IKK alpha

Summary

Gene Symbol: IKK alpha
Description: conserved helix-loop-helix ubiquitous kinase
Alias: IKBKA, IKK-alpha, IKK1, IKKA, NFKBIKA, TCF16, inhibitor of nuclear factor kappa-B kinase subunit alpha, I-kappa-B kinase 1, I-kappa-B kinase-alpha, IKK-a kinase, IkB kinase alpha subunit, Nuclear factor NFkappaB inhibitor kinase alpha, TCF-16, transcription factor 16
Species: human
Products:     IKK alpha

Top Publications

  1. Liu B, Park E, Zhu F, Bustos T, Liu J, Shen J, et al. A critical role for I kappaB kinase alpha in the development of human and mouse squamous cell carcinomas. Proc Natl Acad Sci U S A. 2006;103:17202-7 pubmed
    ..Thus, overexpression of IKKalpha in the epidermis antagonized chemical carcinogen-induced mitogenic and angiogenic activities, repressing tumor progression and metastases. ..
  2. Wu Z, Shi Y, Tibbetts R, Miyamoto S. Molecular linkage between the kinase ATM and NF-kappaB signaling in response to genotoxic stimuli. Science. 2006;311:1141-6 pubmed
    ..Thus, regulated nuclear shuttling of NEMO links two signaling kinases, ATM and IKK, to activate NF-kappaB by genotoxic signals. ..
  3. DiDonato J, Hayakawa M, Rothwarf D, Zandi E, Karin M. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature. 1997;388:548-54 pubmed
    ..A component of IKK was molecularly cloned and identified as a serine kinase. IKK turns out to be the long-sought-after protein kinase that mediates the critical regulatory step in NF-kappaB activation. ..
  4. Sakurai H, Suzuki S, Kawasaki N, Nakano H, Okazaki T, Chino A, et al. Tumor necrosis factor-alpha-induced IKK phosphorylation of NF-kappaB p65 on serine 536 is mediated through the TRAF2, TRAF5, and TAK1 signaling pathway. J Biol Chem. 2003;278:36916-23 pubmed
  5. Lee F, Peters R, Dang L, Maniatis T. MEKK1 activates both IkappaB kinase alpha and IkappaB kinase beta. Proc Natl Acad Sci U S A. 1998;95:9319-24 pubmed
    ..We conclude that IKK-alpha and IKK-beta can mediate the NF-kappaB-inducing activity of MEKK1. ..
  6. Tu Z, Prajapati S, Park K, Kelly N, Yamamoto Y, Gaynor R. IKK alpha regulates estrogen-induced cell cycle progression by modulating E2F1 expression. J Biol Chem. 2006;281:6699-706 pubmed
    ..Taken together, these data suggest a novel mechanism by which IKKalpha can influence estrogen-mediated cell cycle progression through its regulation of E2F1. ..
  7. Zandi E, Rothwarf D, Delhase M, Hayakawa M, Karin M. The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell. 1997;91:243-52 pubmed
    ..While the interactions between IKKalpha and IKKbeta may be mediated through their leucine zipper motifs, their helix-loop-helix motifs may be involved in interactions with essential regulatory subunits. ..
  8. Rushe M, Silvian L, Bixler S, Chen L, Cheung A, Bowes S, et al. Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site. Structure. 2008;16:798-808 pubmed publisher
    ..We demonstrate that the NEMO core domain is a dimer that binds two IKK fragments and identify energetic hot spots that can be exploited to inhibit IKK complex formation with a therapeutic agent. ..
  9. Ninomiya Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K. The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature. 1999;398:252-6 pubmed
    ..Activated TAK1 phosphorylates NIK, which stimulates IKK-alpha activity. Our results indicate that TAK1 links TRAF6 to the NIK-IKK cascade in the IL-1 signalling pathway. ..

More Information

Publications82

  1. Chen R, Ryzhakov G, Cooray S, Randow F, Smith G. Inhibition of IkappaB kinase by vaccinia virus virulence factor B14. PLoS Pathog. 2008;4:e22 pubmed publisher
    ..This suggested that phosphorylation of these serine residues in the activation loop of IKKbeta is targeted by B14, and this was confirmed using Ab specific for phospho-IKKbeta. ..
