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O88351

- IKKB_MOUSE

UniProt

O88351 - IKKB_MOUSE

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Protein

Inhibitor of nuclear factor kappa-B kinase subunit beta

Gene

Ikbkb

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

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 2 critical 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. In addition to the NF-kappa-B inhibitors, phosphorylates several other components of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE. IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Also phosphorylates other substrates including NCOA3, BCL10 and IRS1. Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation (By similarity).By similarity

Catalytic activityi

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

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei44 – 441ATPPROSITE-ProRule annotation
Active sitei145 – 1451Proton 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: MGI
  3. protein heterodimerization activity Source: UniProtKB
  4. protein homodimerization activity Source: UniProtKB
  5. protein kinase activity Source: UniProtKB
  6. receptor signaling protein serine/threonine kinase activity Source: MGI
  7. scaffold protein binding Source: MGI

GO - Biological processi

  1. B cell homeostasis Source: MGI
  2. cellular response to tumor necrosis factor Source: UniProtKB
  3. I-kappaB phosphorylation Source: MGI
  4. positive regulation of cation channel activity Source: MGI
  5. positive regulation of NF-kappaB transcription factor activity Source: MGI
  6. positive regulation of sodium ion transport Source: MGI
  7. positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  8. signal transduction by phosphorylation Source: GOC
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.10. 3474.
ReactomeiREACT_198543. IRAK1 recruits IKK complex.
REACT_198546. IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation.
REACT_199121. Activation of NF-kappaB in B cells.
REACT_202898. TRAF6 mediated NF-kB activation.
REACT_205561. FCERI mediated NF-kB activation.
REACT_205717. NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10.
REACT_211125. NOD1/2 Signaling Pathway.
REACT_214670. p75NTR recruits signalling complexes.
REACT_218887. NF-kB is activated and signals survival.
REACT_219800. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
REACT_222971. RIP-mediated NFkB activation via ZBP1.
REACT_224208. Interleukin-1 signaling.
REACT_225145. Downstream TCR signaling.
REACT_226192. IKK complex recruitment mediated by RIP1.

Names & Taxonomyi

Protein namesi
Recommended name:
Inhibitor of nuclear factor kappa-B kinase subunit beta (EC:2.7.11.10)
Short name:
I-kappa-B-kinase beta
Short name:
IKK-B
Short name:
IKK-beta
Short name:
IkBKB
Alternative name(s):
I-kappa-B kinase 2
Short name:
IKK2
Nuclear factor NF-kappa-B inhibitor kinase beta
Short name:
NFKBIKB
Gene namesi
Name:Ikbkb
Synonyms:Ikkb
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 8

Organism-specific databases

MGIiMGI:1338071. Ikbkb.

Subcellular locationi

Cytoplasm By similarity. Nucleus By similarity. Membrane raft By similarity
Note: Colocalized with DPP4 in membrane rafts.By similarity

GO - Cellular componenti

  1. CD40 receptor complex Source: BHF-UCL
  2. cytoplasm Source: MGI
  3. cytoplasmic side of plasma membrane Source: BHF-UCL
  4. nucleus Source: UniProtKB-KW
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Disruption phenotypei

Mice present extensive liver damage from apoptosis and die as embryos. They show a marked reduction in TNF-alpha and IL1-alpha-induced NF-kappa-B activity.2 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 757757Inhibitor of nuclear factor kappa-B kinase subunit betaPRO_0000086014Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei177 – 1771Phosphoserine; by TBK1 and PKC/PRKCZBy similarity
Modified residuei179 – 1791S-nitrosocysteineBy similarity
Modified residuei181 – 1811Phosphoserine; by TBK1, PKC/PRKCZ and PDPK1By similarity
Modified residuei191 – 1911HydroxyprolineBy similarity
Modified residuei670 – 6701Phosphoserine; by autocatalysisBy similarity
Modified residuei672 – 6721Phosphoserine; by autocatalysisBy similarity
Modified residuei675 – 6751Phosphoserine; by autocatalysisBy similarity
Modified residuei682 – 6821Phosphoserine; by autocatalysisBy similarity
Modified residuei689 – 6891Phosphoserine; by autocatalysisBy similarity
Modified residuei692 – 6921Phosphoserine; by autocatalysisBy similarity
Modified residuei697 – 6971Phosphoserine; by autocatalysisBy similarity
Modified residuei705 – 7051Phosphoserine; by autocatalysisBy similarity
Modified residuei733 – 7331Phosphoserine; by autocatalysisBy similarity
Modified residuei740 – 7401Phosphoserine; by autocatalysisBy similarity

