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Gene Review

CHUK  -  conserved helix-loop-helix ubiquitous kinase

Homo sapiens

Synonyms: Conserved helix-loop-helix ubiquitous kinase, I-kappa-B kinase 1, I-kappa-B kinase alpha, IKBKA, IKK-A, ...
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Disease relevance of CHUK


Psychiatry related information on CHUK

  • This crosstalk constitutes a decision-making process that determines the consequences of NF-kappaB and IKK activation and, ultimately, cell fate [5].

High impact information on CHUK

  • Our genetic evidence confirms that p100 is required and sufficient as a fourth IkappaB protein for noncanonical NF-kappaB signaling downstream of NIK and IKK1 [6].
  • CHUK specifically phosphorylates IkappaB-alpha on both serine 32 and serine 36, modifications that are required for targeted degradation of IkappaB-alpha via the ubiquitin-proteasome pathway [7].
  • Overexpression of CHUK activates a NF-kappaB-dependent reporter gene [7].
  • Histone H3 phosphorylation by IKK-alpha is critical for cytokine-induced gene expression [8].
  • We find that IKK is composed of similar amounts of IKK-alpha, IKK-beta and two other polypeptides, for which we obtained partial sequences [9].

Chemical compound and disease context of CHUK


Biological context of CHUK

  • The nucleotide sequence of a near full-length murine CHUK cDNA clone revealed an encoded polypeptide specifying: a carboxyl-terminal H-L-H domain, an amino terminal serine-threonine kinase catalytic domain, and a leucine zipper-like amphipathic alpha-helix juxtaposed in between the H-L-H and kinase domains [11].
  • CHUK may provide new insights into the regulated transmission of cytoplasmic signals to specific nuclear factors manifesting rapid alterations in patterns of cellular gene expression [11].
  • Taken together, our results not only reveal the IKK-mediated phosphorylation of SRC-3 to be a regulated event that plays an important role but also substantiate the role of SRC-3 in multiple signaling pathways [12].
  • However, the precise molecular mechanisms by which IKK may contribute to the development of insulin resistance are not well understood [13].
  • In addition to modulation of IKK activity, the NF-kappa B pathway is also regulated by other processes, including the nucleocytoplasmic shuttling of various components of this pathway and the post-translational modification of factors bound to NF-kappa B-dependent promoters [14].

Anatomical context of CHUK

  • CHUK is highly conserved in evolution and ubiquitously expressed in diverse types of established cell lines, whereas it is differentially expressed in normal murine tissues [11].
  • IKK beta overexpression in a Jurkat cell line resulted in the formation of a constitutively active IKK complex, which was CD3/CD28 inducible [15].
  • There was none or very little expression of COX-2, NF-kappa B and IKK alpha in non-neoplastic colon epithelial cells, while the expression of all three of these proteins was significantly increased (P<0.05, Wilcoxon's signed rank test) in adjacent cancerous cells [3].
  • In the present study, C-terminal truncated forms of IKK gamma--Delta C-IKK gamma 306 and Delta C-IKK gamma 261--were stably expressed in the myeloid cell line U937 by retroviral-mediated gene transfer [16].
  • Tumor necrosis factor alpha triggers proliferation of adult neural stem cells via IKK/NF-kappaB signaling [17].

Associations of CHUK with chemical compounds

  • Geldanamycin (GA), an antitumor agent that disrupts the formation of this heterocomplex, prevents TNF-induced activation of IKK and NF-kappaB [18].
  • IKK activity was stimulated by both TNF-alpha and TPA, and these effects were inhibited by staurosporine or herbimycin [19].
  • Prolonged incubation in the presence of LMB also leads to nuclear accumulation of IKK1, which was dependent on a lysine residue at position 44, which is also essential for kinase activity [20].
  • We describe a small molecule, selective inhibitor of IKK-2, SC-514, which does not inhibit other IKK isoforms or other serine-threonine and tyrosine kinases [21].
  • Role of IKK1 and IKK2 in lipopolysaccharide signaling in human monocytic cells [22].