  2. Chihara T, Hashimoto M, Osman A, Hiyoshi Yoshidomi Y, Suzu I, Chutiwitoonchai N, et al. HIV-1 proteins preferentially activate anti-inflammatory M2-type macrophages. J Immunol. 2012;188:3620-7 pubmed publisher
  3. Ninomiya Tsuji J, Kajino T, Ono K, Ohtomo T, Matsumoto M, Shiina M, et al. A resorcylic acid lactone, 5Z-7-oxozeaenol, prevents inflammation by inhibiting the catalytic activity of TAK1 MAPK kinase kinase. J Biol Chem. 2003;278:18485-90 pubmed
    ..Furthermore, in vivo 5Z-7-oxozeaenol was able to inhibit picryl chloride-induced ear swelling. Thus, 5Z-7-oxozeaenol blocks proinflammatory signaling by selectively inhibiting TAK1 MAPKKK. ..
  4. Zhou H, Wertz I, O Rourke K, Ultsch M, Seshagiri S, Eby M, et al. Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO. Nature. 2004;427:167-71 pubmed
    ..Thus, the adaptor protein Bcl10 promotes activation of NF-kappaB transcription factors through paracaspase- and UBC13-dependent ubiquitination of NEMO. ..
  5. Arch R, Gedrich R, Thompson C. Tumor necrosis factor receptor-associated factors (TRAFs)--a family of adapter proteins that regulates life and death. Genes Dev. 1998;12:2821-30 pubmed
  6. Hoberg J, Yeung F, Mayo M. SMRT derepression by the IkappaB kinase alpha: a prerequisite to NF-kappaB transcription and survival. Mol Cell. 2004;16:245-55 pubmed
    ..Our work provides evidence that IKKalpha orchestrates SMRT derepression, a prerequisite for NF-kappaB transcription and survival. ..
  7. Mangino G, Percario Z, Fiorucci G, Vaccari G, Manrique S, Romeo G, et al. In vitro treatment of human monocytes/macrophages with myristoylated recombinant Nef of human immunodeficiency virus type 1 leads to the activation of mitogen-activated protein kinases, IkappaB kinases, and interferon regulatory factor 3 and to the r. J Virol. 2007;81:2777-91 pubmed
    ..In addition, we have observed the activation of interferon regulatory factor 3, leading to the synthesis of beta interferon mRNA and protein, which in turn induces STAT2 phosphorylation. All of these effects require Nef myristoylation. ..
  8. Haas T, Emmerich C, Gerlach B, Schmukle A, Cordier S, Rieser E, et al. Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol Cell. 2009;36:831-44 pubmed publisher
    ..Finally, we demonstrate that sustained stability of the TNF-RSC requires LUBAC's enzymatic activity, thereby adding a third form of ubiquitin linkage to the triggering of TNF signaling by the TNF-RSC. ..
  9. Yamamoto Y, Verma U, Prajapati S, Kwak Y, Gaynor R. Histone H3 phosphorylation by IKK-alpha is critical for cytokine-induced gene expression. Nature. 2003;423:655-9 pubmed
    ..These results define a new nuclear role of IKK-alpha in modifying histone function that is critical for the activation of NF-kappaB-directed gene expression. ..
  10. Gloire G, Horion J, El Mjiyad N, Bex F, Chariot A, Dejardin E, et al. Promoter-dependent effect of IKKalpha on NF-kappaB/p65 DNA binding. J Biol Chem. 2007;282:21308-18 pubmed
    ..We conclude that nuclear IKKalpha is required for p65 DNA binding in a gene-specific manner. ..
  11. Fiorentino L, Stehlik C, Oliveira V, Ariza M, Godzik A, Reed J. A novel PAAD-containing protein that modulates NF-kappa B induction by cytokines tumor necrosis factor-alpha and interleukin-1beta. J Biol Chem. 2002;277:35333-40 pubmed
    ..These observations suggest a role for PAN2 in modulating NF-kappaB activity in cells, thus providing the insights into the potential functions of PAAD family proteins and their roles in controlling inflammatory responses. ..