Post-translational modificationi

Upon cytokine stimulation, phosphorylated on Ser-177 and Ser-181 by MEKK1 and/or MAP3K14/NIK as well as TBK1 and PRKCZ; which enhances activity. Once activated, autophosphorylates on the C-terminal serine cluster; which decreases activity and prevents prolonged activation of the inflammatory response. Phosphorylated by the IKK-related kinases TBK1 and IKBKE, which is associated with reduced CHUK/IKKA and IKBKB activity and NF-kappa-B-dependent gene transcription. Dephosphorylated at Ser-177 and Ser-181 by PPM1A and PPM1B (By similarity).By similarity
Acetylation of Thr-180 by Yersinia yopJ prevents phosphorylation and activation, thus blocking the I-kappa-B pathway.By similarity
Ubiquitinated. Monoubiquitination involves TRIM21 that leads to inhibition of Tax-induced NF-kappa-B signaling. 'Ser-163' may not serve as a monoubiquitination site. Ubiquitination on 'Ser-163' may modulate phosphorylation on C-terminal serine residues. Monoubiquitination by TRIM21 is disrupted by Yersinia yopJ (By similarity).By similarity
Hydroxylated by PHD1/EGLN2, loss of hydroxylation under hypoxic conditions results in activation of NF-kappaB.By similarity

Keywords - PTMi

Hydroxylation, Phosphoprotein, S-nitrosylation, Ubl conjugation

Proteomic databases

MaxQBiO88351.
PaxDbiO88351.
PRIDEiO88351.

PTM databases

PhosphoSiteiO88351.

Expressioni

Tissue specificityi

Expressed in liver, kidney and spleen.

Developmental stagei

While it is expressed ubiquitously throughout the mouse embryo, at E9.5 day its expression begins to be localized to the brain, neural ganglia, neural tube, and in liver at E12.5 day. At E15.5 day, the expression is further restricted to specific tissues of the embryo.1 Publication

Gene expression databases

BgeeiO88351.
CleanExiMM_IKBKB.
ExpressionAtlasiO88351. baseline and differential.
GenevestigatoriO88351.

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. Found in a membrane raft complex, at least composed of BCL10, CARD11, DPP4 and IKBKB. Interacts with SQSTM1 through PRKCZ or PRKCI. Forms an NGF-induced complex with IKBKB, PRKCI and TRAF6. May interact with MAVS/IPS1. Interacts with NALP2. Interacts with TICAM1. Interacts with FAF1; the interaction disrupts the IKK complex formation. Interacts with ATM. Part of a ternary complex consisting of TANK, IKBKB and IKBKG. Interacts with NIBP; the interaction is direct. Interacts with ARRB1 and ARRB2. Interacts with TRIM21. Interacts with NLRC5; prevents IKBKB phosphorylation and kinase activity. Interacts with PDPK1. Interacts with EIF2AK2/PKR. The phosphorylated form interacts with PPM1A and PPM1B. Interacts with ZNF268; the interaction is further increased in a TNF-alpha-dependent manner. Interacts with IKBKE. Interacts with IKBKE. Interacts with NAA10, leading to NAA10 degradation (By similarity).By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
ChukQ606804EBI-447960,EBI-646245
Gnb2l1P680404EBI-447960,EBI-296749
IkbkgO885223EBI-447960,EBI-998011
KEAP1Q141452EBI-447960,EBI-751001From a different organism.

Protein-protein interaction databases

BioGridi200601. 22 interactions.
DIPiDIP-29813N.
IntActiO88351. 23 interactions.
MINTiMINT-135217.

Structurei

3D structure databases

ProteinModelPortaliO88351.
SMRiO88351. Positions 2-663, 703-743.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini15 – 300286Protein kinasePROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni458 – 47922Leucine-zipperAdd
BLAST
Regioni737 – 7426NEMO-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 (By similarity).By similarity

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.
GeneTreeiENSGT00770000120525.
HOGENOMiHOG000038048.
HOVERGENiHBG018241.
InParanoidiO88351.
KOiK07209.
PhylomeDBiO88351.

