CHUK

{{Main|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.{{Cite web| title = Entrez Gene: CHUK conserved helix-loop-helix ubiquitous kinase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1147}}

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.

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.{{Cite journal|author1=Qiutang Li |author2=Qingxian Lu |author3=Jason Y. Hwang |author4=Dirk Büscher |author5=Kuo-Fen Lee |author6=Juan Carlos Izpisua-Belmonte |author7=Inder M. Verma | title = IKK1-deficient mice exhibit abnormal development of skin and skeleton | journal = Genes Dev. | volume = 13 | issue = 10 | pages = 1322–8 |date=May 1999 | pmid = 10346820 | pmc = 316728 | doi = 10.1101/gad.13.10.1322}} 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.

The zebrafish homolog of IKK-α has also been shown to play a role in the differentiation of the embryonic epithelium.{{Cite journal|vauthors=Fukazawa C, Santiago C, Park K, Deery W, Gomez de la Torre Canny S, Holterhoff C, Wagner DS | title = poky/chuk/ikk1 is required for differentiation of the zebrafish embryonic epidermis | journal = Developmental Biology | volume = 346 | issue = 2 | pages = 272–83 |date=October 2010 | pmid = 20692251 | pmc = 2956273 | doi = 10.1016/j.ydbio.2010.07.037 }} 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.

IκB kinase α (IKKα) is a regulator of keratinocyte terminal differentiation and proliferation and plays a role in skin cancer.{{cite journal | vauthors = Xie Y, Xie K, Gou Q, Chen N | title = IκB kinase α functions as a tumor suppressor in epithelial-derived tumors through an NF-κB-independent pathway (Review) | journal = Oncology Reports | volume = 34 | issue = 5 | pages = 2225–32 | year = 2015 | pmid = 26323241 | doi = 10.3892/or.2015.4229 | doi-access = free }}

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.{{cite journal | vauthors = Lisse TS, King BL, Rieger S | title = Comparative transcriptomic profiling of hydrogen peroxide signaling networks in zebrafish and human keratinocytes: Implications toward conservation, migration and wound healing | journal = Scientific Reports | volume = 6 | pages = 20328 | date = February 2016 | pmid = 26846883 | pmc = 4742856 | doi = 10.1038/srep20328 | bibcode = 2016NatSR...620328L }} 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 stimulates migration through dynamic interactions with the EGF promoter depending on the redox state within cells.{{cite journal | vauthors = Lisse TS, Rieger S | title = IKKα regulates human keratinocyte migration through surveillance of the redox environment | journal = Journal of Cell Science | volume = 130 | issue = 5 | pages = 975–988 | date = March 2017 | pmid = 28122935 | pmc = 5358334 | doi = 10.1242/jcs.197343 }}

IKK-α has also been reported to regulate the cell cycle protein cyclin D1 in an NF-κB-independent manner.{{Cite journal|vauthors=Kwak YT, Li R, Becerra CR, Tripathy D, Frenkel EP, Verma UN | title = IkappaB kinase alpha regulates subcellular distribution and turnover of cyclin D1 by phosphorylation | journal = J Biol Chem | volume = 280 | issue = 40 | pages = 33945–52 |date=August 2005 | pmid = 16103118 | doi=10.1074/jbc.M506206200| doi-access = free }}{{Cite journal|vauthors=Song L, Dong W, Gao M, Li J, Hu M, Guo N, Huang C | title = A novel role of IKKα in the mediation of UVB-induced G0/G1 cell cycle arrest response by suppressing Cyclin D1 expression | journal = Biochim Biophys Acta | volume = 1803 | issue = 2 | pages = 323–32 |date=February 2010 | pmid = 20080131 | doi=10.1016/j.bbamcr.2010.01.006| pmc = 2850076}}

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.{{cite journal |vauthors=Llona-Minguez S, Baiget J, Mackay SP | year = 2013 | title = Small-molecule inhibitors of IκB kinase (IKK) and IKK-related kinases | journal = Pharm. Pat. Anal. | volume = 2 | pages = 481–498 | pmid = 24237125 | doi = 10.4155/ppa.13.31 | issue = 4 }}

