Alternative titles; symbols
HGNC Approved Gene Symbol: IKBKE
Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38) : 1:206,470,476-206,496,889 (from NCBI)
IKBKE is a noncanonical I-kappa-B (see 164008) kinase (IKK) that is essential for regulating antiviral signaling pathways. IKBKE has also been identified as a breast cancer (114480) oncogene and is amplified and overexpressed in over 30% of breast carcinomas and breast cancer cell lines (Hutti et al., 2009).
By screening a lipopolysaccharide (LPS)-stimulated mouse macrophage cell line with the suppression subtractive hybridization technique, Shimada et al. (1999) obtained a cDNA that they termed IKKI (inducible I-kappa-B kinase), a homolog of the human KIAA0151 cDNA identified by Nagase et al. (1995). Sequence analysis predicted that the 716-amino acid protein contains an N-terminal serine/threonine kinase domain and C-terminal leucine zipper and helix-loop-helix domains. Northern blot analysis revealed expression of a 4.0-kb transcript in spleen, thymus, peripheral blood leukocytes, pancreas, and placenta, with low expression in lung, kidney, prostate, ovary, and colon.
Independently, Peters et al. (2000) reported the identification of a novel PMA-inducible I-kappa-B kinase complex. They characterized one kinase from this complex, which they designated IKK-epsilon (IKBKE). The IKBKE protein shows 33% and 31% amino acid identity with IKBKA (600664) and IKBKB (603258), respectively, within the kinase domain and 27% amino acid identity with each throughout the entire sequence. Northern blot analysis revealed that IKBKE is expressed in many tissues as a 3.2-kb transcript, but is particularly abundant in thymus, spleen, and peripheral blood leukocytes.
Shimada et al. (1999) performed functional analyses showing that IKKI preferentially phosphorylates ser36 rather than ser32 of I-kappa-B-alpha (NFKBIA; 164008). Whereas TNFA (191160) and IL1B (147720) enhance the kinase activity of IKBKA and IKBKB, they do not enhance IKKI kinase activity.
Peters et al. (2000) found that although recombinant IKK-epsilon directly phosphorylates only ser36 of I-kappa-B-alpha, the PMA-activated endogenous IKK complex phosphorylates both critical serine (ser32 and ser36) residues. Remarkably, this activity appears to be due to the presence of a distinct kinase in this complex. A dominant-negative mutant of IKK-epsilon (lys38 to ala) blocks induction of NF-kappa-B by both PMA and activation of the T-cell receptor but has no effect on the activation of NF-kappa-B by TNF or IL1. These observations indicate that the activation of NF-kappa-B requires multiple distinct I-kappa-B kinase complexes that respond to both overlapping and discrete signaling pathways.
Sharma et al. (2003) demonstrated that IKKE and TANK-binding kinase-1 (TBK1; 604834) are components of the virus-activated kinase (VAK) that phosphorylate IRF3 (603734) and IRF7 (605047). They demonstrated an essential role for an IKK-related kinase pathway in triggering the host antiviral response to viral infection. Sharma et al. (2003) demonstrated that expression of IKKE or TBK1 is sufficient to induce phosphorylation of IRF3 and IRF7. This modification permits IRF3 dimerization and translocation to the nucleus, where it induces transcription of interferon and ISG56 genes.
By yeast 2-hybrid screening of a B-cell cDNA library, Zha et al. (2006) found that IKKE interacted with the C terminus of RFP (TRIM27; 602165). Coimmunoprecipitation experiments showed that RFP also interacted with TBK1, IKKA, and IKKB. Immunofluorescence and confocal microscopy demonstrated primarily cytoplasmic expression of RFP and IKKE. In vitro kinase assays showed that RFP was strongly phosphorylated by IKKE and TBK1, but only weakly by IKKA and IKKB. RFP inhibited NFKB (see 164011) and IFN-stimulated response element activation triggered by IKK overexpression or by cytokine or viral infection pathways. Zha et al. (2006) concluded that RFP negatively regulates signaling involved in the antiviral response and inflammation by targeting IKKs.
Using a proteomic and bioinformatic approach, Hutti et al. (2009) identified the optimal motif for phosphorylation by IKK-epsilon and identified a number of putative substrates, including several components of inflammatory and/or oncogenic signaling pathways. One predicted substrate, CYLD (605018), is a deubiquitinase that functions as a tumor suppressor. CYLD was phosphorylated by IKK-epsilon on ser418 in vitro and in vivo. Phosphorylation of CYLD at ser418 decreased its deubiquitinase activity and was necessary for IKK-epsilon-dependent transformation in NIH-3T3 mouse fibroblasts.
