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O88351 (IKKB_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 131. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Inhibitor of nuclear factor kappa-B kinase subunit beta

Short name=I-kappa-B-kinase beta
Short name=IKK-B
Short name=IKK-beta
Short name=IkBKB
EC=2.7.11.10
Alternative name(s):
I-kappa-B kinase 2
Short name=IKK2
Nuclear factor NF-kappa-B inhibitor kinase beta
Short name=NFKBIKB
Gene names
Name:Ikbkb
Synonyms:Ikkb
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length757 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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.

Catalytic activity

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

Subunit structure

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. Ref.8 Ref.9

Subcellular location

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

Tissue specificity

Expressed in liver, kidney and spleen.

Developmental stage

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. Ref.4

Domain

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.

Post-translational modification

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. Ref.1 Ref.5

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.

Hydroxylated by PHD1/EGLN2, loss of hydroxylation under hypoxic conditions results in activation of NF-kappaB By similarity.

Disruption phenotype

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. Ref.3 Ref.6

Sequence similarities

Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Cellular componentCytoplasm
Membrane
Nucleus
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMHydroxylation
Phosphoprotein
S-nitrosylation
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processB cell homeostasis

Inferred from mutant phenotype PubMed 12235208. Source: MGI

I-kappaB phosphorylation

Traceable author statement PubMed 9597130. Source: MGI

cellular response to tumor necrosis factor

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of NF-kappaB transcription factor activity

Inferred from sequence orthology PubMed 15790681. Source: MGI

positive regulation of cation channel activity

Inferred from genetic interaction PubMed 18981174. Source: MGI

positive regulation of sodium ion transport

Inferred from genetic interaction PubMed 18981174. Source: MGI

positive regulation of transcription from RNA polymerase II promoter

Inferred from sequence or structural similarity. Source: UniProtKB

signal transduction by phosphorylation

Traceable author statement PubMed 9597130. Source: GOC

   Cellular_componentCD40 receptor complex

Inferred from direct assay PubMed 20614026. Source: BHF-UCL

cytoplasm

Traceable author statement PubMed 9597130. Source: MGI

cytoplasmic side of plasma membrane

Inferred from direct assay PubMed 20614026. Source: BHF-UCL

membrane raft

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleus

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

IkappaB kinase activity

Inferred from direct assay PubMed 18981174. Source: MGI

protein heterodimerization activity

Inferred from sequence or structural similarity. Source: UniProtKB

protein homodimerization activity

Inferred from sequence or structural similarity. Source: UniProtKB

protein kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

receptor signaling protein serine/threonine kinase activity

Traceable author statement PubMed 9597130. Source: MGI

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

ChukQ606804EBI-447960,EBI-646245
Gnb2l1P680404EBI-447960,EBI-296749
IkbkgO885222EBI-447960,EBI-998011
KEAP1Q141452EBI-447960,EBI-751001From a different organism.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 757757Inhibitor of nuclear factor kappa-B kinase subunit beta
PRO_0000086014

Regions

Domain15 – 300286Protein kinase
Nucleotide binding21 – 299ATP By similarity
Region458 – 47922Leucine-zipper
Region737 – 7426NEMO-binding

Sites

Active site1451Proton acceptor By similarity
Binding site441ATP By similarity

Amino acid modifications

Modified residue1771Phosphoserine; by TBK1 and PKC/PRKCZ By similarity
Modified residue1791S-nitrosocysteine By similarity
Modified residue1811Phosphoserine; by TBK1, PKC/PRKCZ and PDPK1 By similarity
Modified residue1911Hydroxyproline By similarity
Modified residue6701Phosphoserine; by autocatalysis By similarity
Modified residue6721Phosphoserine; by autocatalysis By similarity
Modified residue6751Phosphoserine; by autocatalysis By similarity
Modified residue6821Phosphoserine; by autocatalysis By similarity
Modified residue6891Phosphoserine; by autocatalysis By similarity
Modified residue6921Phosphoserine; by autocatalysis By similarity
Modified residue6971Phosphoserine; by autocatalysis By similarity
Modified residue7051Phosphoserine; by autocatalysis By similarity
Modified residue7331Phosphoserine; by autocatalysis By similarity
Modified residue7401Phosphoserine; by autocatalysis By similarity

Experimental info

Sequence conflict561N → D in AAD52095. Ref.2
Sequence conflict3431N → D in AAD52095. Ref.2
Sequence conflict3561K → E in AAD52095. Ref.2
Sequence conflict3901L → F in AAD52095. Ref.2
Sequence conflict4061P → Q in AAD52095. Ref.2
Sequence conflict5731K → R in AAD52095. Ref.2
Sequence conflict736 – 75722TLDWS…EQACD → VTA Ref.2

Sequences

Sequence LengthMass (Da)Tools
O88351 [UniParc].