Mutations in IKK-α in humans have been linked to lethal fetal malformations.{{Cite journal |vauthors=Lahtela J, Nousiainen HO, Stefanovic V, Tallila J, Viskari H, Karikoski R, Gentile M, Saloranta C, Varilo T, Salonen R, Kestilä M | title = Mutant CHUK and severe fetal encasement malformation | journal = New England Journal of Medicine | volume = 363 | pages = 1631–1637 |date=October 2010 | pmid = 20961246 | doi=10.1056/NEJMoa0911698 | issue=17| doi-access =free }} 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.{{Cite journal|vauthors=Liu B, Park E, Zhu F, Bustos T, Liu J, Shen J, Fischer SM, Hu Y | title = A critical role for IκB kinase α in the development of human and mouse squamous cell carcinomas | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 103 | issue = 46 | pages = 17202–7 |date=November 2006 | pmid = 17079494 | pmc = 1859910 | doi = 10.1073/pnas.0604481103 | bibcode = 2006PNAS..10317202L | doi-access = free }}

IKK-α has been shown to interact with:

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• HDAC9,{{cite journal | vauthors = Asare Y, Campbell-James TA, Bokov Y, Yu LL, Prestel M, El Bounkari O, Roth S, Megens RT, Straub T, Thomas K, Yan G, Schneider M, Ziesch N, Tiedt S, Silvestre-Roig C, Braster Q, Huang Y, Schneider M, Malik R, Haffner C, Liesz A, Soehnlein O, Bernhagen J, Dichgans M | title = Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability | journal = Circulation Research | date = June 2020 | volume = 127 | issue = 6 | pages = 811–823 | pmid = 32546048 | doi = 10.1161/CIRCRESAHA.120.316743 | s2cid = 219726725 | url = https://epub.ub.uni-muenchen.de/72640/ | doi-access = free }}
• AKT1,{{cite journal |vauthors=Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB | title = NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase | journal = Nature | volume = 401 | issue = 6748 | pages = 82–5 |date=September 1999 | pmid = 10485710 | doi = 10.1038/43466 | bibcode = 1999Natur.401...82N | s2cid = 4419076 }}{{cite journal |vauthors=Romashkova JA, Makarov SS | title = NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling | journal = Nature | volume = 401 | issue = 6748 | pages = 86–90 |date=September 1999 | pmid = 10485711 | doi = 10.1038/43474 | bibcode = 1999Natur.401...86R | s2cid = 205033347 }}
• CTNNB1,{{cite journal|author7-link=Richard Gaynor |vauthors=Lamberti C, Lin KM, Yamamoto Y, Verma U, Verma IM, Byers S, Gaynor RB | title = Regulation of beta-catenin function by the IkappaB kinases | journal = J. Biol. Chem. | volume = 276 | issue = 45 | pages = 42276–86 |date=November 2001 | pmid = 11527961 | doi = 10.1074/jbc.M104227200 | doi-access = free }}
• FANCA,{{cite journal |vauthors=Reuter TY, Medhurst AL, Waisfisz Q, Zhi Y, Herterich S, Hoehn H, Gross HJ, Joenje H, Hoatlin ME, Mathew CG, Huber PA | title = Yeast two-hybrid screens imply involvement of Fanconi anemia proteins in transcription regulation, cell signaling, oxidative metabolism, and cellular transport | journal = Exp. Cell Res. | volume = 289 | issue = 2 | pages = 211–21 |date=October 2003 | pmid = 14499622 | doi = 10.1016/S0014-4827(03)00261-1}}
• IKBKG{{cite journal |vauthors=Agou F, Ye F, Goffinont S, Courtois G, Yamaoka S, Israël A, Véron M | title = NEMO trimerizes through its coiled-coil C-terminal domain | journal = J. Biol. Chem. | volume = 277 | issue = 20 | pages = 17464–75 |date=May 2002 | pmid = 11877453 | doi = 10.1074/jbc.M201964200 | doi-access = free }}{{cite journal |vauthors=Shifera AS, Horwitz MS | title = 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 | journal = Mol. Immunol. | volume = 45 | issue = 6 | pages = 1633–45 |date=March 2008 | pmid = 18207244 | doi = 10.1016/j.molimm.2007.09.036 }}