  12. Criollo A, Senovilla L, Authier H, Maiuri M, Morselli E, Vitale I, et al. The IKK complex contributes to the induction of autophagy. EMBO J. 2010;29:619-31 pubmed publisher
    ..Altogether, these results indicate that IKK has a cardinal role in the stimulation of autophagy by physiological and pharmacological stimuli. ..
  13. Ear T, Fortin C, Simard F, McDonald P. Constitutive association of TGF-beta-activated kinase 1 with the IkappaB kinase complex in the nucleus and cytoplasm of human neutrophils and its impact on downstream processes. J Immunol. 2010;184:3897-906 pubmed publisher
  14. Maeda G, Chiba T, Kawashiri S, Satoh T, Imai K. Epigenetic inactivation of IkappaB Kinase-alpha in oral carcinomas and tumor progression. Clin Cancer Res. 2007;13:5041-7 pubmed
  15. Hehner S, Hofmann T, Ushmorov A, Dienz O, Wing Lan Leung I, Lassam N, et al. Mixed-lineage kinase 3 delivers CD3/CD28-derived signals into the IkappaB kinase complex. Mol Cell Biol. 2000;20:2556-68 pubmed
    ..A dominant negative version of MLK3 inhibited NF-kappaB- and CD28RE/AP-dependent transcription elicited by the Rho family GTPases Rac and Cdc42, thereby providing a novel link between these GTPases and the IKC. ..
  16. Song L, Peng Y, Yun J, Rizzo P, Chaturvedi V, Weijzen S, et al. Notch-1 associates with IKKalpha and regulates IKK activity in cervical cancer cells. Oncogene. 2008;27:5833-44 pubmed publisher
    ..Our data indicate that Notch-1 regulates NF-kappaB in cervical cancer cells at least in part via cytoplasmic and nuclear IKK-mediated pathways. ..
  17. Ducut Sigala J, Bottero V, Young D, Shevchenko A, Mercurio F, Verma I. Activation of transcription factor NF-kappaB requires ELKS, an IkappaB kinase regulatory subunit. Science. 2004;304:1963-7 pubmed
    ..These cells were also not protected from apoptosis in response to cytokines. ELKS likely functions by recruiting IkappaBalpha to the IKK complex and thus serves a regulatory function for IKK activation. ..
  18. Liu M, Lee D, Chen C, Yen C, Li L, Lee H, et al. IKK? activation of NOTCH links tumorigenesis via FOXA2 suppression. Mol Cell. 2012;45:171-84 pubmed publisher
    ..Here, we report a TNF?/IKK?/FOXA2/NUMB/NOTCH1 pathway that is critical for inflammation-mediated tumorigenesis and may provide a target for clinical intervention in human cancer. ..
  19. Khoshnan A, Ko J, Tescu S, Brundin P, Patterson P. IKKalpha and IKKbeta regulation of DNA damage-induced cleavage of huntingtin. PLoS ONE. 2009;4:e5768 pubmed publisher
    ..Moreover, IKKbeta-dependent reduction of Bcl-xL is important in this process. Thus, inhibition of IKKbeta may promote neuronal survival in HD as well as other DNA damage-induced neurodegenerative disorders. ..
  20. Xiao G, Fong A, Sun S. Induction of p100 processing by NF-kappaB-inducing kinase involves docking IkappaB kinase alpha (IKKalpha) to p100 and IKKalpha-mediated phosphorylation. J Biol Chem. 2004;279:30099-105 pubmed
    ..These data also provide the first evidence for explaining why overexpression of IKKalpha or its activation by many other stimuli such as tumor necrosis factor and mitogens fails to induce p100 processing. ..