Last modified November 1, 1998. Version 1.
Checksum: FED962F095449C5E

FASTA75786,690
        10         20         30         40         50         60 
MSWSPSLPTQ TCGAWEMKER LGTGGFGNVI RWHNQATGEQ IAIKQCRQEL SPKNRNRWCL 

        70         80         90        100        110        120 
EIQIMRRLNH PNVVAARDVP EGMQNLAPND LPLLAMEYCQ GGDLRRYLNQ FENCCGLREG 

       130        140        150        160        170        180 
AVLTLLSDIA SALRYLHENR IIHRDLKPEN IVLQQGEKRL IHKIIDLGYA KELDQGSLCT 

       190        200        210        220        230        240 
SFVGTLQYLA PELLEQQKYT VTVDYWSFGT LAFECITGFR PFLPNWQPVQ WHSKVRQKSE 

       250        260        270        280        290        300 
VDIVVSEDLN GAVKFSSSLP FPNNLNSVLA ERLEKWLQLM LMWHPRQRGT DPQYGPNGCF 

       310        320        330        340        350        360 
RALDDILNLK LVHVLNMVTG TVHTYPVTED ESLQSLKTRI QENTGILETD QELLQKAGLV 

       370        380        390        400        410        420 
LLPDKPATQC ISDSKTNEGL TLDMDLVFLL DNSKINYETQ ITPRPPPESV SCILQEPKRN 

       430        440        450        460        470        480 
LSFFQLRKVW GQVWHSIQTL KEDCNRLQQG QRAAMMSLLR NNSCLSKMKN AMASTAQQLK 

       490        500        510        520        530        540 
AKLDFFKTSI QIDLEKYKEQ TEFGITSDKL LLAWREMEQA VEQCGRENDV KHLVERMMAL 

       550        560        570        580        590        600 
QTDIVDLQRS PMGRKQGGTL DDLEEQAREL YRKLREKPRD QRTEGDSQEM VRLLLQAIQS 

       610        620        630        640        650        660 
FEKKVRVIYT QLSKTVVCKQ KALELLPKVE EVVSLMNEDE RTVVRLQEKR QKELWNLLKI 

       670        680        690        700        710        720 
ACSKVRGPVS GSPDSMNVSR LSHPGQLMSQ PSSACDSLPE SDKKSEELVA EAHALCSRLE 

       730        740        750 
SALQDTVKEQ DRSFTTLDWS WLQMEDEERC SLEQACD 

« Hide

References

[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]"Telomere-independent Rap1 is an IKK adaptor and regulates NF-kappaB-dependent gene expression."
Teo H., Ghosh S., Luesch H., Ghosh A., Wong E.T., Malik N., Orth A., de Jesus P., Perry A.S., Oliver J.D., Tran N.L., Speiser L.J., Wong M., Saez E., Schultz P., Chanda S.K., Verma I.M., Tergaonkar V.
Nat. Cell Biol. 12:758-767(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TERF2IP.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF026524 mRNA. Translation: AAC23557.1.
AF088910 mRNA. Translation: AAD52095.1.
RefSeqNP_034676.1. NM_010546.2.
UniGeneMm.277886.

3D structure databases

ProteinModelPortalO88351.
SMRO88351. Positions 2-663, 703-743.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid200601. 19 interactions.
DIPDIP-29813N.
IntActO88351. 23 interactions.
MINTMINT-135217.

Chemistry

ChEMBLCHEMBL6012.

PTM databases

PhosphoSiteO88351.

Proteomic databases

PaxDbO88351.
PRIDEO88351.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000063401; ENSMUSP00000064235; ENSMUSG00000031537.
GeneID16150.
KEGGmmu:16150.

Organism-specific databases

CTD3551.
MGIMGI:1338071. Ikbkb.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00530000063051.
HOGENOMHOG000038048.
HOVERGENHBG018241.
InParanoidO88351.
KOK07209.
PhylomeDBO88351.

Enzyme and pathway databases

BRENDA2.7.11.10. 3474.

Gene expression databases

ArrayExpressO88351.
BgeeO88351.
CleanExMM_IKBKB.
GenevestigatorO88351.

Family and domain databases

InterProIPR022007. IKKbetaNEMObind.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF12179. IKKbetaNEMObind. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio288941.
PROO88351.
SOURCESearch...

Entry information

Entry nameIKKB_MOUSE
AccessionPrimary (citable) accession number: O88351
Secondary accession number(s): Q9R1J6
Entry history
Integrated into UniProtKB/Swiss-Prot: June 1, 2001
Last sequence update: November 1, 1998
Last modified: April 16, 2014
This is version 131 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot