Alternative titles; symbols
HGNC Approved Gene Symbol: CHUK
SNOMEDCT: 1220575002;
Cytogenetic location: 10q24.31 Genomic coordinates (GRCh38): 10:100,186,319-100,229,596 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q24.31 | ?Cocoon syndrome | 613630 | Autosomal recessive | 3 |
| ?Popliteal pterygium syndrome, Bartsocas-Papas type 2 | 619339 | Autosomal recessive | 3 |
NFKB1 (164011) or NFKB2 (164012) is bound to REL (164910), RELA (164014), or RELB (604758) to form the NFKB complex. The NFKB complex is inhibited by I-kappa-B proteins (NFKBIA, 164008, or NFKBIB, 604495), which inactivate NF-kappa-B by trapping it in the cytoplasm. Phosphorylation of serine residues on the I-kappa-B proteins by kinases (IKBKA or IKBKB, 603258) marks them for destruction via the ubiquitination pathway, thereby allowing activation of the NF-kappa-B complex. Activated NFKB complex translocates into the nucleus and binds DNA at kappa-B-binding motifs such as 5-prime GGGRNNYYCC 3-prime or 5-prime HGGARNYYCC 3-prime (where H is A, C, or T; R is an A or G purine; and Y is a C or T pyrimidine).
Helix-loop-helix proteins contain stretches of DNA that encode 2 amphipathic alpha-helices joined by a loop structure and are involved in protein dimerization and transcriptional regulation essential to a variety of cellular processes. Mock et al. (1995) performed mapping studies of a new member of this family of proteins in the human and mouse. The protein contains a serine/threonine kinase domain; due to its ubiquitous expression in a broad array of tissues and high degree of conservation across species, it was designated CHUK for 'conserved helix-loop-helix ubiquitous kinase.' The multidomain polypeptide encoded by the CHUK gene also contains leucine zipper motifs.
DiDonato et al. (1997) purified a cytokine-activated protein kinase complex, IKK (for I-kappa-B kinase), that phosphorylates I-kappa-B proteins on the sites that trigger their degradation. They molecularly cloned and identified a component of IKK, IKK-alpha (CHUK), as a serine kinase. Mercurio et al. (1997) independently purified CHUK, which they called IKK1, from HeLa cells. They found that mutant forms of IKK1 had less effect upon NFKB activation than did mutant forms of IKK2 (also called IKBKB, IKK-beta, or IKKB). IKK-alpha is approximately 50% identical to IKK-beta (603258), and both contain kinase, leucine zipper, and helix-loop-helix domains. Although IKK-alpha and IKK-beta can homodimerize, heterodimerization appears to be favored over homodimerization (Mercurio et al., 1997).
By use of NF-kappa-B-inducing kinase (NIK; 604655) as bait in a yeast 2-hybrid screen of a human B-cell line to identify NIK-interacting proteins, Regnier et al. (1997) isolated CHUK, which phosphorylates NFKBIA at ser32 and ser36 and NFKBIB at ser19 and ser23. The phosphorylation of these proteins leads to the release of NFKB and activation of nuclear genes. By screening a Jurkat T-cell cDNA library, Regnier et al. (1997) obtained a full-length CHUK cDNA encoding a 745-amino acid protein that is 96% identical to mouse Chuk. A catalytically inactive CHUK mutant acts as a dominant-negative inhibitor of TNF (191160)-, IL1 (see 147760)-, TRAF2 (601895)-, and NIK-induced NFKB activation.
Hu and Wang (1998) cloned and characterized IKKA and IKKB. Northern blot analysis revealed expression of major 3.6- and minor 7.0-kb IKKA transcripts in all tissues tested, with highest levels in heart, placenta, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, and peripheral blood. IKKB was also ubiquitously expressed as major 3.4- and minor 6.5-kb transcripts. Expression of both transcripts was highest in 7-day mouse embryonic tissue. Hu and Wang (1998) suggested that IKKA and IKKB may be functionally related and cooperate in cells.
Delhase et al. (1999) demonstrated that in mammalian cells, phosphorylation of 2 sites at the activation loop of IKK-beta was essential for activation of IKK by TNF and IL1. Elimination of equivalent sites in IKK-alpha did not interfere with IKK activation. Thus IKK-beta, not IKK-alpha, is the target for proinflammatory stimuli. Once activated, IKK-beta autophosphorylated at a carboxy-terminal serine cluster. This phosphorylation decreased IKK activity and was suggested to prevent prolonged activation of the inflammatory response.
