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O15111

- IKKA_HUMAN

UniProt

O15111 - IKKA_HUMAN

Protein

Inhibitor of nuclear factor kappa-B kinase subunit alpha

Gene

CHUK

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 163 (01 Oct 2014)
      Sequence version 2 (11 Jan 2011)
      Previous versions | rss
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    Functioni

    Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Negatively regulates the pathway by phosphorylating the scaffold protein TAXBP1 and thus promoting the assembly of the A20/TNFAIP3 ubiquitin-editing complex (composed of A20/TNFAIP3, TAX1BP1, and the E3 ligases ITCH and RNF11). Therefore, CHUK plays a key role in the negative feedback of NF-kappa-B canonical signaling to limit inflammatory gene activation. As part of the non-canonical pathway of NF-kappa-B activation, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes. In turn, these complexes regulate genes encoding molecules involved in B-cell survival and lymphoid organogenesis. Participates also in the negative feedback of the non-canonical NF-kappa-B signaling pathway by phosphorylating and destabilizing MAP3K14/NIK. Within the nucleus, phosphorylates CREBBP and consequently increases both its transcriptional and histone acetyltransferase activities. Modulates chromatin accessibility at NF-kappa-B-responsive promoters by phosphorylating histones H3 at 'Ser-10' that are subsequently acetylated at 'Lys-14' by CREBBP. Additionally, phosphorylates the CREBBP-interacting protein NCOA3.5 Publications

    Catalytic activityi

    ATP + [I-kappa-B protein] = ADP + [I-kappa-B phosphoprotein].

    Enzyme regulationi

    Activated when phosphorylated and inactivated when dephosphorylated.

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei44 – 441ATPPROSITE-ProRule annotation
    Active sitei144 – 1441Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi21 – 299ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. IkappaB kinase activity Source: UniProtKB
    3. protein binding Source: UniProtKB
    4. protein heterodimerization activity Source: UniProtKB
    5. protein homodimerization activity Source: UniProtKB
    6. protein kinase activity Source: UniProtKB
    7. scaffold protein binding Source: MGI

    GO - Biological processi

    1. anatomical structure morphogenesis Source: ProtInc
    2. cellular response to tumor necrosis factor Source: UniProtKB
    3. epidermal growth factor receptor signaling pathway Source: Reactome
    4. Fc-epsilon receptor signaling pathway Source: Reactome
    5. fibroblast growth factor receptor signaling pathway Source: Reactome
    6. I-kappaB kinase/NF-kappaB signaling Source: UniProtKB
    7. I-kappaB phosphorylation Source: ProtInc
    8. immune response Source: ProtInc
    9. inflammatory response Source: UniProtKB
    10. innate immune response Source: UniProtKB
    11. lactation Source: Ensembl
    12. mammary gland alveolus development Source: Ensembl
    13. mammary gland epithelial cell proliferation Source: Ensembl
    14. morphogenesis of an epithelial sheet Source: Ensembl
    15. MyD88-dependent toll-like receptor signaling pathway Source: Reactome
    16. MyD88-independent toll-like receptor signaling pathway Source: Reactome
    17. neurotrophin TRK receptor signaling pathway Source: Reactome
    18. nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway Source: Reactome
    19. nucleotide-binding oligomerization domain containing signaling pathway Source: Reactome
    20. odontogenesis of dentin-containing tooth Source: Ensembl
    21. osteoclast differentiation Source: Ensembl
    22. phosphatidylinositol-mediated signaling Source: Reactome
    23. positive regulation of I-kappaB kinase/NF-kappaB signaling Source: Reactome
    24. positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
    25. positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
    26. positive regulation of type I interferon production Source: Reactome
    27. protein phosphorylation Source: UniProtKB
    28. response to amino acid Source: Ensembl
    29. response to drug Source: Ensembl
    30. response to hydroperoxide Source: Ensembl
    31. response to lipopolysaccharide Source: Ensembl
    32. response to toxic substance Source: Ensembl
    33. response to virus Source: UniProtKB
    34. Rho protein signal transduction Source: Ensembl
    35. skeletal muscle contraction Source: Ensembl
    36. striated muscle cell differentiation Source: Ensembl
    37. T cell receptor signaling pathway Source: Reactome
    38. toll-like receptor 10 signaling pathway Source: Reactome
    39. toll-like receptor 2 signaling pathway Source: Reactome
    40. toll-like receptor 3 signaling pathway Source: Reactome
    41. toll-like receptor 4 signaling pathway Source: Reactome
    42. toll-like receptor 5 signaling pathway Source: Reactome
    43. toll-like receptor 9 signaling pathway Source: Reactome
    44. toll-like receptor signaling pathway Source: Reactome
    45. toll-like receptor TLR1:TLR2 signaling pathway Source: Reactome
    46. toll-like receptor TLR6:TLR2 signaling pathway Source: Reactome
    47. TRIF-dependent toll-like receptor signaling pathway Source: Reactome

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    BRENDAi2.7.11.10. 2681.
    ReactomeiREACT_118563. RIP-mediated NFkB activation via ZBP1.
    REACT_118656. Activation of NF-kappaB in B cells.
    REACT_12555. Downstream TCR signaling.
    REACT_12564. AKT phosphorylates targets in the cytosol.
    REACT_147727. Constitutive PI3K/AKT Signaling in Cancer.
    REACT_163994. FCERI mediated NF-kB activation.
    REACT_21281. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
    REACT_22442. Interleukin-1 signaling.
    REACT_24918. IRAK1 recruits IKK complex.
    REACT_24969. TRAF6 mediated NF-kB activation.
    REACT_25039. NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10.
    REACT_25354. IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation.
    REACT_25374. IKK complex recruitment mediated by RIP1.
    REACT_75776. NOD1/2 Signaling Pathway.
    SABIO-RKO15111.
    SignaLinkiO15111.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Inhibitor of nuclear factor kappa-B kinase subunit alpha (EC:2.7.11.10)
    Short name:
    I-kappa-B kinase alpha
    Short name:
    IKK-A
    Short name:
    IKK-alpha
    Short name:
    IkBKA
    Short name:
    IkappaB kinase
    Alternative name(s):
    Conserved helix-loop-helix ubiquitous kinase
    I-kappa-B kinase 1
    Short name:
    IKK1
    Nuclear factor NF-kappa-B inhibitor kinase alpha
    Short name:
    NFKBIKA
    Transcription factor 16
    Short name:
    TCF-16
    Gene namesi
    Name:CHUK
    Synonyms:IKKA, TCF16
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 10

    Organism-specific databases

    HGNCiHGNC:1974. CHUK.

    Subcellular locationi

    Cytoplasm 1 Publication. Nucleus 1 Publication
    Note: Shuttles between the cytoplasm and the nucleus.

    GO - Cellular componenti

    1. CD40 receptor complex Source: BHF-UCL
    2. cytoplasm Source: HPA
    3. cytoplasmic side of plasma membrane Source: BHF-UCL
    4. cytosol Source: Reactome
    5. IkappaB kinase complex Source: UniProtKB
    6. intracellular membrane-bounded organelle Source: HPA
    7. nucleus Source: HPA

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    Pathology & Biotechi

    Involvement in diseasei

    Cocoon syndrome (COCOS) [MIM:613630]: A lethal syndrome characterized by multiple fetal malformations including defective face and seemingly absent limbs, which are bound to the trunk and encased under the skin.1 Publication
    Note: The disease is caused by mutations affecting the gene represented in this entry.

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi23 – 231T → A: Loss of phosphorylation and decrease of kinase activity. 1 Publication
    Mutagenesisi44 – 441K → A: Loss of kinase activity. 2 Publications
    Mutagenesisi44 – 441K → M: Loss of autophosphorylation. 2 Publications
    Mutagenesisi176 – 1761S → A: Loss of phosphorylation and of activity. 2 Publications
    Mutagenesisi176 – 1761S → E: Full activation. 2 Publications
    Mutagenesisi179 – 1791T → A: No change in phosphorylation. 1 Publication
    Mutagenesisi180 – 1801S → A: No change in phosphorylation. 1 Publication

    Organism-specific databases

    MIMi613630. phenotype.
    PharmGKBiPA26510.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 745745Inhibitor of nuclear factor kappa-B kinase subunit alphaPRO_0000086011Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei23 – 231Phosphothreonine; by PKB/AKT1 and SGK12 Publications
    Modified residuei176 – 1761Phosphoserine; by MAP3K141 Publication
    Modified residuei179 – 1791O-acetylthreonine; by Yersinia yopJ1 Publication
    Modified residuei180 – 1801Phosphoserine; by SGK11 Publication

    Post-translational modificationi

    Phosphorylated by MAP3K14/NIK, AKT and to a lesser extent by MEKK1, and dephosphorylated by PP2A. Autophosphorylated.
    Acetylation of Thr-179 by Yersinia yopJ prevents phosphorylation and activation, thus blocking the I-kappa-B signaling pathway.1 Publication

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    MaxQBiO15111.
    PaxDbiO15111.
    PRIDEiO15111.

    PTM databases

    PhosphoSiteiO15111.

    Expressioni

    Tissue specificityi

    Widely expressed.

    Gene expression databases

    BgeeiO15111.
    CleanExiHS_CHUK.
    GenevestigatoriO15111.

    Organism-specific databases

    HPAiCAB004240.
    CAB018564.
    HPA001402.

    Interactioni

    Subunit structurei

    Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-beta/IKBKB dimers are associated with four gamma/IKBKG subunits. The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex. The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65. Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP. Part of a 70-90 kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, IKBKAP and MAP3K14. Directly interacts with IKK-gamma/NEMO and TRPC4AP By similarity. May interact with TRAF2. Interacts with NALP2. May interact with MAVS/IPS1. Interacts with ARRB1 and ARRB2. Interacts with NLRC5; prevents CHUK phosphorylation and kinase activity. Interacts with PIAS1; this interaction induces PIAS1 phosphorylation. Interacts with ZNF268 isoform 2; the interaction is further increased in a TNF-alpha-dependent manner.By similarity8 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    ARRB2P321213EBI-81249,EBI-714559
    CDC37Q165434EBI-81249,EBI-295634
    CDKN1BP465274EBI-81249,EBI-519280
    FKBP5Q134512EBI-81249,EBI-306914
    HSP90AA1P079003EBI-81249,EBI-296047
    IKBKBO1492013EBI-81249,EBI-81266
    IKBKGQ9Y6K919EBI-81249,EBI-81279
    IRF7Q929854EBI-81249,EBI-968267
    MAP3K14Q995586EBI-81249,EBI-358011
    MYCP011063EBI-81249,EBI-447544
    NFKBIAP2596314EBI-81249,EBI-307386
    PQ77M192EBI-81249,EBI-6149376From a different organism.
    RELAQ042062EBI-81249,EBI-73886
    TAX1BP1Q86VP12EBI-81249,EBI-529518
    VACWR196P247723EBI-81249,EBI-4291651From a different organism.

    Protein-protein interaction databases

    BioGridi107569. 118 interactions.
    DIPiDIP-27526N.
    IntActiO15111. 48 interactions.
    MINTiMINT-88648.
    STRINGi9606.ENSP00000359424.

    Structurei

    Secondary structure

    1
    745
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi735 – 7373
    Helixi741 – 7433

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    3BRTX-ray2.25A/C732-745[»]
    ProteinModelPortaliO15111.
    SMRiO15111. Positions 5-659.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiO15111.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini15 – 302288Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni455 – 47622Leucine-zipperAdd
    BLAST
    Regioni738 – 7436NEMO-binding

    Domaini

    The kinase domain is located in the N-terminal region. The leucine zipper is important to allow homo- and hetero-dimerization. At the C-terminal region is located the region responsible for the interaction with NEMO/IKBKG.1 Publication

    Sequence similaritiesi

    Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily.PROSITE-ProRule annotation
    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG0515.
    HOGENOMiHOG000038048.
    HOVERGENiHBG018241.
    InParanoidiO15111.
    KOiK04467.
    OMAiLQLMLNW.
    OrthoDBiEOG7FBRH3.
    PhylomeDBiO15111.
    TreeFamiTF324269.

