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CHUK

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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.[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[edit | edit source]

NF-κB response[edit | edit source]

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[edit | edit source]

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.

Keratinocyte migration[edit | edit source]

IκB kinase α (IKKα) is a regulator of keratinocyte terminal differentiation and proliferation and plays a role in skin cancer.[8]

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.[9] 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 stimulatea migration through dynamic interactions with the EGF promoter depending on the redox state within cells.[10]

Other cellular targets[edit | edit source]

IKK-α has also been reported to regulate the cell cycle protein cyclin D1 in an NF-κB-independent manner.[11][12]

Clinical significance[edit | edit source]

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.[13]

Mutations in IKK-α in humans have been linked to lethal fetal malformations.[14] 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.[15]

Interactions[edit | edit source]

IKK-α has been shown to interact with:

References[edit | edit source]

  1. ↑ Mock BA, Connelly MA, McBride OW, Kozak CA, Marcu KB (May 1995). "CHUK, a conserved helix-loop-helix ubiquitous kinase, maps to human chromosome 10 and mouse chromosome 19". Genomics. 27 (2): 348–51. doi:10.1006/geno.1995.1054. PMID 7558004.
  2. ↑ Häcker H, Karin M (October 2006). "Regulation and function of IKK and IKK-related kinases". Sci. STKE. 2006 (357): re13. doi:10.1126/stke.3572006re13. PMID 17047224.
  3. ↑ 3.0 3.1 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.
  4. ↑ Zhu F, Park E, Liu B, Xia X, Fischer SM, Hu Y (February 2009). "Critical role of IkappaB kinase alpha in embryonic skin development and skin carcinogenesis". Histol. Histopathol. 24 (2): 265–71. PMID 19085841.
  5. ↑ "Entrez Gene: CHUK conserved helix-loop-helix ubiquitous kinase".
  6. ↑ Qiutang Li; Qingxian Lu; Jason Y. Hwang; Dirk Büscher; Kuo-Fen Lee; Juan Carlos Izpisua-Belmonte; Inder M. Verma (May 1999). "IKK1-deficient mice exhibit abnormal development of skin and skeleton". Genes Dev. 13 (10): 1322–8. doi:10.1101/gad.13.10.1322. PMC 316728. PMID 10346820.
  7. ↑ Fukazawa C, Santiago C, Park K, Deery W, Gomez de la Torre Canny S, Holterhoff C, Wagner DS (October 2010). "poky/chuk/ikk1 is required for differentiation of the zebrafish embryonic epidermis". Developmental Biology. 346 (2): 272–83. doi:10.1016/j.ydbio.2010.07.037. PMC 2956273. PMID 20692251.
  8. ↑ Xie Y, Xie K, Gou Q, Chen N (2015). "IκB kinase α functions as a tumor suppressor in epithelial-derived tumors through an NF-κB-independent pathway (Review)". Oncology Reports. 34 (5): 2225–32. doi:10.3892/or.2015.4229. PMID 26323241.
  9. ↑ Lisse TS, King BL, Rieger S (February 2016). "Comparative transcriptomic profiling of hydrogen peroxide signaling networks in zebrafish and human keratinocytes: Implications toward conservation, migration and wound healing". Scientific Reports. 6: 20328. doi:10.1038/srep20328. PMC 4742856. PMID 26846883.
  10. ↑ Lisse TS, Rieger S (March 2017). "IKKα regulates human keratinocyte migration through surveillance of the redox environment". Journal of Cell Science. 130 (5): 975–988. doi:10.1242/jcs.197343. PMC 5358334. PMID 28122935.
  11. ↑ Kwak YT, Li R, Becerra CR, Tripathy D, Frenkel EP, Verma UN (August 2005). "IkappaB kinase alpha regulates subcellular distribution and turnover of cyclin D1 by phosphorylation". J Biol Chem. 280 (40): 33945–52. doi:10.1074/jbc.M506206200. PMID 16103118.
  12. ↑ Song L, Dong W, Gao M, Li J, Hu M, Guo N, Huang C (February 2010). "A novel role of IKKα in the mediation of UVB-induced G0/G1 cell cycle arrest response by suppressing Cyclin D1 expression". Biochim Biophys Acta. 1803 (2): 323–32. doi:10.1016/j.bbamcr.2010.01.006. PMC 2850076. PMID 20080131.