Family and domain databases

InterProiIPR022007. IKKbetaNEMObind.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF12179. IKKbetaNEMObind. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

O88351-1 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MSWSPSLPTQ TCGAWEMKER LGTGGFGNVI RWHNQATGEQ IAIKQCRQEL
60 70 80 90 100
SPKNRNRWCL EIQIMRRLNH PNVVAARDVP EGMQNLAPND LPLLAMEYCQ
110 120 130 140 150
GGDLRRYLNQ FENCCGLREG AVLTLLSDIA SALRYLHENR IIHRDLKPEN
160 170 180 190 200
IVLQQGEKRL IHKIIDLGYA KELDQGSLCT SFVGTLQYLA PELLEQQKYT
210 220 230 240 250
VTVDYWSFGT LAFECITGFR PFLPNWQPVQ WHSKVRQKSE VDIVVSEDLN
260 270 280 290 300
GAVKFSSSLP FPNNLNSVLA ERLEKWLQLM LMWHPRQRGT DPQYGPNGCF
310 320 330 340 350
RALDDILNLK LVHVLNMVTG TVHTYPVTED ESLQSLKTRI QENTGILETD
360 370 380 390 400
QELLQKAGLV LLPDKPATQC ISDSKTNEGL TLDMDLVFLL DNSKINYETQ
410 420 430 440 450
ITPRPPPESV SCILQEPKRN LSFFQLRKVW GQVWHSIQTL KEDCNRLQQG
460 470 480 490 500
QRAAMMSLLR NNSCLSKMKN AMASTAQQLK AKLDFFKTSI QIDLEKYKEQ
510 520 530 540 550
TEFGITSDKL LLAWREMEQA VEQCGRENDV KHLVERMMAL QTDIVDLQRS
560 570 580 590 600
PMGRKQGGTL DDLEEQAREL YRKLREKPRD QRTEGDSQEM VRLLLQAIQS
610 620 630 640 650
FEKKVRVIYT QLSKTVVCKQ KALELLPKVE EVVSLMNEDE RTVVRLQEKR
660 670 680 690 700
QKELWNLLKI ACSKVRGPVS GSPDSMNVSR LSHPGQLMSQ PSSACDSLPE
710 720 730 740 750
SDKKSEELVA EAHALCSRLE SALQDTVKEQ DRSFTTLDWS WLQMEDEERC

SLEQACD
Length:757
Mass (Da):86,690
Last modified:November 1, 1998 - v1
Checksum:iFED962F095449C5E
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti56 – 561N → D in AAD52095. 1 PublicationCurated
Sequence conflicti343 – 3431N → D in AAD52095. 1 PublicationCurated
Sequence conflicti356 – 3561K → E in AAD52095. 1 PublicationCurated
Sequence conflicti390 – 3901L → F in AAD52095. 1 PublicationCurated
Sequence conflicti406 – 4061P → Q in AAD52095. 1 PublicationCurated
Sequence conflicti573 – 5731K → R in AAD52095. 1 PublicationCurated
Sequence conflicti736 – 75722TLDWS…EQACD → VTA1 PublicationCuratedAdd
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF026524 mRNA. Translation: AAC23557.1.
AF088910 mRNA. Translation: AAD52095.1.
CCDSiCCDS52522.1.
RefSeqiNP_034676.1. NM_010546.2.
UniGeneiMm.277886.

Genome annotation databases

EnsembliENSMUST00000063401; ENSMUSP00000064235; ENSMUSG00000031537.
GeneIDi16150.
KEGGimmu:16150.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF026524 mRNA. Translation: AAC23557.1 .
AF088910 mRNA. Translation: AAD52095.1 .
CCDSi CCDS52522.1.
RefSeqi NP_034676.1. NM_010546.2.
UniGenei Mm.277886.

3D structure databases

ProteinModelPortali O88351.
SMRi O88351. Positions 2-663, 703-743.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 200601. 22 interactions.
DIPi DIP-29813N.
IntActi O88351. 23 interactions.
MINTi MINT-135217.

Chemistry

BindingDBi O88351.
ChEMBLi CHEMBL6012.

PTM databases

PhosphoSitei O88351.