  21. Bashan N, Dorfman K, Tarnovscki T, Harman Boehm I, Liberty I, Bluher M, et al. Mitogen-activated protein kinases, inhibitory-kappaB kinase, and insulin signaling in human omental versus subcutaneous adipose tissue in obesity. Endocrinology. 2007;148:2955-62 pubmed
    ..Increased expression of stress-activated kinases and IKK and their phosphorylated forms in omental fat occurs in obesity, potentially contributing to differential roles of omental and sc fat in the pathophysiology of obesity. ..
  22. Ling L, Cao Z, Goeddel D. NF-kappaB-inducing kinase activates IKK-alpha by phosphorylation of Ser-176. Proc Natl Acad Sci U S A. 1998;95:3792-7 pubmed
    ..Conversely, a mutant form of IKK-alpha containing glutamic acid at residue 176 is constitutively active. Thus, the phosphorylation of IKK-alpha on Ser-176 by NIK may be required for cytokine-mediated NF-kappaB activation. ..
  23. Ear T, Cloutier A, McDonald P. Constitutive nuclear expression of the I kappa B kinase complex and its activation in human neutrophils. J Immunol. 2005;175:1834-42 pubmed
    ..More importantly, our findings unveil a hitherto unsuspected mode of activation for the IKK/IkappaB signaling cascade within the cell nucleus. ..
  24. Krappmann D, Wegener E, Sunami Y, Esen M, Thiel A, Mordmuller B, et al. The IkappaB kinase complex and NF-kappaB act as master regulators of lipopolysaccharide-induced gene expression and control subordinate activation of AP-1. Mol Cell Biol. 2004;24:6488-500 pubmed
    ..Thus, our data illustrate that NF-kappaB orchestrates immediate-early effects of LPS signaling and controls secondary AP-1 activation to mount an appropriate biological response. ..
  25. Verma U, Yamamoto Y, Prajapati S, Gaynor R. Nuclear role of I kappa B Kinase-gamma/NF-kappa B essential modulator (IKK gamma/NEMO) in NF-kappa B-dependent gene expression. J Biol Chem. 2004;279:3509-15 pubmed
    The I kappa B kinase (IKK) complex, which is composed of the two kinases IKK alpha and IKK beta and the regulatory subunit IKK gamma/nuclear factor-kappa B (NF-kappa B) essential modulator (NEMO), is important in the cytokine-induced ..
  26. Romashkova J, Makarov S. NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature. 1999;401:86-90 pubmed
    ..These findings establish a role for NF-kappaB in growth factor signalling and define an anti-apoptotic Ras/PI(3)K/Akt/IKK/NF-kappaB pathway, thus linking anti-apoptotic signalling with transcription machinery. ..
  27. Wu R, Qin J, Hashimoto Y, Wong J, Xu J, Tsai S, et al. Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator activity by I kappa B kinase. Mol Cell Biol. 2002;22:3549-61 pubmed
    ..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. ..
  28. Jiang R, Xia Y, Li J, Deng L, Zhao L, Shi J, et al. High expression levels of IKKalpha and IKKbeta are necessary for the malignant properties of liver cancer. Int J Cancer. 2010;126:1263-74 pubmed publisher
    ..We anticipate that IKK-targeted gene therapy can be used in the treatment of HCC, a cancer that is notoriously resistant to radiation and chemotherapy. ..
  29. Brandl M, Seidler B, Haller F, Adamski J, Schmid R, Saur D, et al. IKK(?) controls canonical TGF(ß)-SMAD signaling to regulate genes expressing SNAIL and SLUG during EMT in panc1 cells. J Cell Sci. 2010;123:4231-9 pubmed publisher
    ..Taken together, these findings indicate that IKK? contributes to the tumor-promoting function of the TGF?-SMAD signaling pathway in particular cancers. ..
  30. Olivotto E, Borzi R, Vitellozzi R, Pagani S, Facchini A, Battistelli M, et al. Differential requirements for IKKalpha and IKKbeta in the differentiation of primary human osteoarthritic chondrocytes. Arthritis Rheum. 2008;58:227-39 pubmed publisher
  31. Jung Y, Kim H, Min S, Rhee S, Jeong W. Dynein light chain LC8 negatively regulates NF-kappaB through the redox-dependent interaction with IkappaBalpha. J Biol Chem. 2008;283:23863-71 pubmed publisher
    ..Together, our results indicate that LC8 binds IkappaBalpha in a redox-dependent manner and thereby prevents its phosphorylation by IKK. TRP14 contributes to this inhibitory activity by maintaining LC8 in a reduced state. ..
