O88351 (IKKB_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified July 9, 2014. Version 134. History...
Names and origin
|Protein names||Recommended name:|
Inhibitor of nuclear factor kappa-B kinase subunit beta
Short name=I-kappa-B-kinase beta
I-kappa-B kinase 2
Nuclear factor NF-kappa-B inhibitor kinase beta
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||757 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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.
ATP + [I-kappa-B protein] = ADP + [I-kappa-B phosphoprotein].
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. Ref.8 Ref.9
Expressed in liver, kidney and spleen.
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
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.
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.
Contains 1 protein kinase domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 757||757||Inhibitor of nuclear factor kappa-B kinase subunit beta||PRO_0000086014|
|Domain||15 – 300||286||Protein kinase|
|Nucleotide binding||21 – 29||9||ATP By similarity|
|Region||458 – 479||22||Leucine-zipper|
|Region||737 – 742||6||NEMO-binding|
|Active site||145||1||Proton acceptor By similarity|
|Binding site||44||1||ATP By similarity|
Amino acid modifications
|Modified residue||177||1||Phosphoserine; by TBK1 and PKC/PRKCZ By similarity|
|Modified residue||179||1||S-nitrosocysteine By similarity|
|Modified residue||181||1||Phosphoserine; by TBK1, PKC/PRKCZ and PDPK1 By similarity|
|Modified residue||191||1||Hydroxyproline By similarity|
|Modified residue||670||1||Phosphoserine; by autocatalysis By similarity|
|Modified residue||672||1||Phosphoserine; by autocatalysis By similarity|
|Modified residue||675||1||Phosphoserine; by autocatalysis By similarity|
|Modified residue||682||1||Phosphoserine; by autocatalysis By similarity|
|Modified residue||689||1||Phosphoserine; by autocatalysis By similarity|
|Modified residue||692||1||Phosphoserine; by autocatalysis By similarity|
|Modified residue||697||1||Phosphoserine; by autocatalysis By similarity|
|Modified residue||705||1||Phosphoserine; by autocatalysis By similarity|
|Modified residue||733||1||Phosphoserine; by autocatalysis By similarity|
|Modified residue||740||1||Phosphoserine; by autocatalysis By similarity|
|Sequence conflict||56||1||N → D in AAD52095. Ref.2|
|Sequence conflict||343||1||N → D in AAD52095. Ref.2|
|Sequence conflict||356||1||K → E in AAD52095. Ref.2|
|Sequence conflict||390||1||L → F in AAD52095. Ref.2|
|Sequence conflict||406||1||P → Q in AAD52095. Ref.2|
|Sequence conflict||573||1||K → R in AAD52095. Ref.2|
|Sequence conflict||736 – 757||22||TLDWS…EQACD → VTA Ref.2|
|||"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.
|||"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].
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.|
|AF026524 mRNA. Translation: AAC23557.1.|
AF088910 mRNA. Translation: AAD52095.1.
|RefSeq||NP_034676.1. NM_010546.2. |
3D structure databases
|SMR||O88351. Positions 2-663, 703-743. |
Protein-protein interaction databases
|BioGrid||200601. 19 interactions.|
|IntAct||O88351. 23 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000063401; ENSMUSP00000064235; ENSMUSG00000031537. |
|MGI||MGI:1338071. Ikbkb. |
Enzyme and pathway databases
|BRENDA||220.127.116.11. 3474. |
Gene expression databases
Family and domain databases
|InterPro||IPR022007. IKKbetaNEMObind. |
|Pfam||PF12179. IKKbetaNEMObind. 1 hit. |
PF00069. Pkinase. 1 hit.
|SUPFAM||SSF56112. SSF56112. 1 hit. |
|PROSITE||PS50011. PROTEIN_KINASE_DOM. 1 hit. |
PS00108. PROTEIN_KINASE_ST. 1 hit.
|Accession||Primary (citable) accession number: O88351|
Secondary accession number(s): Q9R1J6
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|