    Family and domain databases

    InterProiIPR022007. IKKbetaNEMObind.
    IPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view]
    PfamiPF12179. IKKbetaNEMObind. 1 hit.
    PF00069. Pkinase. 1 hit.
    [Graphical view]
    SMARTiSM00220. S_TKc. 1 hit.
    [Graphical view]
    SUPFAMiSSF56112. SSF56112. 1 hit.
    PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    O15111-1 [UniParc]FASTAAdd to Basket

    « Hide

    MERPPGLRPG AGGPWEMRER LGTGGFGNVC LYQHRELDLK IAIKSCRLEL    50
    STKNRERWCH EIQIMKKLNH ANVVKACDVP EELNILIHDV PLLAMEYCSG 100
    GDLRKLLNKP ENCCGLKESQ ILSLLSDIGS GIRYLHENKI IHRDLKPENI 150
    VLQDVGGKII HKIIDLGYAK DVDQGSLCTS FVGTLQYLAP ELFENKPYTA 200
    TVDYWSFGTM VFECIAGYRP FLHHLQPFTW HEKIKKKDPK CIFACEEMSG 250
    EVRFSSHLPQ PNSLCSLVVE PMENWLQLML NWDPQQRGGP VDLTLKQPRC 300
    FVLMDHILNL KIVHILNMTS AKIISFLLPP DESLHSLQSR IERETGINTG 350
    SQELLSETGI SLDPRKPASQ CVLDGVRGCD SYMVYLFDKS KTVYEGPFAS 400
    RSLSDCVNYI VQDSKIQLPI IQLRKVWAEA VHYVSGLKED YSRLFQGQRA 450
    AMLSLLRYNA NLTKMKNTLI SASQQLKAKL EFFHKSIQLD LERYSEQMTY 500
    GISSEKMLKA WKEMEEKAIH YAEVGVIGYL EDQIMSLHAE IMELQKSPYG 550
    RRQGDLMESL EQRAIDLYKQ LKHRPSDHSY SDSTEMVKII VHTVQSQDRV 600
    LKELFGHLSK LLGCKQKIID LLPKVEVALS NIKEADNTVM FMQGKRQKEI 650
    WHLLKIACTQ SSARSLVGSS LEGAVTPQTS AWLPPTSAEH DHSLSCVVTP 700
    QDGETSAQMI EENLNCLGHL STIIHEANEE QGNSMMNLDW SWLTE 745
    Length:745
    Mass (Da):84,640
    Last modified:January 11, 2011 - v2
    Checksum:i4EA55C6FFC66FA16
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti543 – 5431E → G in AAC51671. (PubMed:9252186)Curated
    Sequence conflicti604 – 6041L → R in AAC50713. (PubMed:8777433)Curated
    Sequence conflicti679 – 6802TS → AY in AAC50713. (PubMed:8777433)Curated
    Sequence conflicti684 – 6841P → A no nucleotide entry (PubMed:9346484)Curated
    Sequence conflicti684 – 6841P → A in AAC50713. (PubMed:8777433)Curated
    Sequence conflicti686 – 6872TS → DL in AAC50713. (PubMed:8777433)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti126 – 1261S → C.1 Publication
    Corresponds to variant rs34427437 [ dbSNP | Ensembl ].
    VAR_040565
    Natural varianti155 – 1551V → A.1 Publication
    Corresponds to variant rs2230803 [ dbSNP | Ensembl ].
    VAR_040566
    Natural varianti268 – 2681V → I.6 Publications
    Corresponds to variant rs2230804 [ dbSNP | Ensembl ].
    VAR_021359

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF012890 mRNA. Translation: AAC51662.1.
    AF009225 mRNA. Translation: AAC51671.1.
    AF080157 mRNA. Translation: AAD08996.1.
    AY652653 Genomic DNA. Translation: AAT49098.1.
    AL138921 Genomic DNA. Translation: CAH72401.1.
    U22512 mRNA. Translation: AAC50713.1.
    CCDSiCCDS7488.1.
    RefSeqiNP_001269.3. NM_001278.3.
    UniGeneiHs.198998.

