp[1]
Gene location (Mouse) Chr. Chromosome 19 (mouse)[2] Band 19 C3|19 36.71 cM Start 44,073,335 bp[2] End 44,107,480 bp[2]
Gene ontology Molecular function • transferase activity • protein kinase activity • IkappaB kinase activity • nucleotide binding • protein homodimerization activity • scaffold protein binding • kinase activity • protein serine/threonine kinase activity • GO:0001948 protein binding • protein heterodimerization activity • ATP binding • identical protein binding Cellular component • intracellular membrane-bounded organelle • nucleoplasm • CD40 receptor complex • cytoplasmic side of plasma membrane • IkappaB kinase complex • cell nucleus • cytoplasm • cytosol Biological process • response to amino acid • phosphorylation • regulation of tumor necrosis factor-mediated signaling pathway • skeletal muscle contraction • anatomical structure morphogenesis • response to virus • cellular response to tumor necrosis factor • stimulatory C-type lectin receptor signaling pathway • response to hydroperoxide • response to organic substance • TRIF-dependent toll-like receptor signaling pathway • Fc-epsilon receptor signaling pathway • protein phosphorylation • response to lipopolysaccharide • positive regulation of NF-kappaB transcription factor activity • stress-activated MAPK cascade • response to acetate • immune response • Rho protein signal transduction • positive regulation of I-kappaB kinase/NF-kappaB signaling • striated muscle cell differentiation • innate immune system • inflammatory response • T cell receptor signaling pathway • response to toxic substance • response to drug • positive regulation of transcription from RNA polymerase II promoter • I-kappaB phosphorylation • antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent • peptidyl-serine phosphorylation • tumor necrosis factor-mediated signaling pathway • I-kappaB kinase/NF-kappaB signaling • cellular response to reactive oxygen species • NIK/NF-kappaB signaling • positive regulation of transcription, DNA-templated • cellular response to cadmium ion • cellular response to virus • positive regulation of interferon-alpha secretion • negative regulation of NF-kappaB transcription factor activity • MyD88-independent toll-like receptor signaling pathway • interleukin-1-mediated signaling pathway • response to cholecystokinin Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
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 Mb	Chr 19: 44.07 – 44.11 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

NF-κB response

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

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

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 stimulatea migration through dynamic interactions with the EGF promoter depending on the redox state within cells.[14]

Other cellular targets

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

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.[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

IKK-α has been shown to interact with:

• HDAC9,[20]
• AKT1,[21][22]
• AKT2,[23]
• CTNNB1,[24]
• FANCA,[25][26]
• IKBKG[27][28][29][30]
• IKK2,[26][28][29][31][32][33][34]
• IRAK1,[35][36]
• MAP3K14,[37][38][39][40]
• MAP3K7,[40][41]
• MAP3K8,[42]
• NFKBIA,[33][40][43][44]
• NCOA3,[45]
• PPM1B,[46]
• PRKDC,[47] and
• TRAF2.[37][48][49]

References

1. GRCh38: Ensembl release 89: ENSG00000213341 - Ensembl, May 2017
2. 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.
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7. 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. 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.
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26. Otsuki T, Young DB, Sasaki DT, Pando MP, Li J, Manning A, Hoekstra M, Hoatlin ME, Mercurio F, Liu JM (2002). "Fanconi anemia protein complex is a novel target of the IKK signalsome" (PDF). J. Cell. Biochem. 86 (4): 613–23. doi:10.1002/jcb.10270. PMID 12210728.
27. Agou F, Ye F, Goffinont S, Courtois G, Yamaoka S, Israël A, Véron M (May 2002). "NEMO trimerizes through its coiled-coil C-terminal domain". J. Biol. Chem. 277 (20): 17464–75. doi:10.1074/jbc.M201964200. PMID 11877453.
28. Chen G, Cao P, Goeddel DV (February 2002). "TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90". Mol. Cell. 9 (2): 401–10. doi:10.1016/S1097-2765(02)00450-1. PMID 11864612.
29. Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ (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.
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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32. 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.
33. 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.
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External links

• Human CHUK genome location and CHUK gene details page in the UCSC Genome Browser.