  13. ↑ Llona-Minguez S, Baiget J, Mackay SP (2013). "Small-molecule inhibitors of IκB kinase (IKK) and IKK-related kinases". Pharm. Pat. Anal. 2 (4): 481–498. doi:10.4155/ppa.13.31. PMID 24237125.
  14. ↑ Lahtela J, Nousiainen HO, Stefanovic V, Tallila J, Viskari H, Karikoski R, Gentile M, Saloranta C, Varilo T, Salonen R, Kestilä M (October 2010). "Mutant CHUK and severe fetal encasement malformation". New England Journal of Medicine. 363 (17): 1631–1637. doi:10.1056/NEJMoa0911698. PMID 20961246.
  15. ↑ Liu B, Park E, Zhu F, Bustos T, Liu J, Shen J, Fischer SM, Hu Y (November 2006). "A critical role for IκB kinase α in the development of human and mouse squamous cell carcinomas". Proc. Natl. Acad. Sci. U.S.A. 103 (46): 17202–7. doi:10.1073/pnas.0604481103. PMC 1859910. PMID 17079494.
  16. ↑ Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB (September 1999). "NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase". Nature. 401 (6748): 82–5. doi:10.1038/43466. PMID 10485710.
  17. ↑ Romashkova JA, Makarov SS (September 1999). "NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling". Nature. 401 (6748): 86–90. doi:10.1038/43474. PMID 10485711.
  18. ↑ Yuan ZQ, Feldman RI, Sun M, Olashaw NE, Coppola D, Sussman GE, Shelley SA, Nicosia SV, Cheng JQ (August 2002). "Inhibition of JNK by cellular stress- and tumor necrosis factor alpha-induced AKT2 through activation of the NF kappa B pathway in human epithelial Cells". J. Biol. Chem. 277 (33): 29973–82. doi:10.1074/jbc.M203636200. PMID 12048203.
  19. ↑ Lamberti C, Lin KM, Yamamoto Y, Verma U, Verma IM, Byers S, Gaynor RB (November 2001). "Regulation of beta-catenin function by the IkappaB kinases". J. Biol. Chem. 276 (45): 42276–86. doi:10.1074/jbc.M104227200. PMID 11527961.
  20. ↑ Reuter TY, Medhurst AL, Waisfisz Q, Zhi Y, Herterich S, Hoehn H, Gross HJ, Joenje H, Hoatlin ME, Mathew CG, Huber PA (October 2003). "Yeast two-hybrid screens imply involvement of Fanconi anemia proteins in transcription regulation, cell signaling, oxidative metabolism, and cellular transport". Exp. Cell Res. 289 (2): 211–21. doi:10.1016/S0014-4827(03)00261-1. PMID 14499622.
  21. ↑ 21.0 21.1 Otsuki T, Young DB, Sasaki DT, Pando MP, Li J, Manning A, Hoekstra M, Hoatlin ME, Mercurio F, Liu JM (2002). "Fanconi anemia protein complex is a novel target of the IKK signalsome". J. Cell. Biochem. 86 (4): 613–23. doi:10.1002/jcb.10270. PMID 12210728.
  22. ↑ Agou F, Ye F, Goffinont S, Courtois G, Yamaoka S, Israël A, Véron M (May 2002). "NEMO trimerizes through its coiled-coil C-terminal domain". J. Biol. Chem. 277 (20): 17464–75. doi:10.1074/jbc.M201964200. PMID 11877453.
  23. ↑ 23.0 23.1 Chen G, Cao P, Goeddel DV (February 2002). "TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90". Mol. Cell. 9 (2): 401–10. doi:10.1016/S1097-2765(02)00450-1. PMID 11864612.
  24. ↑ 24.0 24.1 Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ (October 2000). "Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain". Cell. 103 (2): 351–61. doi:10.1016/S0092-8674(00)00126-4. PMID 11057907.
  25. ↑ Shifera AS, Horwitz MS (March 2008). "Mutations in the zinc finger domain of IKK gamma block the activation of NF-kappa B and the induction of IL-2 in stimulated T lymphocytes". Mol. Immunol. 45 (6): 1633–45. doi:10.1016/j.molimm.2007.09.036. PMID 18207244.
  26. ↑ Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M (October 1997). "The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation". Cell. 91 (2): 243–52. doi:10.1016/S0092-8674(00)80406-7. PMID 9346241.
  27. ↑ May MJ, D'Acquisto F, Madge LA, Glöckner J, Pober JS, Ghosh S (September 2000). "Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex". Science. 289 (5484): 1550–4. doi:10.1126/science.289.5484.1550. PMID 10968790.
  28. ↑ 28.0 28.1 Woronicz JD, Gao X, Cao Z, Rothe M, Goeddel DV (October 1997). "IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK". Science. 278 (5339): 866–9. doi:10.1126/science.278.5339.866. PMID 9346485.