Ozes et al. (1999) showed that AKT1 (164730) is involved in the activation of NFKB1 by TNF, following the activation of phosphatidylinositol 3-kinase (PIK3; see 171834). Constitutively active AKT1 induces NFKB1 activity, mediated by phosphorylation of IKK-alpha at threonine 23, which can be blocked by activated NIK. Conversely, NIK activation of NFKB1, mediated by phosphorylation of IKK-alpha at serine 176, is blocked by an AKT1 mutant lacking kinase activity (i.e., kinase dead AKT), indicating that both AKT1 and NIK are necessary for TNF activation of NFKB1 through the phosphorylation of IKK-alpha. IKK-beta is not phosphorylated by either NIK or AKT1 and is apparently differentially regulated.
May et al. (2000) determined that an N-terminal alpha-helical region of NEMO (300248) associates with a region of IKKA and IKKB that they termed the NBD for 'NEMO-binding domain.' The NBD is a 6-amino acid C-terminal segment within the region denoted alpha-2 of IKKA and IKKB. Wildtype, but not mutant, NDB peptide inhibited cytokine-induced NFKB activation and ameliorated experimental acute inflammation.
Anest et al. (2003) demonstrated nuclear accumulation of IKKA after cytokine exposure, suggesting a nuclear function for this protein. Consistent with this, chromatin immunoprecipitation assays revealed that IKKA was recruited to the promoter regions of NF-kappa-B-regulated genes on stimulation with TNFA (191160). Notably, NF-kappa-B-regulated gene expression was suppressed by the loss of IKKA, and this correlated with a complete loss of gene-specific phosphorylation of histone H3 (see 602810) on serine-10, a modification previously associated with positive gene expression. Furthermore, Anest et al. (2003) showed that IKKA can directly phosphorylate histone H3 in vitro, suggesting a new substrate for this kinase. Anest et al. (2003) proposed that IKKA is an essential regulator of NFKB-dependent gene expression through control of promoter-associated histone phosphorylation after cytokine exposure.
Yamamoto et al. (2003) independently demonstrated that IKKA functions in the nucleus to activate the expression of NF-kappa-B-responsive genes after stimulation with cytokines. IKKA interactions with CREB-binding protein (600140) and in conjunction with RELA (164014) is recruited to NF-kappa-B-responsive promoters and mediates the cytokine-induced phosphorylation and subsequent acetylation of specific residues in histone H3. Yamamoto et al. (2003) concluded that their results define a new nuclear role of IKKA in modifying histone function that is critical for the activation of NF-kappa-B-directed gene expression.
Using mouse embryo fibroblasts lacking both Ikbkb and Ikbka, Sizemore et al. (2004) found that both proteins were required for induction of a subset of Ifng (147570)-stimulated genes independent of Nfkb activation and with no defect in Stat1 (600555) activation or function. Sizemore et al. (2004) concluded that the IKK-dependent pathway is an additional important pathway for IFNG-stimulated gene expression.
Hoberg et al. (2004) presented evidence that IKK-alpha phosphorylates chromatin-bound SMRT (NCOR2; 600848), stimulating its removal from chromatin and allowing recruitment of NFKB to promoters and transcription of NFKB-dependent genes.
Park et al. (2005) presented evidence that IKKA is important for the activation of estrogen-mediated gene expression.
Lawrence et al. (2005) described a role for IKK-alpha in the negative regulation of macrophage activation and inflammation. IKK-alpha contributes to suppression of NF-kappa-B activity by accelerating both the turnover of the NF-kappa-B subunits Rela and c-Rel and their removal from proinflammatory gene promoters. Inactivation of IKK-alpha in mice enhanced inflammation and bacterial clearance. Lawrence et al. (2005) concluded that the 2 IKK catalytic subunits have evolved opposing but complementary roles needed for the intricate control of inflammation and innate immunity.
Werner et al. (2005) demonstrated that different inflammatory stimuli induce distinct IKK profiles, and they examined the underlying molecular mechanisms. Although TNFA-induced IKK activity was rapidly attenuated by negative feedback, lipopolysaccharide signaling and lipopolysaccharide-specific gene expression programs were dependent on a cytokine-mediated positive feedback mechanism. Thus, Werner et al. (2005) concluded that the distinct biologic responses to LPS and TNFA depend on signaling pathway-specific mechanisms that regulate the temporal profile of IKK activity.
Using an RNA interference-based screen, Tang et al. (2006) found 4 negative regulators of insulin-responsive glucose transport in mouse adipocytes: Pctk1 (311550), Pftk1 (610679), Ikbka, and Map4k4 (604666).
Wu et al. (2006) demonstrated that NEMO (300248), the regulatory subunit of the IKK complex, associates with activated ATM (607585) after the induction of DNA double-strand breaks. ATM is exported in a NEMO-dependent manner to the cytoplasm, where it associates with and causes the activation of IKK in a manner dependent on another IKK regulator, a protein rich in glutamate, leucine, lysine, and serine (ELKS; 607127). Thus, Wu et al. (2006) concluded that regulated nuclear shuttling of NEMO links 2 signaling kinases, ATM and IKK, to activate NF-kappa-B by genotoxic signals.