• IKK2,{{cite journal |vauthors=Otsuki T, Young DB, Sasaki DT, Pando MP, Li J, Manning A, Hoekstra M, Hoatlin ME, Mercurio F, Liu JM | title = Fanconi anemia protein complex is a novel target of the IKK signalsome | journal = J. Cell. Biochem. | volume = 86 | issue = 4 | pages = 613–23 | year = 2002 | pmid = 12210728 | doi = 10.1002/jcb.10270 | s2cid = 42471384 | url =https://zenodo.org/record/1229210 }}{{cite journal |vauthors=Chen G, Cao P, Goeddel DV | title = TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90 | journal = Mol. Cell | volume = 9 | issue = 2 | pages = 401–10 |date=February 2002 | pmid = 11864612 | doi = 10.1016/S1097-2765(02)00450-1| doi-access = free }}{{cite journal |vauthors=Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ | title = Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain | journal = Cell | volume = 103 | issue = 2 | pages = 351–61 |date=October 2000 | pmid = 11057907 | doi = 10.1016/S0092-8674(00)00126-4 | s2cid = 18154645 | doi-access = free }}{{cite journal |vauthors=Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M | title = The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation | journal = Cell | volume = 91 | issue = 2 | pages = 243–52 |date=October 1997 | pmid = 9346241 | doi = 10.1016/S0092-8674(00)80406-7| s2cid = 6399108 | doi-access = free }}{{cite journal |vauthors=May MJ, D'Acquisto F, Madge LA, Glöckner J, Pober JS, Ghosh S | title = Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex | journal = Science | volume = 289 | issue = 5484 | pages = 1550–4 |date=September 2000 | pmid = 10968790 | doi = 10.1126/science.289.5484.1550| bibcode = 2000Sci...289.1550M }}{{cite journal |vauthors=Woronicz JD, Gao X, Cao Z, Rothe M, Goeddel DV | title = IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK | journal = Science | volume = 278 | issue = 5339 | pages = 866–9 |date=October 1997 | pmid = 9346485 | doi = 10.1126/science.278.5339.866 | bibcode = 1997Sci...278..866W }}{{cite journal |vauthors=Yeung KC, Rose DW, Dhillon AS, Yaros D, Gustafsson M, Chatterjee D, McFerran B, Wyche J, Kolch W, Sedivy JM | title = Raf Kinase Inhibitor Protein Interacts with NF-κB-Inducing Kinase and TAK1 and Inhibits NF-κB Activation | journal = Mol. Cell. Biol. | volume = 21 | issue = 21 | pages = 7207–17 |date=November 2001 | pmid = 11585904 | pmc = 99896 | doi = 10.1128/MCB.21.21.7207-7217.2001 }}
• IRAK1,{{cite journal |vauthors=Vig E, Green M, Liu Y, Yu KY, Kwon HJ, Tian J, Goebl MG, Harrington MA | title = SIMPL is a tumor necrosis factor-specific regulator of nuclear factor-kappaB activity | journal = J. Biol. Chem. | volume = 276 | issue = 11 | pages = 7859–66 |date=March 2001 | pmid = 11096118 | doi = 10.1074/jbc.M010399200 | doi-access = free }}{{cite journal |vauthors=Windheim M, Stafford M, Peggie M, Cohen P | title = 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 | journal = Mol. Cell. Biol. | volume = 28 | issue = 5 | pages = 1783–91 |date=March 2008 | pmid = 18180283 | pmc = 2258775 | doi = 10.1128/MCB.02380-06 }}
• MAP3K14,{{cite journal |vauthors=Régnier CH, Song HY, Gao X, Goeddel DV, Cao Z, Rothe M | title = Identification and characterization of an IkappaB kinase | journal = Cell | volume = 90 | issue = 2 | pages = 373–83 |date=July 1997 | pmid = 9244310 | doi = 10.1016/S0092-8674(00)80344-X | s2cid = 16217708 | doi-access = free }}{{cite journal |vauthors=Xiao G, Sun SC | title = Negative regulation of the nuclear factor kappa B-inducing kinase by a cis-acting domain | journal = J. Biol. Chem. | volume = 275 | issue = 28 | pages = 21081–5 |date=July 2000 | pmid = 10887201 | doi = 10.1074/jbc.M002552200 | doi-access = free }}{{cite journal |vauthors=Luftig MA, Cahir-McFarland E, Mosialos G, Kieff E | title = Effects of the NIK aly mutation on NF-kappaB activation by the Epstein-Barr virus latent infection membrane protein, lymphotoxin beta receptor, and CD40 | journal = J. Biol. Chem. | volume = 276 | issue = 18 | pages = 14602–6 |date=May 2001 | pmid = 11278268 | doi = 10.1074/jbc.C100103200 | doi-access = free }}{{cite journal |vauthors=Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K | title = The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway | journal = Nature | volume = 398 | issue = 6724 | pages = 252–6 |date=March 1999 | pmid = 10094049 | doi = 10.1038/18465 | bibcode = 1999Natur.398..252N | s2cid = 4421236 }}