Physical interactions of CHUK


Enzymatic interactions of CHUK

  • In addition, we showed that SRC-3 was phosphorylated by the IKK complex in vitro [12].
  • A mutant form of IKK-alpha containing alanine at residue 176 cannot be phosphorylated or activated by NIK and acts as a dominant negative inhibitor of interleukin 1- and tumor necrosis factor-induced NF-kappaB activation [27].

Regulatory relationships of CHUK

  • NIK cannot phosphorylate IkappaB-alpha directly, but it appears to be a functionally important subunit, because mutated NIK inhibited stimulus-induced kappaB-dependent transcription more effectively than mutated IKK-alpha or -beta [28].
  • Our laboratory has delineated that the phosphatidylinositol 3' kinase (PI3K)/AKT/I kappa B kinase (IKK) pathway positively regulates NF kappa B and beta-catenin, both important transcriptional regulators in colorectal cancer (CRC) [29].
  • IKK activity was stimulated by either IL-1beta or TPA, and these effects were inhibited by Ro 31-8220 or tyrphostin 23 [30].
  • Finally, we show that IKK-alpha is present in the MEKK1-inducible, high molecular weight IkappaB kinase complex and treatment of this complex with MEKK1 induces phosphorylation of IKK-alpha in vitro [31].
  • Nonetheless, dibutyryl-cAMP or forskolin did not affect the IKK activation induced by IL-1 [32].
  • These results indicate that FAF1 inhibits IKK activation and its downstream signaling by interrupting the IKK complex assembly through physical interaction with IKKbeta [33].

Other interactions of CHUK

  • The IKK complex, containing two catalytic subunits IKKalpha and IKKbeta and a regulatory subunit NEMO, plays central roles in signal-dependent activation of NF-kappaB [18].
  • We identify Cdc37 and Hsp90 as two additional components of the IKK complex [18].
  • Canonical activation of NF-kappa B is mediated via phosphorylation of the inhibitory I kappa B proteins by the I kappa B kinase complex (IKK) [34].
  • The TANK binding domain within NEMO/IKK gamma is required for proper functioning of this IKK subunit [34].
  • In a yeast two-hybrid screen for NIK-interacting proteins, we have identified a protein kinase previously known as CHUK [7].