TLR7 (300365) and TLR9 (605474) associate with the cytoplasmic adaptor protein MYD88 (602170), which associates with IRF7 (605047). IRF7 associates with TRAF6 (602355) and IRAK1 (300283), and these 3 proteins are critical for induction of IFNA (IFNA1; 147660) production, but not cytokine production. Hoshino et al. (2006) found that mouse plasmacytoid dendritic cells deficient in Ikka were severely impaired in Tlr7- or Tlr9-induced Ifna production, but were able to produce detectable inflammatory cytokines. Expression of a kinase-deficient Ikka inhibited the ability of Myd88 or Traf6 to activate the Ifna promoter in synergy with Irf7. Coimmunoprecipitation analysis showed that Ikka associated with and phosphorylated Irf7. Hoshino et al. (2006) concluded that IKKA is a critical component of the cytoplasmic transductional-transcriptional processor leading to induction of IFNA production.
Liu et al. (2006) identified somatic mutations in IKKA exon 15 in 8 of 9 squamous cell carcinomas (SCCs) examined. More transition mutations than transversion mutations were detected. In chemical carcinogen-induced skin cancer in mice, overexpression of wildtype human IKKA reduced development of SCCs and metastases. The IKKA transgene increased terminal differentiation and reduced mitogenic activity in the epidermis, and decreased angiogenic activity in the skin stroma. Liu et al. (2006) concluded that IKKA in the epidermis antagonizes mitogenic and angiogenic signals and represses tumor progression and metastases.
Zhu et al. (2007) identified 14-3-3-sigma (SFN; 601290) as a downstream target of Ikka in cell cycle regulation in response to DNA damage and found that the 14-3-3-sigma locus was hypermethylated in Ikka -/- mouse keratinocytes, but not in wildtype keratinocytes. Trimethylated histone H3-lys9 associated with Suv39h1 (300254) and Dnmt3a (602769) in the methylated 14-3-3-sigma locus. Reintroduction of Ikka restored 14-3-3-sigma expression by associating with H3 and preventing access of Suv39h1 to H3, thereby preventing hypermethylation of 14-3-3-sigma. Zhu et al. (2007) concluded that IKKA protects the 14-3-3-sigma locus from hypermethylation, which serves as a mechanism of maintaining genomic stability in keratinocytes.
Mittal et al. (2006) found that the Yersinia YopJ virulence factor inhibited the host inflammatory response and induced apoptosis of immune cells by catalyzing acetylation of 2 ser residues in the activation loop of MEK2 (MAP2K2; 601263), thereby blocking MEK2 activation and signal propagation. YopJ also caused acetylation of a thr residue in the activation loop of both IKKA and IKKB. Mittal et al. (2006) concluded that ser/thr acetylation is a mode of action for bacterial toxins that may also occur under nonpathogenic conditions to regulate protein function.
Luo et al. (2007) examined IKK-alpha involvement in prostate cancer (see 176807) and its progression. They demonstrated that a mutation that prevents IKK-alpha activation slowed down prostate cancer growth and inhibited metastatogenesis in TRAMP mice, which express SV40 T antigen in the prostate epithelium. Decreased metastasis correlated with elevated expression of the metastasis suppressor Maspin (154790), the ablation of which restored metastatic activity. IKK-alpha activation by RANK ligand (RANKL; 602642) inhibited Maspin expression in prostate epithelial cells, whereas repression of Maspin transcription required nuclear translocation of active IKK-alpha. The amount of active nuclear IKK-alpha in mouse and human prostate cancer correlated with metastatic progression, reduced Maspin expression, and infiltration of prostate tumors with RANKL-expressing inflammatory cells. Luo et al. (2007) proposed that tumor-infiltrating RANKL-expressing cells leads to nuclear IKK-alpha activation and inhibition of Maspin transcription, thereby promoting the metastatic phenotype.
Lahtela et al. (2010) detected 21 exons in the CHUK gene.
By somatic cell hybrid analyses, Mock et al. (1995) mapped the CHUK gene to chromosome 10q24-q25. By FISH, Hu and Wang (1998) mapped the gene to 10q24.
By a combination of somatic cell hybrid, recombinant inbred, and backcross analyses, Mock et al. (1995) mapped the mouse Chuk gene and a related sequence, Chuk-rs1, to chromosomes 19 and 16, respectively.
Fetal Encasement Syndrome
Lahtela et al. (2010) identified homozygosity for a nonsense mutation (600664.0001) in 2 fetuses from 1 family with autosomal recessive fetal encasement syndrome (613630).
Bartsocas-Papas Syndrome 2
By exome sequencing in a Saudi infant with Bartsocas-Papas syndrome (BPS2; 619339), Leslie et al. (2015) identified a homozygous splice site mutation in the CHUK gene (600664.0002). Sanger sequencing confirmed that the parents were heterozygous for the mutation.