  32. Yang S, Yao H, Rajendrasozhan S, Chung S, Edirisinghe I, Valvo S, et al. RelB is differentially regulated by IkappaB Kinase-alpha in B cells and mouse lung by cigarette smoke. Am J Respir Cell Mol Biol. 2009;40:147-58 pubmed publisher
    ..Rapid degradation of RelB signals for RelA/p65 activation and loss of its protective ability to suppress the proinflammatory cytokine release in lymphoid B cells. ..
  33. Li Q, Engelhardt J. Interleukin-1beta induction of NFkappaB is partially regulated by H2O2-mediated activation of NFkappaB-inducing kinase. J Biol Chem. 2006;281:1495-505 pubmed
    ..In summary, our studies have demonstrated that redox regulation of NIK by H2O2 is mechanistically important in IL-1beta induction of NFkappaB activation. ..
  34. Zhu F, Xia X, Liu B, Shen J, Hu Y, Person M, et al. IKKalpha shields 14-3-3sigma, a G(2)/M cell cycle checkpoint gene, from hypermethylation, preventing its silencing. Mol Cell. 2007;27:214-27 pubmed
    ..Thus, IKKalpha protects the 14-3-3sigma locus from hypermethylation, which serves as a mechanism of maintaining genomic stability in keratinocytes. ..
  35. Descargues P, Sil A, Karin M. IKKalpha, a critical regulator of epidermal differentiation and a suppressor of skin cancer. EMBO J. 2008;27:2639-47 pubmed publisher
    ..Although these are not the only functions of nuclear IKKalpha, this multifunctional protein is a key regulator of keratinocyte and epidermal differentiation and a critical suppressor of skin cancer. ..
  36. Sanjo H, Zajonc D, Braden R, Norris P, Ware C. Allosteric regulation of the ubiquitin:NIK and ubiquitin:TRAF3 E3 ligases by the lymphotoxin-beta receptor. J Biol Chem. 2010;285:17148-55 pubmed publisher
    ..These results indicate the LTbetaR modifies the ubiquitin:NIK E3 ligase, and also acts as an allosteric regulator of the ubiquitin:TRAF E3 ligase. ..
  37. Liu L, Eby M, Rathore N, Sinha S, Kumar A, Chaudhary P. The human herpes virus 8-encoded viral FLICE inhibitory protein physically associates with and persistently activates the Ikappa B kinase complex. J Biol Chem. 2002;277:13745-51 pubmed
    ..Our results suggest that HHV8 vFLIP might contribute to the persistent NF-kappaB activation observed in PEL cells by associating with and stimulating the activity of the cellular IKK complex. ..
  38. Moreno Maldonado R, Ramirez A, Navarro M, Fernández Aceñero M, Villanueva C, Page A, et al. IKKalpha enhances human keratinocyte differentiation and determines the histological variant of epidermal squamous cell carcinomas. Cell Cycle. 2008;7:2021-9 pubmed
    ..The tight correlation between the properties of both murine and human ASCC variants strongly suggests that IKKalpha is responsible for the development of this human SCC variant. ..
  39. Temmerman S, Ma C, Zhao Y, Keenan J, Aksentijevich I, Fessler M, et al. Defective nuclear IKK? function in patients with ectodermal dysplasia with immune deficiency. J Clin Invest. 2012;122:315-26 pubmed publisher
    ..Our findings suggest that NEMO regulates the nuclear function of IKK? and offer new insights into the mechanisms underlying diminished NF-?B signaling in patients with EDI. ..