  29. ↑ Yeung KC, Rose DW, Dhillon AS, Yaros D, Gustafsson M, Chatterjee D, McFerran B, Wyche J, Kolch W, Sedivy JM (November 2001). "Raf Kinase Inhibitor Protein Interacts with NF-κB-Inducing Kinase and TAK1 and Inhibits NF-κB Activation". Mol. Cell. Biol. 21 (21): 7207–17. doi:10.1128/MCB.21.21.7207-7217.2001. PMC 99896. PMID 11585904.
  30. ↑ Vig E, Green M, Liu Y, Yu KY, Kwon HJ, Tian J, Goebl MG, Harrington MA (March 2001). "SIMPL is a tumor necrosis factor-specific regulator of nuclear factor-kappaB activity". J. Biol. Chem. 276 (11): 7859–66. doi:10.1074/jbc.M010399200. PMID 11096118.
  31. ↑ Windheim M, Stafford M, Peggie M, Cohen P (March 2008). "Interleukin-1 (IL-1) Induces the Lys63-Linked Polyubiquitination of IL-1 Receptor-Associated Kinase 1 To Facilitate NEMO Binding and the Activation of IκBα Kinase". Mol. Cell. Biol. 28 (5): 1783–91. doi:10.1128/MCB.02380-06. PMC 2258775. PMID 18180283.
  32. ↑ 32.0 32.1 Régnier CH, Song HY, Gao X, Goeddel DV, Cao Z, Rothe M (July 1997). "Identification and characterization of an IkappaB kinase". Cell. 90 (2): 373–83. doi:10.1016/S0092-8674(00)80344-X. PMID 9244310.
  33. ↑ Xiao G, Sun SC (July 2000). "Negative regulation of the nuclear factor kappa B-inducing kinase by a cis-acting domain". J. Biol. Chem. 275 (28): 21081–5. doi:10.1074/jbc.M002552200. PMID 10887201.
  34. ↑ Luftig MA, Cahir-McFarland E, Mosialos G, Kieff E (May 2001). "Effects of the NIK aly mutation on NF-kappaB activation by the Epstein-Barr virus latent infection membrane protein, lymphotoxin beta receptor, and CD40". J. Biol. Chem. 276 (18): 14602–6. doi:10.1074/jbc.C100103200. PMID 11278268.
  35. ↑ 35.0 35.1 35.2 Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K (March 1999). "The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway". Nature. 398 (6724): 252–6. doi:10.1038/18465. PMID 10094049.
  36. ↑ Sakurai H, Miyoshi H, Toriumi W, Sugita T (April 1999). "Functional interactions of transforming growth factor beta-activated kinase 1 with IkappaB kinases to stimulate NF-kappaB activation". J. Biol. Chem. 274 (15): 10641–8. doi:10.1074/jbc.274.15.10641. PMID 10187861.
  37. ↑ Lin X, Cunningham ET, Mu Y, Geleziunas R, Greene WC (February 1999). "The proto-oncogene Cot kinase participates in CD3/CD28 induction of NF-kappaB acting through the NF-kappaB-inducing kinase and IkappaB kinases". Immunity. 10 (2): 271–80. doi:10.1016/S1074-7613(00)80027-8. PMID 10072079.
  38. ↑ DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M (August 1997). "A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB". Nature. 388 (6642): 548–54. doi:10.1038/41493. PMID 9252186.
  39. ↑ Cohen L, Henzel WJ, Baeuerle PA (September 1998). "IKAP is a scaffold protein of the IkappaB kinase complex". Nature. 395 (6699): 292–6. doi:10.1038/26254. PMID 9751059.
  40. ↑ Wu RC, Qin J, Hashimoto Y, Wong J, Xu J, Tsai SY, Tsai MJ, O'Malley BW (May 2002). "Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator Activity by IκB Kinase". Mol. Cell. Biol. 22 (10): 3549–61. doi:10.1128/MCB.22.10.3549-3561.2002. PMC 133790. PMID 11971985.
  41. ↑ Prajapati S, Verma U, Yamamoto Y, Kwak YT, Gaynor RB (January 2004). "Protein phosphatase 2Cbeta association with the IkappaB kinase complex is involved in regulating NF-kappaB activity". J. Biol. Chem. 279 (3): 1739–46. doi:10.1074/jbc.M306273200. PMID 14585847.
  42. ↑ Liu L, Kwak YT, Bex F, García-Martínez LF, Li XH, Meek K, Lane WS, Gaynor RB (July 1998). "DNA-Dependent Protein Kinase Phosphorylation of IκBα and IκBβ Regulates NF-κB DNA Binding Properties". Mol. Cell. Biol. 18 (7): 4221–34. PMC 109006. PMID 9632806.
  43. ↑ Devin A; Lin Y; Yamaoka S; Li Z; Karin M; Liu Zg (June 2001). "The α and β Subunits of IκB Kinase (IKK) Mediate TRAF2-Dependent IKK Recruitment to Tumor Necrosis Factor (TNF) Receptor 1 in Response to TNF". Mol. Cell. Biol. 21 (12): 3986–94. doi:10.1128/MCB.21.12.3986-3994.2001. PMC 87061. PMID 11359906.
  44. ↑ Li S, Wang L, Dorf ME (January 2009). "PKC phosphorylation of TRAF2 mediates IKKα/β recruitment and K63-linked polyubiquitination". Mol. Cell. 33 (1): 30–42. doi:10.1016/j.molcel.2008.11.023. PMC 2643372. PMID 19150425.

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