Proteomic databases

MaxQBi O88351.
PaxDbi O88351.
PRIDEi O88351.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000063401 ; ENSMUSP00000064235 ; ENSMUSG00000031537 .
GeneIDi 16150.
KEGGi mmu:16150.

Organism-specific databases

CTDi 3551.
MGIi MGI:1338071. Ikbkb.

Phylogenomic databases

eggNOGi COG0515.
GeneTreei ENSGT00770000120525.
HOGENOMi HOG000038048.
HOVERGENi HBG018241.
InParanoidi O88351.
KOi K07209.
PhylomeDBi O88351.

Enzyme and pathway databases

BRENDAi 2.7.11.10. 3474.
Reactomei REACT_198543. IRAK1 recruits IKK complex.
REACT_198546. IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation.
REACT_199121. Activation of NF-kappaB in B cells.
REACT_202898. TRAF6 mediated NF-kB activation.
REACT_205561. FCERI mediated NF-kB activation.
REACT_205717. NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10.
REACT_211125. NOD1/2 Signaling Pathway.
REACT_214670. p75NTR recruits signalling complexes.
REACT_218887. NF-kB is activated and signals survival.
REACT_219800. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
REACT_222971. RIP-mediated NFkB activation via ZBP1.
REACT_224208. Interleukin-1 signaling.
REACT_225145. Downstream TCR signaling.
REACT_226192. IKK complex recruitment mediated by RIP1.

Miscellaneous databases

NextBioi 288941.
PROi O88351.
SOURCEi Search...

Gene expression databases

Bgeei O88351.
CleanExi MM_IKBKB.
ExpressionAtlasi O88351. baseline and differential.
Genevestigatori O88351.

Family and domain databases

InterProi IPR022007. IKKbetaNEMObind.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view ]
Pfami PF12179. IKKbetaNEMObind. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view ]
SUPFAMi SSF56112. SSF56112. 1 hit.
PROSITEi PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

  1. "Differential regulation of IkappaB kinase alpha and beta by two upstream kinases, NF-kappaB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1."
    Nakano H., Shindo M., Sakon S., Nishinaka S., Mihara M., Yagita H., Okumura K.
    Proc. Natl. Acad. Sci. U.S.A. 95:3537-3542(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], PHOSPHORYLATION BY MEKK1.
    Strain: C57BL/6.
    Tissue: Spleen.
  2. "Murine IkB kinase-B, a developmentally regulated protein kinase that constitutively phosphorylates serine residues of IkB."
    Hu M.C.-T., Wang Y.-P., Mikhail A., Qiu W.R.
    Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
  3. "Embryonic lethality, liver degeneration, and impaired NF-kappa B activation in IKK-beta-deficient mice."
    Tanaka M., Fuentes M.E., Yamaguchi K., Durnin M.H., Dalrymple S.A., Hardy K.L., Goeddel D.V.
    Immunity 10:421-429(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISRUPTION PHENOTYPE.
  4. "Hematopoietic progenitor kinase-1 (HPK1) stress response signaling pathway activates IkappaB kinases (IKK-alpha/beta) and IKK-beta is a developmentally regulated protein kinase."
    Hu M.C.-T., Wang Y.-P., Qiu W.R., Mikhail A., Meyer C.F., Tan T.-H.
    Oncogene 18:5514-5524(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: DEVELOPMENTAL STAGE.
  5. "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.
  6. "Severe liver degeneration in mice lacking the IkappaB kinase 2 gene."
    Li Q., Van Antwerp D., Mercurio F., Lee K.F., Verma I.M.
    Science 284:321-325(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISRUPTION PHENOTYPE.
  7. "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.
  8. "PKR stimulates NF-kappaB irrespective of its kinase function by interacting with the IkappaB kinase complex."
    Bonnet M.C., Weil R., Dam E., Hovanessian A.G., Meurs E.F.
    Mol. Cell. Biol. 20:4532-4542(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH EIF2AK2.
  9. Cited for: INTERACTION WITH TERF2IP.

Entry informationi

Entry nameiIKKB_MOUSE
AccessioniPrimary (citable) accession number: O88351
Secondary accession number(s): Q9R1J6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 1, 2001
Last sequence update: November 1, 1998
Last modified: November 26, 2014
This is version 138 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3