Analytical, diagnostic and therapeutic context of CHUK


  1. IkappaB kinase complex is an intracellular target for endotoxic lipopolysaccharide in human monocytic cells. Hawiger, J., Veach, R.A., Liu, X.Y., Timmons, S., Ballard, D.W. Blood (1999) [Pubmed]
  2. NF-kappa B regulation by I kappa B kinase in primary fibroblast-like synoviocytes. Aupperle, K.R., Bennett, B.L., Boyle, D.L., Tak, P.P., Manning, A.M., Firestein, G.S. J. Immunol. (1999) [Pubmed]
  3. Upregulation of cyclooxygenase-2 is accompanied by increased expression of nuclear factor-kappa B and I kappa B kinase-alpha in human colorectal cancer epithelial cells. Charalambous, M.P., Maihöfner, C., Bhambra, U., Lightfoot, T., Gooderham, N.J. Br. J. Cancer (2003) [Pubmed]
  4. NF-kappa B regulation by I kappa B kinase-2 in rheumatoid arthritis synoviocytes. Aupperle, K., Bennett, B., Han, Z., Boyle, D., Manning, A., Firestein, G. J. Immunol. (2001) [Pubmed]
  5. Integrating cell-signalling pathways with NF-kappaB and IKK function. Perkins, N.D. Nat. Rev. Mol. Cell Biol. (2007) [Pubmed]
  6. A Fourth IkappaB Protein within the NF-kappaB Signaling Module. Basak, S., Kim, H., Kearns, J.D., Tergaonkar, V., O'dea, E., Werner, S.L., Benedict, C.A., Ware, C.F., Ghosh, G., Verma, I.M., Hoffmann, A. Cell (2007) [Pubmed]
  7. Identification and characterization of an IkappaB kinase. Régnier, C.H., Song, H.Y., Gao, X., Goeddel, D.V., Cao, Z., Rothe, M. Cell (1997) [Pubmed]
  8. Histone H3 phosphorylation by IKK-alpha is critical for cytokine-induced gene expression. Yamamoto, Y., Verma, U.N., Prajapati, S., Kwak, Y.T., Gaynor, R.B. Nature (2003) [Pubmed]
  9. IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Rothwarf, D.M., Zandi, E., Natoli, G., Karin, M. Nature (1998) [Pubmed]
  10. Suppression of NF-kappaB and NF-kappaB-regulated gene expression by sulforaphane and PEITC through IkappaBalpha, IKK pathway in human prostate cancer PC-3 cells. Xu, C., Shen, G., Chen, C., Gélinas, C., Kong, A.N. Oncogene (2005) [Pubmed]
  11. CHUK, a new member of the helix-loop-helix and leucine zipper families of interacting proteins, contains a serine-threonine kinase catalytic domain. Connelly, M.A., Marcu, K.B. Cell. Mol. Biol. Res. (1995) [Pubmed]
  12. Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator activity by I kappa B kinase. Wu, R.C., Qin, J., Hashimoto, Y., Wong, J., Xu, J., Tsai, S.Y., Tsai, M.J., O'Malley, B.W. Mol. Cell. Biol. (2002) [Pubmed]
  13. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. Gao, Z., Hwang, D., Bataille, F., Lefevre, M., York, D., Quon, M.J., Ye, J. J. Biol. Chem. (2002) [Pubmed]
  14. Nuclear role of I kappa B Kinase-gamma/NF-kappa B essential modulator (IKK gamma/NEMO) in NF-kappa B-dependent gene expression. Verma, U.N., Yamamoto, Y., Prajapati, S., Gaynor, R.B. J. Biol. Chem. (2004) [Pubmed]
  15. Primary human CD4+ T cells contain heterogeneous I kappa B kinase complexes: role in activation of the IL-2 promoter. Khoshnan, A., Kempiak, S.J., Bennett, B.L., Bae, D., Xu, W., Manning, A.M., June, C.H., Nel, A.E. J. Immunol. (1999) [Pubmed]
  16. Disruption of NF-kappa B signaling and chemokine gene activation by retroviral mediated expression of IKK gamma/NEMO mutants. Le Page, C., Popescu, O., Génin, P., Lian, J., Paquin, A., Galipeau, J., Hiscott, J. Virology (2001) [Pubmed]
  17. Tumor necrosis factor alpha triggers proliferation of adult neural stem cells via IKK/NF-kappaB signaling. Widera, D., Mikenberg, I., Elvers, M., Kaltschmidt, C., Kaltschmidt, B. BMC neuroscience [electronic resource]. (2006) [Pubmed]
  18. TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90. Chen, G., Cao, P., Goeddel, D.V. Mol. Cell (2002) [Pubmed]
  19. TNF-alpha-induced cyclooxygenase-2 expression in human lung epithelial cells: involvement of the phospholipase C-gamma 2, protein kinase C-alpha, tyrosine kinase, NF-kappa B-inducing kinase, and I-kappa B kinase 1/2 pathway. Chen, C.C., Sun, Y.T., Chen, J.J., Chiu, K.T. J. Immunol. (2000) [Pubmed]