  40. Descargues P, Sil A, Sano Y, Korchynskyi O, Han G, Owens P, et al. IKKalpha is a critical coregulator of a Smad4-independent TGFbeta-Smad2/3 signaling pathway that controls keratinocyte differentiation. Proc Natl Acad Sci U S A. 2008;105:2487-92 pubmed publisher
    ..We suggest that a TGFbeta-Smad2/3-IKKalpha axis is a critical Smad4-independent regulator of keratinocyte proliferation and differentiation. ..
  41. Cohen L, Henzel W, Baeuerle P. IKAP is a scaffold protein of the IkappaB kinase complex. Nature. 1998;395:292-6 pubmed
    ..We show that IKAP is a scaffold protein and a regulator for three different kinases involved in pro-inflammatory cytokine signalling. ..
  42. Wu L, Nakano H, Wu Z. The C-terminal activating region 2 of the Epstein-Barr virus-encoded latent membrane protein 1 activates NF-kappaB through TRAF6 and TAK1. J Biol Chem. 2006;281:2162-9 pubmed
    ..Thus, LMP1 utilizes two distinct pathways to activate NF-kappaB: a major one through CTAR2/TRAF6/TAK1/IKKbeta (canonical pathway) and a minor one through CTAR1/TRAF3/NIK/IKKalpha (noncanonical pathway). ..
  43. Park K, Krishnan V, O Malley B, Yamamoto Y, Gaynor R. Formation of an IKKalpha-dependent transcription complex is required for estrogen receptor-mediated gene activation. Mol Cell. 2005;18:71-82 pubmed
    ..These results suggest that IKKalpha plays a major role in regulating the biological effects of estrogen via its promoter association and modification of components of the transcription complex. ..
  44. Li T, Morgan M, Choksi S, Zhang Y, Kim Y, Liu Z. MicroRNAs modulate the noncanonical transcription factor NF-kappaB pathway by regulating expression of the kinase IKKalpha during macrophage differentiation. Nat Immunol. 2010;11:799-805 pubmed publisher
    ..Thus, a decrease in certain microRNAs probably prevents macrophage hyperactivation yet primes the macrophage for certain responses to proinflammatory stimuli. ..
  45. Wu X, Sun S. Retroviral oncoprotein Tax deregulates NF-kappaB by activating Tak1 and mediating the physical association of Tak1-IKK. EMBO Rep. 2007;8:510-5 pubmed
    ..These findings show a pathological mechanism of IKK activation by Tax and provide an example for how IKK is persistently activated in cancer cells. ..
  46. Prajapati S, Tu Z, Yamamoto Y, Gaynor R. IKKalpha regulates the mitotic phase of the cell cycle by modulating Aurora A phosphorylation. Cell Cycle. 2006;5:2371-80 pubmed
    ..Taken together, these data provide the evidence that IKKalpha regulates the M phase of the cell cycle by modulating Aurora A phosphorylation and activation leading to the regulation of the M phase of the cell cycle. ..
  47. Lam L, Davis R, Ngo V, Lenz G, Wright G, Xu W, et al. Compensatory IKKalpha activation of classical NF-kappaB signaling during IKKbeta inhibition identified by an RNA interference sensitization screen. Proc Natl Acad Sci U S A. 2008;105:20798-803 pubmed publisher
    ..These results suggest that therapy for ABC DLBCL may be improved by targeting both IKKalpha and IKKbeta, possibly through CARD11 inhibition. ..
  48. Hacker H, Karin M. Regulation and function of IKK and IKK-related kinases. Sci STKE. 2006;2006:re13 pubmed
    ..Together, the IKKs and IKK-related kinases are instrumental for activation of the host defense system. This Review focuses on the functions of IKK and IKK-related kinases and the molecular mechanisms that regulate their activities. ..
  49. Rothwarf D, Zandi E, Natoli G, Karin M. IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature. 1998;395:297-300 pubmed
    ..IKK-gamma interacts preferentially with IKK-beta and is required for the activation of the IKK complex. An IKK-gamma carboxy-terminal truncation mutant that still binds IKK-beta blocks the activation of IKK and NF-kappaB. ..