Associations Pending Confirmation
Khandelwal et al. (2017) described a 10-year-old girl with an EEC3 (see 603273)/AEC (106260) syndrome-like phenotype with ankyloblepharon, ectodermal defects, cleft palate, ectrodactyly, and syndactyly, with the additional features of hypogammaglobulinemia and growth delay. Sequencing of the TP63 gene, which is mutated in most patients with EEC and AEC, did not identify any mutations. However, trio exome sequencing identified 3 de novo heterozygous variants: S319F in the PTGER4 gene (601586), N171D in the IFIT2 gene (147040), and H142R (c.425A-G, NM_001278) in the CHUK gene. As CHUK is known to be regulated by TP63, the authors proposed that the mutation in CHUK was responsible for the phenotype in their patient. They noted that the CHUK variant occurs at a highly conserved nucleotide and affects a highly conserved residue situated close to the amino acid (Asp144) responsible for kinase activity. The mutation is predicted to impair CHUK kinase activity but not its capacity to engage in homomeric and heteromeric complexes. The authors considered it likely that the mutant CHUK protein can heterodimerize with IKK-beta in the IKK complex and exhibit a dominant-negative effect toward the wildtype protein to affect the canonical NFKB activation. They stated that in agreement with this dominant-negative model of deregulating the NFKB pathway, mutations in NEMO (300248) have been found to lead to an ectodermal dysplasia syndrome with immunodeficiency (300291).
Cadieux-Dion et al. (2018) performed SNP array and whole-exome sequencing in a child with ectodermal dysplasia and additional clinical findings. They identified a 2-Mb deletion on chromosome 1q21.1q21.2 (145,885,645-147,929,115, GRCh37) by microarray analysis. Parental studies were not performed to determine if this deletion was de novo. Whole-exome sequencing identified compound heterozygous mutations in trans in exon 8 of the CHUK gene (NM_001278.3): a 1-bp deletion, c.1365del, predicted to result in a frameshift and premature termination (Arg457AspfsTer6), and a c.1388C-A transversion, resulting in a thr463-to-lys (T463K) substitution. The frameshift was found to be maternally inherited, and the missense mutation was found to be de novo. Cadieux-Dion et al. (2018) proposed that the chromosome 1q21.1 deletion was unlikely to account for all of the clinical features in the patient, although it could contribute to his small size, dysmorphisms, and failure to thrive. Cadieux-Dion et al. (2018) further proposed that the mutations in the CHUK gene were responsible for the patient's ectodermal dysplasia and possibly his immune deficiency.
Takeda et al. (1999) disrupted the Ikka gene in mice. Ikka -/- mice died within 4 hours of birth. They had abnormal limb and craniofacial development despite normal skeletal development. The skin appeared abnormally shiny. The epidermal cells of Ikka-deficient mouse fetuses were highly proliferative with dysregulated epidermal differentiation. In the basal layer of the epidermis, degradation of I-kappa-B and nuclear localization of NFKB were not observed. Thus, Ikka is essential for NFKB activation in the limb and skin during embryogenesis. Surprisingly, there was no impairment of NFKB activation in response to either TNF-alpha or IL1 in Ikka-deficient embryonic fibroblasts or thymocytes, indicating that Ikka is not essential for cytokine-induced activation of NFKB.
Hu et al. (1999) generated Ikka-deficient mice. Homozygous mutant mice died within 30 minutes of birth. At embryonic day 18, Ikka -/- mice had rudimentary protrusions instead of normal limbs. They lacked well-formed tails and their heads were shorter than normal, with a truncated snout and no external ears. They had an omphalocele and taut skin. At autopsy, there were no morphologic abnormalities of heart, lung, liver, kidneys, spleen, brain, and spinal cord; however, the placentae were severely congested with bulging vessels and blood sinuses on the maternal surface and normal fetal surface. Skeletal preparations revealed fused sacral and cervical vertebrae and a short sternum with delayed ossification and split xiphoid. Microscopic examination of the skin revealed hyperplasia of the stratum spinosum, and mutant epidermis lacked a stratum granulosum and stratum corneum. The lack of Ikka appeared to completely disrupt keratinocyte differentiation. Hu et al. (1999) hypothesized that the increased thickness and adhesiveness of mutant skin prevented the emergence of limb outgrowths.
Yoshida et al. (2000) examined wildtype and Ikka -/- mice on embryonic days 18 and 19 by light and electron microscopy or immunocytochemistry. During normal development of the conjunctiva and cornea, nuclear localization of NFKB1 p50 was seen in areas where basal undifferentiated cells give rise to differentiated cell types. However, in the Ikka -/- tissues, no nuclear p50 staining was detected. The authors concluded that IKKA is specifically required for formation of cornea and conjunctiva. They stated that this function might be exerted through an effect on NFKB activity.