  20. Signaling molecules of the NF-kappa B pathway shuttle constitutively between cytoplasm and nucleus. Birbach, A., Gold, P., Binder, B.R., Hofer, E., de Martin, R., Schmid, J.A. J. Biol. Chem. (2002) [Pubmed]
  21. A selective IKK-2 inhibitor blocks NF-kappa B-dependent gene expression in interleukin-1 beta-stimulated synovial fibroblasts. Kishore, N., Sommers, C., Mathialagan, S., Guzova, J., Yao, M., Hauser, S., Huynh, K., Bonar, S., Mielke, C., Albee, L., Weier, R., Graneto, M., Hanau, C., Perry, T., Tripp, C.S. J. Biol. Chem. (2003) [Pubmed]
  22. Role of IKK1 and IKK2 in lipopolysaccharide signaling in human monocytic cells. O'Connell, M.A., Bennett, B.L., Mercurio, F., Manning, A.M., Mackman, N. J. Biol. Chem. (1998) [Pubmed]
  23. Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complex. Gil, J., Alcamí, J., Esteban, M. Oncogene (2000) [Pubmed]
  24. Kinetic mechanisms of IkappaB-related kinases (IKK) inducible IKK and TBK-1 differ from IKK-1/IKK-2 heterodimer. Huynh, Q.K., Kishore, N., Mathialagan, S., Donnelly, A.M., Tripp, C.S. J. Biol. Chem. (2002) [Pubmed]
  25. Peptides corresponding to the N and C termini of IkappaB-alpha, -beta, and -epsilon as probes of the two catalytic subunits of IkappaB kinase, IKK-1 and IKK-2. Burke, J.R., Wood, M.K., Ryseck, R.P., Walther, S., Meyers, C.A. J. Biol. Chem. (1999) [Pubmed]
  26. Suppression of NF-kappaB activation by Entamoeba histolytica in intestinal epithelial cells is mediated by heat shock protein 27. Kammanadiminti, S.J., Chadee, K. J. Biol. Chem. (2006) [Pubmed]
  27. NF-kappaB-inducing kinase activates IKK-alpha by phosphorylation of Ser-176. Ling, L., Cao, Z., Goeddel, D.V. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  28. Differential effects of lipopolysaccharide and tumor necrosis factor on monocytic IkappaB kinase signalsome activation and IkappaB proteolysis. Fischer, C., Page, S., Weber, M., Eisele, T., Neumeier, D., Brand, K. J. Biol. Chem. (1999) [Pubmed]
  29. The AKT/I kappa B kinase pathway promotes angiogenic/metastatic gene expression in colorectal cancer by activating nuclear factor-kappa B and beta-catenin. Agarwal, A., Das, K., Lerner, N., Sathe, S., Cicek, M., Casey, G., Sizemore, N. Oncogene (2005) [Pubmed]
  30. Protein kinase calpha but not p44/42 mitogen-activated protein kinase, p38, or c-Jun NH(2)-terminal kinase is required for intercellular adhesion molecule-1 expression mediated by interleukin-1beta: involvement of sequential activation of tyrosine kinase, nuclear factor-kappaB-inducing kinase, and IkappaB kinase 2. Chen, C.C., Chen, J.J., Chou, C.Y. Mol. Pharmacol. (2000) [Pubmed]
  31. MEKK1 activates both IkappaB kinase alpha and IkappaB kinase beta. Lee, F.S., Peters, R.T., Dang, L.C., Maniatis, T. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  32. Inhibitor of nuclear factor-kappaB induction by cAMP antagonizes interleukin-1-induced human macrophage-colony-stimulating-factor expression. Kamthong, P.J., Wu , M. Biochem. J. (2001) [Pubmed]
  33. FAF1 suppresses IkappaB kinase (IKK) activation by disrupting the IKK complex assembly. Park, M.Y., Moon, J.H., Lee, K.S., Choi, H.I., Chung, J., Hong, H.J., Kim, E. J. Biol. Chem. (2007) [Pubmed]
  34. Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases. Chariot, A., Leonardi, A., Muller, J., Bonif, M., Brown, K., Siebenlist, U. J. Biol. Chem. (2002) [Pubmed]
  35. Identification and characterization of the IKKalpha promoter: positive and negative regulation by ETS-1 and p53, respectively. Gu, L., Zhu, N., Findley, H.W., Woods, W.G., Zhou, M. J. Biol. Chem. (2004) [Pubmed]
  36. A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Zonana, J., Elder, M.E., Schneider, L.C., Orlow, S.J., Moss, C., Golabi, M., Shapira, S.K., Farndon, P.A., Wara, D.W., Emmal, S.A., Ferguson, B.M. Am. J. Hum. Genet. (2000) [Pubmed]
  37. Hypothermia enhances phosphorylation of I{kappa}B kinase and prolongs nuclear localization of NF-{kappa}B in lipopolysaccharide-activated macrophages. Fairchild, K.D., Singh, I.S., Carter, H.C., Hester, L., Hasday, J.D. Am. J. Physiol., Cell Physiol. (2005) [Pubmed]
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