BioPAX pathway converted from "IKBKB phosphorylates TPL2 (MAP3K8) at Ser400" in the Reactome database. 2.7.11.10 IKBKB phosphorylates TPL2 (MAP3K8) at Ser400 IKBKB phosphorylates TPL2 (MAP3K8) at Ser400 The activity of tumor progression locus-2 (TPL2, also known as COT and MAP3K8) is regulated by means of phosphorylation. MAP3K8 undergoes phosphorylated on S400 in its C-terminal tail to activate MAP2Ks (MEK1/2) following LPS stimulation of macrophages. Different experimental systems have suggested that S400 is either autophosphosphorylated by MAPK3P8 (IL-1?-stimulated IL-1R-293T cells) or transphosphorylated by an unknown kinase (LPS-stimulated RAW264.7 macrophages). Authored: Shamovsky, Veronica, 2015-05-12 Reviewed: Jupe, Steve, 2015-04-14 Reviewed: DeCicco-Skinner, Kathleen L., 2015-08-20 Edited: Shamovsky, Veronica, 2015-08-25 Reactome DB_ID: 451638 1 cytosol GO 0005829 NFKB1:MAP3K8:TNIP2 [cytosol] NFKB1:MAP3K8:TNIP2 NFKB p105:TPL2:ABIN2 Reactome DB_ID: 389388 1 UniProt:P41279 MAP3K8 MAP3K8 ESTF COT MAP3K8 FUNCTION Required for lipopolysaccharide (LPS)-induced, TLR4-mediated activation of the MAPK/ERK pathway in macrophages, thus being critical for production of the proinflammatory cytokine TNF-alpha (TNF) during immune responses. Involved in the regulation of T-helper cell differentiation and IFNG expression in T-cells. Involved in mediating host resistance to bacterial infection through negative regulation of type I interferon (IFN) production. In vitro, activates MAPK/ERK pathway in response to IL1 in an IRAK1-independent manner, leading to up-regulation of IL8 and CCL4. Transduces CD40 and TNFRSF1A signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production. May also play a role in the transduction of TNF signals that activate JNK and NF-kappa-B in some cell types. In adipocytes, activates MAPK/ERK pathway in an IKBKB-dependent manner in response to IL1B and TNF, but not insulin, leading to induction of lipolysis. Plays a role in the cell cycle. Isoform 1 shows some transforming activity, although it is much weaker than that of the activated oncogenic variant.SUBUNIT Forms a ternary complex with NFKB1/p105 and TNIP2. Interacts with NFKB1; the interaction increases the stability of MAP3K8 but inhibits its MEK phosphorylation activity, whereas loss of interaction following LPS stimulation leads to its degradation. Interacts with CD40 and TRAF6; the interaction is required for ERK activation. Interacts with KSR2; the interaction inhibits ERK and NF-kappa-B activation.TISSUE SPECIFICITY Expressed in several normal tissues and human tumor-derived cell lines.DEVELOPMENTAL STAGE Isoform 1 is activated specifically during the S and G2/M phases of the cell cycle.INDUCTION Up-regulated by IL12 in T-lymphocytes. Up-regulated in subcutaneous adipose tissue of obese individuals.PTM Autophosphorylated (PubMed:8226782, PubMed:1833717). Isoform 1 undergoes phosphorylation mainly on Ser residues, and isoform 2 on both Ser and Thr residues (PubMed:8226782). Phosphorylated on Thr-290; the phosphorylation is necessary but not sufficient for full kinase activity in vitro and for the dissociation of isoform 1 from NFKB1, leading to its degradation (PubMed:15466476, PubMed:15699325). Phosphorylated on Ser-400 by IKBKB; the phosphorylation is required for LPS-stimulated activation of the MAPK/ERK pathway in macrophages (PubMed:17472361, PubMed:22988300).MISCELLANEOUS Can be converted to an oncogenic protein by proviral activation, leading to a C-terminally truncated protein with transforming activity.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.CAUTION A paper describing a role for this protein in IRAK1-independent activation of the MAPK/ERK pathway in response to IL1 has been retracted, because some of the experimental data could not be reproduced. Reactome http://www.reactome.org Homo sapiens NCBI Taxonomy 9606 UniProt P41279 Chain Coordinates 1 EQUAL 467 EQUAL Reactome DB_ID: 451607 1 UniProt:P19838 NFKB1 NFKB1 NFKB1 FUNCTION NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and RelB-p50 complexes are transcriptional activators. The NF-kappa-B p50-p50 homodimer is a transcriptional repressor, but can act as a transcriptional activator when associated with BCL3. NFKB1 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p105 and generation of p50 by a cotranslational processing. The proteasome-mediated process ensures the