Using an ex vivo mouse keratinocyte culture system, immunofluorescence microscopy, and Western blot analysis, Hu et al. (2001) showed that keratinocytes derived from Ikka-deficient mice exhibit a hyperproliferative phenotype, fail to undergo terminal differentiation, and do not express the appropriate differentiation markers, loricrin (152445) and filaggrin (135940). This phenotype was observed in the absence of a defect in NFKB activation. Introduction of Ikka into Ikka -/- keratinocytes restores keratinocyte differentiation and filaggrin expression. Mutation and immunoblot analysis established that induction of keratinocyte differentiation does not require the protein kinase activity of Ikka. Fetal Ikka -/- skin transplanted to immunodeficient mice differentiated normally and expressed proliferation and differentiation markers including Pcna (176740), Krt5 (148040), Krt1 (139350), and filaggrin, suggesting that normal skin contains a factor that induces terminal differentiation of Ikka-deficient keratinocytes. The authors demonstrated that wildtype keratinocytes produce, independently of NFKB activation, a keratinocyte differentiation-inducing factor (kDIF) protein. Hu et al. (2001) concluded that the defect in Ikka -/- keratinocytes is continuous proliferation even in the presence of growth-inhibiting levels of extracellular calcium. Although Ikka is replaceable by, and is less efficient than, Ikkb for activating NFKB, it is essential for normal epidermal development.
By radiation chimera and flow cytometric analyses, Senftleben et al. (2001) found reduced levels of mature B lymphocytes in spleen and lymph nodes correlated with high turnover and apoptosis rates in immature B cells in Ikka -/- reconstituted mice. In vivo, the spleens of chimeric animals exhibited poor germinal center formation in response to immunization. Immunoblot and electrophoretic mobility shift analyses showed that Ikka -/- B cells contained little p52 and increased amounts of p100, indicative of defective processing of NFKB2. Viable mice carrying mutations in the activating phosphorylation sites of Ikka (ser176 to ala and ser180 to ala) expressed a similar, sometimes more severe, phenotype, suggesting a requirement for the phosphorylation of these residues either by Ikka itself or by NIK. Recombinant Ikka was much more efficient than Ikkb or NIK in phosphorylation of the C-terminal regulatory domain of NFKB2, whereas it was less efficient in the phosphorylation of IKBA. Senftleben et al. (2001) proposed that defective NFKB2 processing likely interferes with B-cell maturation. They concluded that IKKA is required for the activation of NFKB2, which leads to B-cell maturation and germinal center formation.
Matsushima et al. (2001) found that both Nik -/- and Ikka -/- mice had impaired NFKB activation in response to lymphotoxin B receptor (600979) stimulation but not TNF receptor-1 (191190) stimulation. These mice also had defective development of Peyer patches.
Cao et al. (2001) generated an Ikka(AA) knockin allele containing alanines instead of serines in the activation loop. Ikka(AA/AA) mice were healthy and fertile, but females displayed a severe lactation defect due to impaired proliferation of mammary epithelial cells. Ikka activity was required for NFKB activation in mammary epithelial cells during pregnancy and in response to RANK ligand but not TNF. Ikka and NFKB activation were also required for optimal cyclin D1 (168461) induction. Defective RANK signaling or cyclin D1 expression resulted in the same phenotypic effect as the Ikka(AA) mutation, which could be completely suppressed by a mammary-specific cyclin D1 transgene. Thus, IKKA is a critical intermediate in a pathway that controls mammary epithelial proliferation in response to RANK signaling via cyclin D1.
Sil et al. (2004) postulated that the morphogenetic defects in Ikk-alpha-deficient mice are not caused by reduced NF-kappa-B activity but instead are due to failed epidermal differentiation that disrupts proper epidermal-mesodermal interactions. Sil et al. (2004) tested this hypothesis by introducing an epidermal-specific Ikka transgene into Ikk-alpha-deficient mice. Mice lacking Ikk-alpha in all cell types including bone and cartilage, but not in basal epidermal keratinocytes, exhibit normal epidermal differentiation and skeletal morphology. Thus, epidermal differentiation is required for proper morphogenesis of mesodermally derived skeletal elements. One way by which IKK-alpha controls skeletal and craniofacial morphogenesis is by repressing expression of fibroblast growth factor family members, such as FGF8 (600483), whose expression is specifically elevated in the limb bud ectoderm of Ikk-alpha-deficient mice.
Ohazama et al. (2004) determined that Ikka is expressed in mouse tooth epithelium and has an essential role in incisor and molar tooth development. Molar teeth in Ikka mutant mice had abnormal cusp morphology due to a reduction of the Nfkb pathway. Incisors, however, had a more severe and earlier phenotype where tooth buds failed to invaginate into the underlying mesenchyme but instead evaginated into the developing oral cavity. A similar evagination of epithelium was also observed in whisker follicles. Unlike cusp morphogenesis, the Nfkb pathway was not involved in the invagination of incisor tooth epithelium. Changes in the expression of Notch1 (190198), Notch2 (600275), Wnt7b (601967), and Shh (600725) in incisor epithelium of Ikka mutants suggested that the Nfkb-independent function is mediated by Notch/Wnt/Shh signaling pathways.
