CHUK

Conserved helix-loop-helix ubiquitous kinase
Identifiers
Symbols	CHUK; IKBKA; IKK-alpha; IKK1; IKKA; NFKBIKA; TCF16
External IDs	OMIM: 600664 MGI: 99484 HomoloGene: 979 GeneCards: CHUK Gene
EC number	2.7.11.10
Gene Ontology Molecular function • nucleotide binding • protein kinase activity • protein binding • ATP binding • IkappaB kinase activity • identical protein binding Cellular component • nucleus • nucleolus • cytoplasm • cytosol • cytosol • internal side of plasma membrane • CD40 receptor complex • intracellular membrane-bounded organelle Biological process • morphogenesis of an epithelial sheet • toll-like receptor signaling pathway • MyD88-dependent toll-like receptor signaling pathway • MyD88-dependent toll-like receptor signaling pathway • MyD88-independent toll-like receptor signaling pathway • MyD88-independent toll-like receptor signaling pathway • protein phosphorylation • immune response • I-kappaB phosphorylation • lactation • Toll signaling pathway • anatomical structure morphogenesis • osteoclast differentiation • mammary gland epithelial cell proliferation • toll-like receptor 1 signaling pathway • toll-like receptor 2 signaling pathway • toll-like receptor 3 signaling pathway • toll-like receptor 4 signaling pathway • odontogenesis of dentine-containing tooth • positive regulation of I-kappaB kinase/NF-kappaB cascade • innate immune response • nerve growth factor receptor signaling pathway • phosphatidylinositol-mediated signaling • T cell receptor signaling pathway • positive regulation of NF-kappaB transcription factor activity • mammary gland alveolus development Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	1147	12675
Ensembl	ENSG00000213341	ENSMUSG00000025199
UniProt	O15111	A0AUV3
RefSeq (mRNA)	NM_001278.3	NM_007700
RefSeq (protein)	NP_001269.3	NP_031726
Location (UCSC)	Chr 10: 101.95 – 101.99 Mb	Chr 19: 44.15 – 44.18 Mb
PubMed search	[1]	[2]

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

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.^[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.

Other cellular targets

IKK-α has also been reported to regulate the cell cycle protein cyclin D1 in an NF-κB-independent manner.^[8][9]

Clinical significance

Mutations in IKK-α in humans have been linked to lethal fetal malformations.^[10] 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.^[11]

Interactions

IKK-α has been shown to interact with:

• AKT1,^[12][13]
• AKT2,^[14]
• CTNNB1,^[15]
• FANCA,^[16][17]
• IKBKG^{[18][19][20][21]}
• IKK2,^{[17][19][20][22][23][24][25]}
• IRAK1,^[26][27]
• MAP3K14,^{[28][29][30][31]}
• MAP3K7,^[31][32]
• MAP3K8,^[33]
• NFKBIA,^{[24][31][34][35]}
• NCOA3,^[36]
• PPM1B,^[37]
• PRKDC,^[38] and
• TRAF2.^[28][39][40]

References

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3. ^ ^{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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2556095. 
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