production of both p50 and p105 and preserves their independent function, although processing of NFKB1/p105 also appears to occur post-translationally. p50 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. In a complex with MAP3K8, NFKB1/p105 represses MAP3K8-induced MAPK signaling; active MAP3K8 is released by proteasome-dependent degradation of NFKB1/p105.SUBUNIT Component of the NF-kappa-B p65-p50 complex (PubMed:1740106). Homodimer; component of the NF-kappa-B p50-p50 complex. Component of the NF-kappa-B p105-p50 complex. Component of the NF-kappa-B p50-c-Rel complex (PubMed:15102766, PubMed:8152812). Component of a complex consisting of the NF-kappa-B p50-p50 homodimer and BCL3 (PubMed:10469655). Also interacts with MAP3K8 (PubMed:9950430, PubMed:15485931). NF-kappa-B p50 subunit interacts with NCOA3 coactivator, which may coactivate NF-kappa-B dependent expression via its histone acetyltransferase activity (PubMed:11094166). Interacts with DSIPI; this interaction prevents nuclear translocation and DNA-binding (PubMed:11468175, PubMed:12393603). Interacts with SPAG9 and UNC5CL (PubMed:14769797, PubMed:14743216). NFKB1/p105 interacts with CFLAR; the interaction inhibits p105 processing into p50 (PubMed:13679070). NFKB1/p105 forms a ternary complex with MAP3K8 and TNIP2 (PubMed:15169888). Interacts with GSK3B; the interaction prevents processing of p105 to p50 (PubMed:12871932). NFKB1/p50 interacts with NFKBIE (PubMed:9315679). NFKB1/p50 interacts with NFKBIZ (By similarity). Nuclear factor NF-kappa-B p50 subunit interacts with NFKBID (By similarity). Directly interacts with MEN1 (PubMed:11526476). Interacts with HIF1AN (PubMed:17003112). Interacts with FEM1A; interaction is direct (By similarity).INDUCTION By phorbol ester and TNF.DOMAIN The C-terminus of p105 might be involved in cytoplasmic retention, inhibition of DNA-binding, and transcription activation.DOMAIN Glycine-rich region (GRR) appears to be a critical element in the generation of p50.PTM While translation occurs, the particular unfolded structure after the GRR repeat promotes the generation of p50 making it an acceptable substrate for the proteasome. This process is known as cotranslational processing. The processed form is active and the unprocessed form acts as an inhibitor (I kappa B-like), being able to form cytosolic complexes with NF-kappa B, trapping it in the cytoplasm. Complete folding of the region downstream of the GRR repeat precludes processing.PTM Phosphorylation at 'Ser-903' and 'Ser-907' primes p105 for proteolytic processing in response to TNF-alpha stimulation. Phosphorylation at 'Ser-927' and 'Ser-932' are required for BTRC/BTRCP-mediated proteolysis.PTM Polyubiquitination seems to allow p105 processing.PTM S-nitrosylation of Cys-61 affects DNA binding.PTM The covalent modification of cysteine by 15-deoxy-Delta12,14-prostaglandin-J2 is autocatalytic and reversible. It may occur as an alternative to other cysteine modifications, such as S-nitrosylation and S-palmitoylation. UniProt P19838 1 EQUAL 968 EQUAL Reactome DB_ID: 451661 1 UniProt:Q8NFZ5 TNIP2 TNIP2 TNIP2 FLIP1 ABIN2 FUNCTION Inhibits NF-kappa-B activation by blocking the interaction of RIPK1 with its downstream effector NEMO/IKBKG. Forms a ternary complex with NFKB1 and MAP3K8 but appears to function upstream of MAP3K8 in the TLR4 signaling pathway that regulates MAP3K8 activation. Involved in activation of the MEK/ERK signaling pathway during innate immune response; this function seems to be stimulus- and cell type specific. Required for stability of MAP3K8. Involved in regulation of apoptosis in endothelial cells; promotes TEK agonist-stimulated endothelial survival. May act as transcriptional coactivator when translocated to the nucleus. Enhances CHUK-mediated NF-kappa-B activation involving NF-kappa-B p50-p65 and p50-c-Rel complexes.SUBUNIT Interacts with STK11/LKB1, TNFAIP3, IKBKG, NFKB1, MAP3K8, TEK, RIPK1, CHUK, IKBKB and SMARCD1. Interacts with polyubiquitin.TISSUE SPECIFICITY Ubiquitously expressed in all tissues examined.PTM In vitro phosphorylated by CHUK.PTM Ubiquitinated; undergoes 'Lys-48'-linked polyubiquitination probably leading to constitutive proteasomal degradation which can be impaired by IKK-A/CHUK or IKBKB probably involving deubiquitination. UniProt Q8NFZ5 1 EQUAL 429 EQUAL Reactome Database ID Release 81 451638 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451638 