In 2 fetuses with fetal encasement syndrome (613630) from a Finnish family, Lahtela et al. (2010) identified homozygosity for a C-to-T transition at nucleotide 1264 in exon 12 of the CHUK gene, resulting in a glu-to-stop substitution at codon 422 (E422X). This mutation was identified in heterozygosity in both of the carrier parents and was not identified in any of 100 ancestrally-matched control subjects. Fibroblast DNA from the affected fetuses had no CHUK protein expression.
In a Saudi infant with Bartsocas-Papas syndrome-2 (BPS2; 619339), Leslie et al. (2015) identified a homozygous splice site mutation (c.934-2A-G, NM_001278.3) in exon 10 of the CHUK gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation is predicted to result in premature termination after the kinase domain.
Anest, V., Hanson, J. L., Cogswell, P. C., Steinbrecher, K. A., Strahl, B. D., Baldwin, A. S. A nucleosomal function for I-kappa-B kinase-alpha in NF-kappa-B-dependent gene expression. Nature 423: 659-663, 2003. [PubMed: 12789343] [Full Text: https://doi.org/10.1038/nature01648]
Cadieux-Dion, M., Safina, N. P., Engleman, K., Saunders, C., Repnikova, E., Raje, N., Canty, K., Farrow, E., Miller, N., Zellmer, L., Thiffault, I. Novel heterozygous pathogenic variants in CHUK in a patient with AEC-like phenotype, immune deficiencies and 1q21.1 microdeletion syndrome: a case report. BMC Med. Genet. 19: 41, 2018. [PubMed: 29523099] [Full Text: https://doi.org/10.1186/s12881-018-0556-2]
Cao, Y., Bonizzi, G., Seagroves, T. N., Greten, F. R., Johnson, R., Schmidt, E. V., Karin, M. IKK-alpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development. Cell 107: 763-775, 2001. [PubMed: 11747812] [Full Text: https://doi.org/10.1016/s0092-8674(01)00599-2]
Delhase, M., Hayakawa, M., Chen, Y., Karin, M. Positive and negative regulation of I-kappa-B kinase activity through IKK-beta subunit phosphorylation. Science 284: 309-312, 1999. [PubMed: 10195894] [Full Text: https://doi.org/10.1126/science.284.5412.309]
DiDonato, J. A., Hayakawa, M., Rothwarf, D. M., Zandi, E., Karin, M. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature 388: 548-554, 1997. [PubMed: 9252186] [Full Text: https://doi.org/10.1038/41493]
Hoberg, J. E., Yeung, F., Mayo, M. W. SMRT derepression by the I-kappa-B kinase alpha: a prerequisite to NF-kappa-B transcription and survival. Molec. Cell 16: 245-255, 2004. [PubMed: 15494311] [Full Text: https://doi.org/10.1016/j.molcel.2004.10.010]
Hoshino, K., Sugiyama, T., Matsumoto, M., Tanaka, T., Saito, M., Hemmi, H., Ohara, O., Akira, S., Kaisho, T. I-kappa-B kinase-alpha is critical for interferon-alpha production induced by Toll-like receptors 7 and 9. Nature 440: 949-953, 2006. [PubMed: 16612387] [Full Text: https://doi.org/10.1038/nature04641]
Hu, M. C.-T., Wang, Y. I-kappa-B kinase-alpha and -beta genes are coexpressed in adult and embryonic tissues but localized to different human chromosomes. Gene 222: 31-40, 1998. [PubMed: 9813230] [Full Text: https://doi.org/10.1016/s0378-1119(98)00462-4]
Hu, Y., Baud, V., Delhase, M., Zhang, P., Deerinck, T., Ellisman, M., Johnson, R., Karin, M. Abnormal morphogenesis but intact IKK activation in mice lacking the IKK-alpha subunit of I-kappa-B kinase. Science 284: 316-320, 1999. [PubMed: 10195896] [Full Text: https://doi.org/10.1126/science.284.5412.316]
Hu, Y., Baud, V., Oga, T., Kim, K. I., Yoshida, K., Karin, M. IKK-alpha controls formation of the epidermis independently of NF-kappa-B. Nature 410: 710-714, 2001. [PubMed: 11287960] [Full Text: https://doi.org/10.1038/35070605]