The International Radiation Hybrid Mapping Consortium mapped the KIAA0151 gene to chromosome 1 (T95631).
TenOever et al. (2007) reported that although mice lacking Ikke produced normal amounts of interferon-beta (IFNB; 147640), they were hypersusceptible to viral infection because of a defect in the IFN signaling pathway. Specifically, a subset of type I IFN-stimulated genes were not activated in the absence of Ikke because the interferon-stimulated gene factor-3 complex (ISGF3; see 147574) did not bind to promoter elements of the affected genes. TenOever et al. (2007) demonstrated that Ikke was activated by Ifnb and that Ikke directly phosphorylated signal transducer and activator of transcription-1 (STAT1; 600555), a component of Isgf3. They concluded that IKKE plays a critical role in the IFN-inducible antiviral transcriptional response.
Obesity produces a state of chronic low-grade inflammation accompanied by increased circulating levels of proinflammatory cytokines, many of which block insulin action. Chiang et al. (2009) found that a high-fat diet induced expression of Ikke in both liver and white adipose tissue in mice. Ikke-knockout mice were protected from diet-induced obesity, liver and adipose inflammation, hepatic steatosis, and insulin resistance.
Chiang, S.-H., Bazuine, M., Lumeng, C. N., Geletka, L. M., Mowers, J., White, N. M., Ma, J.-T., Zhou, J., Qi, N., Westcott, D., Delproposto, J. B., Blackwell, T. S., Yull, F. E., Saltiel, A. R. The protein kinase IKK-epsilon regulates energy balance in obese mice. Cell 138: 961-975, 2009. [PubMed: 19737522] [Full Text: https://doi.org/10.1016/j.cell.2009.06.046]
Hutti, J. E., Shen, R. R., Abbott, D. W., Zhou, A. Y., Sprott, K. M., Asara, J. M., Hahn, W. C., Cantley, L. C. Phosphorylation of the tumor suppressor CYLD by the breast cancer oncogene IKK-epsilon promotes cell transformation. Molec. Cell 34: 461-472, 2009. [PubMed: 19481526] [Full Text: https://doi.org/10.1016/j.molcel.2009.04.031]
Nagase, T., Seki, N., Tanaka, A., Ishikawa, K., Nomura, N. Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 2: 167-174, 1995. [PubMed: 8590280] [Full Text: https://doi.org/10.1093/dnares/2.4.167]
Peters, R. T., Liao, S.-M., Maniatis, T. IKK-epsilon is part of a novel PMA-inducible I-kappa-B kinase complex. Molec. Cell 5: 513-522, 2000. [PubMed: 10882136] [Full Text: https://doi.org/10.1016/s1097-2765(00)80445-1]
Sharma, S., tenOever, B. R., Grandvaux, N., Zhou, G.-P., Lin, R., Hiscott, J. Triggering the interferon antiviral response through an IKK-related pathway. Science 300: 1148-1151, 2003. [PubMed: 12702806] [Full Text: https://doi.org/10.1126/science.1081315]
Shimada, T., Kawai, T., Takeda, K., Matsumoto, M., Inoue, J., Tatsumi, Y., Kanamaru, A., Akira, S. IKK-i, a novel lipopolysaccharide-inducible kinase that is related to I-kappa-B kinases. Int. Immun. 11: 1357-1362, 1999. [PubMed: 10421793] [Full Text: https://doi.org/10.1093/intimm/11.8.1357]
tenOever, B. R., Ng, S.-L., Chua, M. A., McWhirter, S. M., Garcia-Sastre, A., Maniatis, T. Multiple functions of the IKK-related kinase IKK-epsilon in interferon-mediated antiviral immunity. Science 315: 1274-1278, 2007. [PubMed: 17332413] [Full Text: https://doi.org/10.1126/science.1136567]
Zha, J., Han, K.-J., Xu, L.-G., He, W., Zhou, Q., Chen, D., Zhai, Z., Shu, H.-B. The Ret finger protein inhibits signaling mediated by the noncanonical and canonical I-kappa-B kinase family members. J. Immun. 176: 1072-1080, 2006. [PubMed: 16393995] [Full Text: https://doi.org/10.4049/jimmunol.176.2.1072]