  50. Razani B, Zarnegar B, Ytterberg A, Shiba T, Dempsey P, Ware C, et al. Negative feedback in noncanonical NF-kappaB signaling modulates NIK stability through IKKalpha-mediated phosphorylation. Sci Signal. 2010;3:ra41 pubmed publisher
  51. Lallena M, Diaz Meco M, Bren G, Paya C, Moscat J. Activation of IkappaB kinase beta by protein kinase C isoforms. Mol Cell Biol. 1999;19:2180-8 pubmed
    ..Collectively, these results demonstrate a critical role for the PKC isoforms in the NF-kappaB pathway at the level of IKKbeta activation and IkappaB degradation. ..
  52. Mercurio F, Zhu H, Murray B, Shevchenko A, Bennett B, Li J, et al. IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science. 1997;278:860-6 pubmed
    ..Mutant versions of IKK-2 had pronounced effects on RelA nuclear translocation and NF-kappaB-dependent reporter activity, consistent with a critical role for the IKK kinases in the NF-kappaB signaling pathway. ..
  53. Dan H, Cooper M, Cogswell P, Duncan J, Ting J, Baldwin A. Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK. Genes Dev. 2008;22:1490-500 pubmed publisher
    ..The results provide insight into the effects of Akt/mTOR-dependent signaling on gene expression and into the therapeutic action of rapamycin. ..
  54. Prajapati S, Verma U, Yamamoto Y, Kwak Y, Gaynor R. Protein phosphatase 2Cbeta association with the IkappaB kinase complex is involved in regulating NF-kappaB activity. J Biol Chem. 2004;279:1739-46 pubmed
    ..These studies are consistent with the ability of PP2Cbeta to down-regulate cytokine-induced NF-kappaB activation by altering IKK activity. ..
  55. Solt L, May M. The IkappaB kinase complex: master regulator of NF-kappaB signaling. Immunol Res. 2008;42:3-18 pubmed publisher
  56. Zandi E, Chen Y, Karin M. Direct phosphorylation of IkappaB by IKKalpha and IKKbeta: discrimination between free and NF-kappaB-bound substrate. Science. 1998;281:1360-3 pubmed
    ..This result explains how free IkappaB can accumulate in cells in which IKK is still active and thus can contribute to the termination of NF-kappaB activation. ..
  57. Regnier C, Song H, Gao X, Goeddel D, Cao Z, Rothe M. Identification and characterization of an IkappaB kinase. Cell. 1997;90:373-83 pubmed
    ..This phosphorylation of IkappaB-alpha is greatly enhanced by NIK costimulation. Thus, CHUK is a NIK-activated IkappaB-alpha kinase that links TNF- and IL-1-induced kinase cascades to NF-kappaB activation. ..
  58. Furuya K, Ozaki T, Hanamoto T, Hosoda M, Hayashi S, Barker P, et al. Stabilization of p73 by nuclear IkappaB kinase-alpha mediates cisplatin-induced apoptosis. J Biol Chem. 2007;282:18365-78 pubmed
  59. Yamamoto Y, Yin M, Gaynor R. IkappaB kinase alpha (IKKalpha) regulation of IKKbeta kinase activity. Mol Cell Biol. 2000;20:3655-66 pubmed
    ..These results indicate that IKKalpha, in addition to its previously described ability to phosphorylate IkappaBalpha, can increase the ability of IKKbeta to phosphorylate IkappaBalpha. ..
  60. Hu M, Lee D, Xia W, Golfman L, Ou Yang F, Yang J, et al. IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell. 2004;117:225-37 pubmed
    ..These results suggest the negative regulation of FOXO factors by IKK as a key mechanism for promoting cell growth and tumorigenesis. ..
  61. Lamberti C, Lin K, Yamamoto Y, Verma U, Verma I, Byers S, et al. Regulation of beta-catenin function by the IkappaB kinases. J Biol Chem. 2001;276:42276-86 pubmed
  62. Yamaguchi T, Kimura J, Miki Y, Yoshida K. The deubiquitinating enzyme USP11 controls an IkappaB kinase alpha (IKKalpha)-p53 signaling pathway in response to tumor necrosis factor alpha (TNFalpha). J Biol Chem. 2007;282:33943-8 pubmed
    ..Importantly, the ectopic expression of IKKalpha into cells silenced for USP11 restores p53 expression, demonstrating that USP11 functions as an upstream regulator of an IKKalpha-p53 signaling pathway. ..