Khandelwal, K. D., Ockeloen, C. W., Venselaar, H., Boulanger, C., Brichard, B., Sokal, E., Pfundt, R., Rinne, T., van Beusekom, E., Bloemen, M., Vriend, G., Revencu, N., Carels, C. E. L., van Bokhoven, H., Zhou, H. Identification of a de novo variant in CHUK in a patient with an EEC/AEC syndrome-like phenotype and hypogammaglobinemia. Am. J. Med. Genet. 173A: 1813-1820, 2017. [PubMed: 28513979] [Full Text: https://doi.org/10.1002/ajmg.a.38274]
Lahtela, J., Nousiainen, H. O., Stefanovic, V., Tallila, J., Viskari, H., Karikoski, R., Gentile, M., Saloranta, C., Varilo, T., Salonen, R., Kestila, M. Mutant CHUK and severe fetal encasement malformation. New Eng. J. Med. 363: 1631-1637, 2010. [PubMed: 20961246] [Full Text: https://doi.org/10.1056/NEJMoa0911698]
Lawrence, T., Bebien, M., Liu, G. Y., Nizet, V., Karin, M. IKK-alpha limits macrophage NF-kappa-B activation and contributes to the resolution of inflammation. Nature 434: 1138-1143, 2005. [PubMed: 15858576] [Full Text: https://doi.org/10.1038/nature03491]
Leslie, E. J., O'Sullivan, J., Cunningham, M. L., Singh, A., Goudy, S. L., Ababneh, F., Alsubaie, L., Ch'ng, G.-S., van der Laar, I. M. B. H., Hoogeboom, A. J. M., Dunnwald, M., Kapoor, S., Jiramkolchai, P., Standley, J., Manak, J. R., Murray, J. C., Dixon, M. J. Expanding the genetic and phenotypic spectrum of popliteal pterygium disorders. Am. J. Med. Genet. 167A: 545-552, 2015. [PubMed: 25691407] [Full Text: https://doi.org/10.1002/ajmg.a.36896]
Liu, B., Park, E., Zhu, F., Bustos, T., Liu, J., Shen, J., Fischer, S. M., Hu, Y. A critical role for I-kappa-B kinase alpha in the development of human and mouse squamous cell carcinomas. Proc. Nat. Acad. Sci. 103: 17202-17207, 2006. [PubMed: 17079494] [Full Text: https://doi.org/10.1073/pnas.0604481103]
Luo, J.-L., Tan, W., Ricono, J. M., Korchynskyi, O., Zhang, M., Gonias, S. L., Cheresh, D. A., Karin, M. Nuclear cytokine-activated IKK-alpha controls prostate cancer metastasis by repressing Maspin. Nature 446: 690-694, 2007. Note: Erratum: Nature 457: 920 only, 2009. [PubMed: 17377533] [Full Text: https://doi.org/10.1038/nature05656]
Matsushima, A., Kaisho, T., Rennert, P. D., Nakano, H., Kurosawa, K., Uchida, D., Takeda, K., Akira, S., Matsumoto, M. Essential role of nuclear factor (NF)-kappa-B-inducing kinase and inhibitor of kappa-B (I-kappa-B) kinase alpha in NF-kappa-B activation through lymphotoxin beta receptor, but not through tumor necrosis factor receptor I. J. Exp. Med. 193: 631-636, 2001. [PubMed: 11238593] [Full Text: https://doi.org/10.1084/jem.193.5.631]
May, M. J., D'Acquisto, F., Madge, L. A., Glockner, J., Pober, J. S., Ghosh, S. Selective inhibition of NF-kappa-B activation by a peptide that blocks the interaction of NEMO with the I-kappa-B kinase complex. Science 289: 1550-1554, 2000. [PubMed: 10968790] [Full Text: https://doi.org/10.1126/science.289.5484.1550]
Mercurio, F., Zhu, H., Murray, B. W., Shevchenko, A., Bennett, B. L., Li, J., Young, D. B., Barbosa, M., Mann, M., Manning, A., Rao, A. IKK-1 and IKK-2: cytokine-activated I-kappa-B kinases essential for NF-kappa-B activation. Science 278: 860-866, 1997. [PubMed: 9346484] [Full Text: https://doi.org/10.1126/science.278.5339.860]
Mittal, R., Peak-Chew, S.-Y., McMahon, H. T. Acetylation of MEK2 and I-kappa-B kinase (IKK) activation loop residues by YopJ inhibits signaling. Proc. Nat. Acad. Sci. 103: 18574-18579, 2006. [PubMed: 17116858] [Full Text: https://doi.org/10.1073/pnas.0608995103]
Mock, B. A., Connelly, M. A., McBride, O. W., Kozak, C. A., Marcu, K. B. CHUK, a conserved helix-loop-helix ubiquitous kinase, maps to human chromosome 10 and mouse chromosome 19. Genomics 27: 348-351, 1995. [PubMed: 7558004] [Full Text: https://doi.org/10.1006/geno.1995.1054]
