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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, BPS2
External IDs	OMIM: 600664; MGI: 99484; HomoloGene: 979; GeneCards: CHUK; OMA:CHUK - orthologs
Gene location (Human) Chr. Chromosome 10 (human) Band 10q24.31 Start 100,188,300 bp End 100,229,596 bp
Gene location (Mouse) Chr. Chromosome 19 (mouse) Band 19 C3|19 36.71 cM Start 44,061,774 bp End 44,095,919 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in secondary oocyte middle frontal gyrus Brodmann area 10 islet of Langerhans palpebral conjunctiva germinal epithelium gingival epithelium monocyte gonad Achilles tendon Top expressed in neural layer of retina right kidney seminal vesicula proximal tubule jejunum human kidney liver epithelium of small intestine intestinal villus ventricular zone More reference expression data BioGPS n/a
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 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 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 response inflammatory response T cell receptor signaling pathway response to toxic substance positive regulation of transcription by RNA polymerase II 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 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: 44.06 – 44.1 Mb PubMed search
Wikidata
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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. IKK-α is part of the IκB kinase complex that plays an important role in regulating the NF-κB transcription factor. However, IKK-α has many additional cellular targets, and is thought to function independently of the NF-κB pathway to regulate epidermal differentiation.

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.

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. 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.

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

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. 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.

Other cellular targets

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

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.

Mutations in IKK-α in humans have been linked to lethal fetal malformations. 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.

Interactions

IKK-α has been shown to interact with:

• HDAC9,
• AKT1,
• AKT2,
• CTNNB1,
• FANCA,
• IKBKG
• IKK2,
• IRAK1,
• MAP3K14,
• MAP3K7,
• MAP3K8,
• NFKBIA,
• NCOA3,
• PPM1B,
• PRKDC, and
• TRAF2.

References

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• Biology

External links

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

• Genes on human chromosome 10
• EC 2.7.11