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MGP001599

UniProt Annotations

Entry Information
Gene Nameinhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta
Protein EntryIKKB_HUMAN
UniProt IDO14920
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=4; Name=1; IsoId=O14920-1; Sequence=Displayed; Name=2; IsoId=O14920-2; Sequence=VSP_041825; Name=3; IsoId=O14920-3; Sequence=VSP_041826, VSP_041827; Name=4; IsoId=O14920-4; Sequence=VSP_043408; Note=No experimental confirmation available.;
Catalytic ActivityATP + [I-kappa-B protein] = ADP + [I-kappa-B phosphoprotein].
DiseaseImmunodeficiency 15 (IMD15) [MIM:615592]: An autosomal recessive primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinemia with relatively normal numbers of B and T- cells, and impaired differentiation and activation of immune cells. {ECO:0000269|PubMed:24369075}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DomainThe 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. {ECO:0000269|PubMed:18626576}.
FunctionSerine 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. {ECO:0000269|PubMed:11297557, ECO:0000269|PubMed:17213322, ECO:0000269|PubMed:19716809, ECO:0000269|PubMed:20410276, ECO:0000269|PubMed:20434986, ECO:0000269|PubMed:20797629, ECO:0000269|PubMed:21138416}.
InteractionQ16543:CDC37; NbExp=3; IntAct=EBI-81266, EBI-295634; O15111:CHUK; NbExp=13; IntAct=EBI-81266, EBI-81249; Q92793:CREBBP; NbExp=2; IntAct=EBI-81266, EBI-81215; P08238:HSP90AB1; NbExp=2; IntAct=EBI-81266, EBI-352572; Q9Y6K9:IKBKG; NbExp=25; IntAct=EBI-81266, EBI-81279; Q14145:KEAP1; NbExp=6; IntAct=EBI-81266, EBI-751001; Q99558:MAP3K14; NbExp=3; IntAct=EBI-81266, EBI-358011; Q9Y6Q9:NCOA3; NbExp=3; IntAct=EBI-81266, EBI-81196; P25963:NFKBIA; NbExp=12; IntAct=EBI-81266, EBI-307386; P67775:PPP2CA; NbExp=3; IntAct=EBI-81266, EBI-712311; P23396:RPS3; NbExp=4; IntAct=EBI-81266, EBI-351193; Q9UGK3:STAP2; NbExp=7; IntAct=EBI-81266, EBI-1553984; P03409:tax (xeno); NbExp=3; IntAct=EBI-81266, EBI-5236464; Q92574:TSC1; NbExp=3; IntAct=EBI-81266, EBI-1047085; P24772:VACWR196 (xeno); NbExp=3; IntAct=EBI-81266, EBI-4291651; Q5D1E7:Zc3h12a (xeno); NbExp=4; IntAct=EBI-81266, EBI-5326026;
PtmAcetylation of Thr-180 by Yersinia yopJ prevents phosphorylation and activation, thus blocking the I-kappa-B pathway. {ECO:0000269|PubMed:16728640, ECO:0000269|PubMed:17116858}.
PtmHydroxylated by PHD1/EGLN2, loss of hydroxylation under hypoxic conditions results in activation of NF-kappaB. {ECO:0000269|PubMed:17114296}.
PtmUbiquitinated. Monoubiquitination involves TRIM21 that leads to inhibition of Tax-induced NF-kappa-B signaling. According to PubMed:19675099, 'Ser-163' does not serve as a monoubiquitination site. According to PubMed:16267042, ubiquitination on 'Ser-163' modulates phosphorylation on C-terminal serine residues. Monoubiquitination by TRIM21 is disrupted by Yersinia yopJ. {ECO:0000269|PubMed:16267042, ECO:0000269|PubMed:19675099}.
PtmUpon 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. {ECO:0000269|PubMed:10022904, ECO:0000269|PubMed:10195894, ECO:0000269|PubMed:10783893, ECO:0000269|PubMed:16207722}.
SimilarityBelongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
SimilarityContains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.
Subcellular LocationCytoplasm. Nucleus. Membrane raft. Note=Colocalized with DPP4 in membrane rafts.
SubunitComponent 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 Yersinia yopJ. 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 isoform 2; the interaction is further increased in a TNF-alpha-dependent manner. Interacts with IKBKE. Interacts with NAA10, leading to NAA10 degradation (By similarity). {ECO:0000250}.
Tissue SpecificityHighly expressed in heart, placenta, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis and peripheral blood.
Web ResourceName=SeattleSNPs; URL="http://pga.gs.washington.edu/data/ikbkb/";
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