Ohazama, A., Hu, Y., Schmidt-Ullrich, R., Cao, Y., Scheidereit, C., Karin, M., Sharpe, P. T. A dual role for Ikk-alpha in tooth development. Dev. Cell 6: 219-227, 2004. [PubMed: 14960276] [Full Text: https://doi.org/10.1016/s1534-5807(04)00024-3]
Ozes, O. N., Mayo, L. D., Gustin, J. A., Pfeffer, S. R., Pfeffer, L. M., Donner, D. B. NF-kappa-B activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401: 82-85, 1999. [PubMed: 10485710] [Full Text: https://doi.org/10.1038/43466]
Park, K.-J., Krishnan, V., O'Malley, B. W., Yamamoto, Y., Gaynor, R. B. Formation of an IKK-alpha-dependent transcription complex is required for estrogen receptor-mediated gene activation. Molec. Cell 18: 71-82, 2005. [PubMed: 15808510] [Full Text: https://doi.org/10.1016/j.molcel.2005.03.006]
Regnier, C. H., Song, H. Y., Gao, X., Goeddel, D. V., Cao, Z., Rothe, M. Identification and characterization of an I-kappa-B kinase. Cell 90: 373-383, 1997. [PubMed: 9244310] [Full Text: https://doi.org/10.1016/s0092-8674(00)80344-x]
Senftleben, U., Cao, Y., Xiao, G., Greten, F. R., Krahn, G., Bonizzi, G., Chen, Y., Hu, Y., Fong, A., Sun, S.-C., Karin, M. Activation by IKK-alpha of a second, evolutionarily conserved, NF-kappa-B signaling pathway. Science 293: 1495-1499, 2001. [PubMed: 11520989] [Full Text: https://doi.org/10.1126/science.1062677]
Sil, A. K., Maeda, S., Sano, Y., Roop, D. R., Karin, M. I-kappa-B kinase-alpha acts in the epidermis to control skeletal and craniofacial morphogenesis. Nature 428: 660-664, 2004. [PubMed: 15071597] [Full Text: https://doi.org/10.1038/nature02421]
Sizemore, N., Agarwal, A., Das, K., Lerner, N., Sulak, M., Rani, S., Ransohoff, R., Shultz, D., Stark, G. R. Inhibitor of kappa-B kinase is required to activate a subset of interferon gamma-stimulated genes. Proc. Nat. Acad. Sci. 101: 7994-7998, 2004. [PubMed: 15148408] [Full Text: https://doi.org/10.1073/pnas.0401593101]
Takeda, K., Takeuchi, O., Tsujimura, T., Itami, S., Adachi, O., Kawai, T., Sanjo, H., Yoshikawa, K., Terada, N., Akira, S. Limb and skin abnormalities in mice lacking IKK-alpha. Science 284: 313-316, 1999. [PubMed: 10195895] [Full Text: https://doi.org/10.1126/science.284.5412.313]
Tang, X., Guilherme, A., Chakladar, A., Powelka, A. M., Konda, S., Virbasius, J. V., Nicoloro, S. M. C., Straubhaar, J., Czech, M. P. An RNA interference-based screen identifies MAP4K4/NIK as a negative regulator of PPAR-gamma, adipogenesis, and insulin-responsive hexose transport. Proc. Nat. Acad. Sci. 103: 2087-2092, 2006. [PubMed: 16461467] [Full Text: https://doi.org/10.1073/pnas.0507660103]
Werner, S. L., Barken, D., Hoffmann, A. Stimulus specificity of gene expression programs determined by temporal control of IKK activity. Science 309: 1857-1861, 2005. [PubMed: 16166517] [Full Text: https://doi.org/10.1126/science.1113319]
Wu, Z.-H., Shi, Y., Tibbetts, R. S., Miyamoto, S. Molecular linkage between the kinase ATM and NF-kappaB signaling in response to genotoxic stimuli. Science 311: 1141-1146, 2006. [PubMed: 16497931] [Full Text: https://doi.org/10.1126/science.1121513]
Yamamoto, Y., Verma, U. N., Prajapati, S., Kwak, Y.-T., Gaynor, R. B. Histone H3 phosphorylation by IKK-alpha is critical for cytokine-induced gene expression. Nature 423: 655-659, 2003. [PubMed: 12789342] [Full Text: https://doi.org/10.1038/nature01576]
Yoshida, K., Hu, Y., Karin, M. I-kappa-B kinase alpha is essential for development of the mammalian cornea and conjunctiva. Invest. Ophthal. Vis. Sci. 41: 3665-3669, 2000. [PubMed: 11053261]
Zhu, F., Xia, X., Liu, B., Shen, J., Hu, Y., Person, M., Hu, Y. IKK-alpha shields 14-3-3-sigma, a G2/M cell cycle checkpoint gene, from hypermethylation, preventing its silencing. Molec. Cell 27: 214-227, 2007. [PubMed: 17643371] [Full Text: https://doi.org/10.1016/j.molcel.2007.05.042]