• MAP3K7,{{cite journal |vauthors=Sakurai H, Miyoshi H, Toriumi W, Sugita T | title = Functional interactions of transforming growth factor beta-activated kinase 1 with IkappaB kinases to stimulate NF-kappaB activation | journal = J. Biol. Chem. | volume = 274 | issue = 15 | pages = 10641–8 |date=April 1999 | pmid = 10187861 | doi = 10.1074/jbc.274.15.10641| doi-access = free }}
• MAP3K8,{{cite journal |vauthors=Lin X, Cunningham ET, Mu Y, Geleziunas R, Greene WC | title = The proto-oncogene Cot kinase participates in CD3/CD28 induction of NF-kappaB acting through the NF-kappaB-inducing kinase and IkappaB kinases | journal = Immunity | volume = 10 | issue = 2 | pages = 271–80 |date=February 1999 | pmid = 10072079 | doi = 10.1016/S1074-7613(00)80027-8| doi-access = free }}
• NFKBIA,{{cite journal |vauthors=DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M | title = A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB | journal = Nature | volume = 388 | issue = 6642 | pages = 548–54 |date=August 1997 | pmid = 9252186 | doi = 10.1038/41493 | bibcode = 1997Natur.388..548D | s2cid = 4354442 | doi-access = free }}{{cite journal |vauthors=Cohen L, Henzel WJ, Baeuerle PA | title = IKAP is a scaffold protein of the IkappaB kinase complex | journal = Nature | volume = 395 | issue = 6699 | pages = 292–6 |date=September 1998 | pmid = 9751059 | doi = 10.1038/26254 | bibcode = 1998Natur.395..292C | s2cid = 4327300 }}
• NCOA3,{{cite journal |vauthors=Wu RC, Qin J, Hashimoto Y, Wong J, Xu J, Tsai SY, Tsai MJ, O'Malley BW |author7-link=Ming-Jer Tsai | title = Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator Activity by IκB Kinase | journal = Mol. Cell. Biol. | volume = 22 | issue = 10 | pages = 3549–61 |date=May 2002 | pmid = 11971985 | pmc = 133790 | doi = 10.1128/MCB.22.10.3549-3561.2002 }}
• PPM1B,{{cite journal |vauthors=Prajapati S, Verma U, Yamamoto Y, Kwak YT, Gaynor RB | title = Protein phosphatase 2Cbeta association with the IkappaB kinase complex is involved in regulating NF-kappaB activity | journal = J. Biol. Chem. | volume = 279 | issue = 3 | pages = 1739–46 |date=January 2004 | pmid = 14585847 | doi = 10.1074/jbc.M306273200 | doi-access = free }}
• PRKDC,{{cite journal |vauthors=Liu L, Kwak YT, Bex F, García-Martínez LF, Li XH, Meek K, Lane WS, Gaynor RB | title = DNA-Dependent Protein Kinase Phosphorylation of IκBα and IκBβ Regulates NF-κB DNA Binding Properties | journal = Mol. Cell. Biol. | volume = 18 | issue = 7 | pages = 4221–34 |date=July 1998 | pmid = 9632806 | pmc = 109006 | doi = 10.1128/MCB.18.7.4221}} and
• TRAF2.{{cite journal |author1=Devin A |author2=Lin Y |author3=Yamaoka S |author4=Li Z |author5=Karin M |author6=Liu Zg | title = 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 | journal = Mol. Cell. Biol. | volume = 21 | issue = 12 | pages = 3986–94 |date=June 2001 | pmid = 11359906 | pmc = 87061 | doi = 10.1128/MCB.21.12.3986-3994.2001 }}{{cite journal |vauthors=Li S, Wang L, Dorf ME | title = PKC phosphorylation of TRAF2 mediates IKKα/β recruitment and K63-linked polyubiquitination | journal = Mol. Cell | volume = 33 | issue = 1 | pages = 30–42 |date=January 2009 | pmid = 19150425 | pmc = 2643372 | doi = 10.1016/j.molcel.2008.11.023 }}

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{{Reflist|2}}

{{Serine/threonine-specific protein kinases}}

{{Enzymes}}

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• {{UCSC gene info|CHUK}}

Category:EC 2.7.11