  63. Agou F, Ye F, Goffinont S, Courtois G, Yamaoka S, Israel A, et al. NEMO trimerizes through its coiled-coil C-terminal domain. J Biol Chem. 2002;277:17464-75 pubmed
    ..We propose a model in which the activation of the IKK complex occurs through the trimerization of NEMO upon binding to a not yet identified upstream activator. ..
  64. Khan K, Abbas W, Varin A, Kumar A, Di Martino V, Dichamp I, et al. HIV-1 Nef interacts with HCV Core, recruits TRAF2, TRAF5 and TRAF6, and stimulates HIV-1 replication in macrophages. J Innate Immun. 2013;5:639-56 pubmed publisher
  65. Liu B, Yang Y, Chernishof V, Loo R, Jang H, Tahk S, et al. Proinflammatory stimuli induce IKKalpha-mediated phosphorylation of PIAS1 to restrict inflammation and immunity. Cell. 2007;129:903-14 pubmed
    ..Our results identify a signaling pathway in which proinflammatory stimuli activate the IKKalpha-mediated sumoylation-dependent phosphorylation of PIAS1 for the immediate repression of inflammatory gene activation. ..
  66. Huang W, Ju T, Hung M, Chen C. Phosphorylation of CBP by IKKalpha promotes cell growth by switching the binding preference of CBP from p53 to NF-kappaB. Mol Cell. 2007;26:75-87 pubmed
    ..Our results suggest that phosphorylation of CBP by IKKalpha regulates the CBP-mediated crosstalk between NF-kappaB and p53 and thus may be a critical factor in the promotion of cell proliferation and tumor growth. ..
  67. Delhase M, Hayakawa M, Chen Y, Karin M. Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation. Science. 1999;284:309-13 pubmed
    ..Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. ..
  68. Woronicz J, Gao X, Cao Z, Rothe M, Goeddel D. IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science. 1997;278:866-9 pubmed
    ..Overexpression of a catalytically inactive form of IKK-beta blocked cytokine-induced NF-kappaB activation. Thus, an active IkappaB kinase complex may require three distinct protein kinases. ..
  69. Hoberg J, Popko A, Ramsey C, Mayo M. IkappaB kinase alpha-mediated derepression of SMRT potentiates acetylation of RelA/p65 by p300. Mol Cell Biol. 2006;26:457-71 pubmed
  70. Tegethoff S, Behlke J, Scheidereit C. Tetrameric oligomerization of IkappaB kinase gamma (IKKgamma) is obligatory for IKK complex activity and NF-kappaB activation. Mol Cell Biol. 2003;23:2029-41 pubmed
    ..These data thus suggest that IKKgamma tetramerization enforces a spatial positioning of two kinase dimers to facilitate transautophosphorylation and activation. ..
  71. Chen G, Cao P, Goeddel D. TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90. Mol Cell. 2002;9:401-10 pubmed
    ..Therefore, heterocomplex formation with Cdc37/Hsp90 is a prerequisite for TNF-induced activation and trafficking of IKK from the cytoplasm to the membrane. ..
  72. May M, D Acquisto F, Madge L, Glockner J, Pober J, Ghosh S. Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex. Science. 2000;289:1550-4 pubmed
    ..The NBD provides a target for the development of drugs that would block proinflammatory activation of the IKK complex without inhibiting basal NF-kappaB activity. ..
  73. Ozes O, Mayo L, Gustin J, Pfeffer S, Pfeffer L, Donner D. NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature. 1999;401:82-5 pubmed
    ..Mutation of this amino acid blocks phosphorylation by Akt or TNF and activation of NF-kappaB. These findings indicate that Akt is part of a signalling pathway that is necessary for inducing key immune and inflammatory responses. ..