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MGP000565

UniProt Annotations

Entry Information
Gene Nameconserved helix-loop-helix ubiquitous kinase
Protein EntryIKKA_HUMAN
UniProt IDO15111
SpeciesHuman
Comments
Comment typeDescription
Catalytic ActivityATP + [I-kappa-B protein] = ADP + [I-kappa-B phosphoprotein].
DiseaseCocoon 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. {ECO:0000269|PubMed:20961246}. 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}.
Enzyme RegulationActivated when phosphorylated and inactivated when dephosphorylated.
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 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. {ECO:0000269|PubMed:12789342, ECO:0000269|PubMed:17434128, ECO:0000269|PubMed:20434986, ECO:0000269|PubMed:20501937, ECO:0000269|PubMed:21765415}.
InteractionQ6TY28:- (xeno); NbExp=2; IntAct=EBI-81249, EBI-9690312; Q6TY35:- (xeno); NbExp=2; IntAct=EBI-81249, EBI-9690239; Q8B5B5:- (xeno); NbExp=2; IntAct=EBI-81249, EBI-9690330; P32121:ARRB2; NbExp=3; IntAct=EBI-81249, EBI-714559; Q16543:CDC37; NbExp=4; IntAct=EBI-81249, EBI-295634; P46527:CDKN1B; NbExp=4; IntAct=EBI-81249, EBI-519280; P03129:E7 (xeno); NbExp=2; IntAct=EBI-81249, EBI-866453; Q07857:E7 (xeno); NbExp=2; IntAct=EBI-81249, EBI-9690349; Q80901:E7 (xeno); NbExp=2; IntAct=EBI-81249, EBI-9690278; Q13451:FKBP5; NbExp=2; IntAct=EBI-81249, EBI-306914; P07900:HSP90AA1; NbExp=3; IntAct=EBI-81249, EBI-296047; O14920:IKBKB; NbExp=13; IntAct=EBI-81249, EBI-81266; Q9Y6K9:IKBKG; NbExp=20; IntAct=EBI-81249, EBI-81279; Q92985:IRF7; NbExp=4; IntAct=EBI-81249, EBI-968267; Q99558:MAP3K14; NbExp=6; IntAct=EBI-81249, EBI-358011; P01106:MYC; NbExp=3; IntAct=EBI-81249, EBI-447544; P25963:NFKBIA; NbExp=14; IntAct=EBI-81249, EBI-307386; Q77M19:P (xeno); NbExp=2; IntAct=EBI-81249, EBI-6149376; Q04206:RELA; NbExp=2; IntAct=EBI-81249, EBI-73886; Q86VP1:TAX1BP1; NbExp=2; IntAct=EBI-81249, EBI-529518; P24772:VACWR196 (xeno); NbExp=3; IntAct=EBI-81249, EBI-4291651;
PtmAcetylation of Thr-179 by Yersinia yopJ prevents phosphorylation and activation, thus blocking the I-kappa-B signaling pathway. {ECO:0000269|PubMed:17116858}.
PtmPhosphorylated by MAP3K14/NIK, AKT and to a lesser extent by MEKK1, and dephosphorylated by PP2A. Autophosphorylated.
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 {ECO:0000269|PubMed:12789342}. Nucleus {ECO:0000269|PubMed:12789342}. Note=Shuttles between the cytoplasm and the nucleus.
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. 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. {ECO:0000250, ECO:0000269|PubMed:11971985, ECO:0000269|PubMed:15173580, ECO:0000269|PubMed:15456791, ECO:0000269|PubMed:16177806, ECO:0000269|PubMed:17540171, ECO:0000269|PubMed:20434986, ECO:0000269|PubMed:23091055, ECO:0000269|PubMed:9751059}.
Tissue SpecificityWidely expressed.
Web ResourceName=SeattleSNPs; URL="http://pga.gs.washington.edu/data/chuk/";
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