    Genome annotation databases

    EnsembliENST00000370397; ENSP00000359424; ENSG00000213341.
    GeneIDi1147.
    KEGGihsa:1147.
    UCSCiuc001kqp.3. human.

    Keywords - Coding sequence diversityi

    Polymorphism

    Cross-referencesi

    Web resourcesi

    SeattleSNPs

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF012890 mRNA. Translation: AAC51662.1 .
    AF009225 mRNA. Translation: AAC51671.1 .
    AF080157 mRNA. Translation: AAD08996.1 .
    AY652653 Genomic DNA. Translation: AAT49098.1 .
    AL138921 Genomic DNA. Translation: CAH72401.1 .
    U22512 mRNA. Translation: AAC50713.1 .
    CCDSi CCDS7488.1.
    RefSeqi NP_001269.3. NM_001278.3.
    UniGenei Hs.198998.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    3BRT X-ray 2.25 A/C 732-745 [» ]
    ProteinModelPortali O15111.
    SMRi O15111. Positions 5-659.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 107569. 118 interactions.
    DIPi DIP-27526N.
    IntActi O15111. 48 interactions.
    MINTi MINT-88648.
    STRINGi 9606.ENSP00000359424.

    Chemistry

    BindingDBi O15111.
    ChEMBLi CHEMBL3476.
    GuidetoPHARMACOLOGYi 1989.

    PTM databases

    PhosphoSitei O15111.

    Proteomic databases

    MaxQBi O15111.
    PaxDbi O15111.
    PRIDEi O15111.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000370397 ; ENSP00000359424 ; ENSG00000213341 .
    GeneIDi 1147.
    KEGGi hsa:1147.
    UCSCi uc001kqp.3. human.

    Organism-specific databases

    CTDi 1147.
    GeneCardsi GC10M101938.
    H-InvDB HIX0201495.
    HGNCi HGNC:1974. CHUK.
    HPAi CAB004240.
    CAB018564.
    HPA001402.
    MIMi 600664. gene.
    613630. phenotype.
    neXtProti NX_O15111.
    PharmGKBi PA26510.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG0515.
    HOGENOMi HOG000038048.
    HOVERGENi HBG018241.
    InParanoidi O15111.
    KOi K04467.
    OMAi LQLMLNW.
    OrthoDBi EOG7FBRH3.
    PhylomeDBi O15111.
    TreeFami TF324269.

    Enzyme and pathway databases

    BRENDAi 2.7.11.10. 2681.
    Reactomei REACT_118563. RIP-mediated NFkB activation via ZBP1.
    REACT_118656. Activation of NF-kappaB in B cells.
    REACT_12555. Downstream TCR signaling.
    REACT_12564. AKT phosphorylates targets in the cytosol.
    REACT_147727. Constitutive PI3K/AKT Signaling in Cancer.
    REACT_163994. FCERI mediated NF-kB activation.
    REACT_21281. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
    REACT_22442. Interleukin-1 signaling.
    REACT_24918. IRAK1 recruits IKK complex.
    REACT_24969. TRAF6 mediated NF-kB activation.
    REACT_25039. NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10.
    REACT_25354. IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation.
    REACT_25374. IKK complex recruitment mediated by RIP1.
    REACT_75776. NOD1/2 Signaling Pathway.
    SABIO-RK O15111.
    SignaLinki O15111.

    Miscellaneous databases

    ChiTaRSi CHUK. human.
    EvolutionaryTracei O15111.
    GeneWikii CHUK.
    GenomeRNAii 1147.
    NextBioi 4772.
    PROi O15111.
    SOURCEi Search...

    Gene expression databases

    Bgeei O15111.
    CleanExi HS_CHUK.
    Genevestigatori O15111.

    Family and domain databases

    InterProi IPR022007. IKKbetaNEMObind.
    IPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view ]
    Pfami PF12179. IKKbetaNEMObind. 1 hit.
    PF00069. Pkinase. 1 hit.
    [Graphical view ]
    SMARTi SM00220. S_TKc. 1 hit.
    [Graphical view ]
    SUPFAMi SSF56112. SSF56112. 1 hit.
    PROSITEi PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Identification and characterization of an IkappaB kinase."
      Regnier C.H., Song H.Y., Gao X., Goeddel D.V., Cao Z., Rothe M.
      Cell 90:373-383(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], MUTAGENESIS OF LYS-44, VARIANT ILE-268.
      Tissue: T-cell.
    2. "A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB."
      DiDonato J.A., Hayakawa M., Rothwarf D.M., Zandi E., Karin M.
      Nature 388:548-554(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE, VARIANT ILE-268.
    3. "IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation."
      Mercurio F., Zhu H., Murray B.W., Shevchenko A., Bennett B.L., Li J.W., Young D.B., Barbosa M., Mann M., Manning A., Rao A.
      Science 278:860-866(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE, MUTAGENESIS OF LYS-44 AND SER-176.
      Tissue: Cervix carcinoma.
    4. "IkappaB kinase-alpha and -beta genes are coexpressed in adult and embryonic tissues but localized to different human chromosomes."
      Hu M.C.-T., Wang Y.-P.
      Gene 222:31-40(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT ILE-268.
      Tissue: Heart.
    5. SeattleSNPs variation discovery resource
      Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    6. "The DNA sequence and comparative analysis of human chromosome 10."
      Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J.
      , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.
      Nature 429:375-381(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT ILE-268.
    7. "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. 41:537-549(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 32-745, VARIANT ILE-268.
      Tissue: Cervix carcinoma.
    8. "Acetylation of MEK2 and I kappa B kinase (IKK) activation loop residues by YopJ inhibits signaling."
      Mittal R., Peak-Chew S.Y., McMahon H.T.
      Proc. Natl. Acad. Sci. U.S.A. 103:18574-18579(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: PROTEIN SEQUENCE OF 169-181, INACTIVATION BY YERSINIA YOPJ, ACETYLATION AT THR-179, IDENTIFICATION BY MASS SPECTROMETRY.
    9. "IKAP is a scaffold protein of the IkappaB kinase complex."
      Cohen L., Henzel W.J., Baeuerle P.A.
      Nature 395:292-296(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: IDENTIFICATION IN A COMPLEX WITH IKBKB; NFKBIA; RELA; IKBKAP AND MAP3K14.
    10. "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. 95:3792-3797(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT SER-176, MUTAGENESIS OF SER-176; THR-179 AND SER-180.
    11. "NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase."
      Ozes O.N., Mayo L.D., Gustin J.A., Pfeffer S.R., Pfeffer L.M., Donner D.B.
      Nature 401:82-85(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT THR-23, MUTAGENESIS OF THR-23.
    12. "Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation."
      Delhase M., Hayakawa M., Chen Y., Karin M.
      Science 284:309-313(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: IKKA-IKKB BINDING.
    13. "Coordinate regulation of IkappaB kinases by mitogen-activated protein kinase kinase kinase 1 and NF-kappaB-inducing kinase."
      Nemoto S., DiDonato J.A., Lin A.
      Mol. Cell. Biol. 18:7336-7343(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: IKK PHOSPHORYLATION.
    14. "The I kappa B/NF-kappa B system: a key determinant of mucosal inflammation and protection."
      Jobin C., Sartor R.B.
      Am. J. Physiol. 278:C451-C462(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW.
    15. "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. 22:3549-3561(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBUNIT OF A COMPLEX CONTAINING CREBBP; NCOA2; NCOA3; IKKB AND IKBKG.
    16. "Tetrameric oligomerization of IkappaB kinase gamma (IKKgamma) is obligatory for IKK complex activity and NF-kappaB activation."
      Tegethoff S., Behlke J., Scheidereit C.
      Mol. Cell. Biol. 23:2029-2041(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: COMPOSITION OF THE IKK COMPLEX.
    17. "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 423:655-659(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION, FUNCTION IN PHOSPHORYLATION OF HISTONE H3.
    18. "PAN1/NALP2/PYPAF2, an inducible inflammatory mediator that regulates NF-kappaB and caspase-1 activation in macrophages."
      Bruey J.-M., Bruey-Sedano N., Newman R., Chandler S., Stehlik C., Reed J.C.
      J. Biol. Chem. 279:51897-51907(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH NALP2.
    19. "beta-Arrestin inhibits NF-kappaB activity by means of its interaction with the NF-kappaB inhibitor IkappaBalpha."
      Witherow D.S., Garrison T.R., Miller W.E., Lefkowitz R.J.
      Proc. Natl. Acad. Sci. U.S.A. 101:8603-8607(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH ARRB1 AND ARRB2.
    20. "Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus."
      Meylan E., Curran J., Hofmann K., Moradpour D., Binder M., Bartenschlager R., Tschopp J.
      Nature 437:1167-1172(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH MAVS.
    21. "Proinflammatory stimuli induce IKKalpha-mediated phosphorylation of PIAS1 to restrict inflammation and immunity."
      Liu B., Yang Y., Chernishof V., Loo R.R., Jang H., Tahk S., Yang R., Mink S., Shultz D., Bellone C.J., Loo J.A., Shuai K.
      Cell 129:903-914(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH PIAS1.
    22. "Phosphorylation of CBP by IKKalpha promotes cell growth by switching the binding preference of CBP from p53 to NF-kappaB."
      Huang W.C., Ju T.K., Hung M.C., Chen C.C.
      Mol. Cell 26:75-87(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN PHOSPHORYLATION OF CREBBP.
    23. "The IkappaB kinase complex: master regulator of NF-kappaB signaling."
      Solt L.A., May M.J.
      Immunol. Res. 42:3-18(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW, DOMAIN.
    24. "SGK1 phosphorylation of IkappaB Kinase alpha and p300 Up-regulates NF-kappaB activity and increases N-Methyl-D-aspartate receptor NR2A and NR2B expression."
      Tai D.J., Su C.C., Ma Y.L., Lee E.H.
      J. Biol. Chem. 284:4073-4089(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT THR-23 AND SER-180 BY SGK1.
    25. "NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways."
      Cui J., Zhu L., Xia X., Wang H.Y., Legras X., Hong J., Ji J., Shen P., Zheng S., Chen Z.J., Wang R.F.
      Cell 141:483-496(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH NLRC5.
    26. Cited for: INVOLVEMENT IN COCOS.
    27. "Negative feedback in noncanonical NF-kappaB signaling modulates NIK stability through IKKalpha-mediated phosphorylation."
      Razani B., Zarnegar B., Ytterberg A.J., Shiba T., Dempsey P.W., Ware C.F., Loo J.A., Cheng G.
      Sci. Signal. 3:RA41-RA41(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN MAP3K14 PHOSPHORYLATION.
    28. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    29. "The kinase IKKalpha inhibits activation of the transcription factor NF-kappaB by phosphorylating the regulatory molecule TAX1BP1."
      Shembade N., Pujari R., Harhaj N.S., Abbott D.W., Harhaj E.W.
      Nat. Immunol. 12:834-843(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN PHOSPHORYLATION OF TAX1BP1.
    30. "The zinc finger protein ZNF268 is overexpressed in human cervical cancer and contributes to tumorigenesis via enhancing NF-kappaB signaling."
      Wang W., Guo M., Hu L., Cai J., Zeng Y., Luo J., Shu Z., Li W., Huang Z.
      J. Biol. Chem. 287:42856-42866(2012) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH ZNF268, SUBUNIT.
    31. "Patterns of somatic mutation in human cancer genomes."
      Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.
      , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
      Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS [LARGE SCALE ANALYSIS] CYS-126; ALA-155 AND ILE-268.
    32. "Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site."
      Rushe M., Silvian L., Bixler S., Chen L.L., Cheung A., Bowes S., Cuervo H., Berkowitz S., Zheng T., Guckian K., Pellegrini M., Lugovskoy A.
      Structure 16:798-808(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 732-745.

    Entry informationi

    Entry nameiIKKA_HUMAN
    AccessioniPrimary (citable) accession number: O15111
    Secondary accession number(s): O14666
    , Q13132, Q5W0I4, Q92467
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: June 1, 2001
    Last sequence update: January 11, 2011
    Last modified: October 1, 2014
    This is version 163 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

    Documents

    1. Human chromosome 10
      Human chromosome 10: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. Human and mouse protein kinases
      Human and mouse protein kinases: classification and index
    7. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3