Reactome R-HSA-451638 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-451638.1 Reactome DB_ID: 113592 1 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 5687880 1 NFKB1:p-S400-MAP3K8:TNIP2 [cytosol] NFKB1:p-S400-MAP3K8:TNIP2 Reactome DB_ID: 451607 1 1 EQUAL 968 EQUAL Reactome DB_ID: 451661 1 1 EQUAL 429 EQUAL Reactome DB_ID: 389738 1 O-phospho-L-serine at 400 400 EQUAL O-phospho-L-serine [MOD:00046] 1 EQUAL 467 EQUAL Reactome Database ID Release 81 5687880 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5687880 Reactome R-HSA-5687880 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5687880.2 Reactome DB_ID: 29370 1 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5'-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 202513 p-S177,S181-IKKB:IKKA:NEMO [cytosol] p-S177,S181-IKKB:IKKA:NEMO CHUK:p-S177,S181-IKBKB:IKBKG IKK complex with phosphorylated IKK beta Reactome DB_ID: 202506 1 UniProt:O14920 IKBKB IKBKB IKBKB IKKB 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 (PubMed:30337470). Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation. 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 (PubMed:11297557, PubMed:20410276). IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Phosphorylates FOXO3, mediating the TNF-dependent inactivation of this pro-apoptotic transcription factor (PubMed:15084260). Also phosphorylates other substrates including NCOA3, BCL10 and IRS1 (PubMed:17213322). Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation (PubMed:11297557). Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (By similarity). Phosphorylates the C-terminus of IRF5, stimulating IRF5 homodimerization and translocation into the nucleus (PubMed:25326418).SUBUNIT 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 (PubMed:32935379). The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (PubMed:12612076). The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (By similarity). Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (PubMed:11971985). Part of a 70-90 kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14 (PubMed:9751059). Found in a membrane raft complex, at least composed of BCL10, CARD11, DPP4 and IKBKB (PubMed:17287217). Interacts with SQSTM1 through PRKCZ or PRKCI (PubMed:10356400). Forms an NGF-induced complex with IKBKB, PRKCI and TRAF6 (By similarity). May interact with MAVS/IPS1 (PubMed:16177806). Interacts with NALP2 (PubMed:15456791). Interacts with TICAM1 (PubMed:14739303). Interacts with FAF1; the interaction disrupts the IKK complex formation (PubMed:17684021). Interacts with ATM (PubMed:16497931). Part of a ternary complex consisting of TANK, IKBKB and IKBKG (PubMed:12133833). Interacts with NIBP; the interaction is direct (PubMed:15951441). Interacts with ARRB1 and ARRB2 (PubMed:15173580). Interacts with TRIM21 (PubMed:19675099). Interacts with NLRC5; prevents IKBKB phosphorylation and kinase activity (PubMed:20434986). Interacts with PDPK1 (PubMed:16207722). Interacts with EIF2AK2/PKR (PubMed:10848580). The phosphorylated form interacts with PPM1A and PPM1B (PubMed:18930133). Interacts with ZNF268 isoform 2; the interaction is further increased in a TNF-alpha-dependent manner (PubMed:23091055). Interacts with IKBKE (PubMed:23453969). Interacts with NAA10, leading to NAA10 degradation (PubMed:19716809). Interacts with FOXO3 (PubMed:15084260). Interacts with AKAP13 (PubMed:23090968). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with LRRC14; disrupts IKBKB-IKBKG interaction preventing I-kappa-B-kinase (IKK) core complex formation and leading to a decrease of IKBKB phosphorylation and NF-kappaB activation (PubMed:27426725). Interacts with SASH1 (PubMed:23776175). Interacts with ARFIP2 (PubMed:26296658).SUBUNIT (Microbial infection) Interacts with Yersinia YopJ.SUBUNIT (Microbial infection) Interacts with vaccinia virus protein B14.TISSUE SPECIFICITY Highly expressed in heart, placenta, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis and peripheral blood.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.PTM 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.PTM (Microbial infection) Acetylation of Thr-180 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the I-kappa-B pathway.PTM Ubiquitinated. 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.PTM (Microbial infection) Monoubiquitination by TRIM21 is disrupted by Yersinia YopJ.PTM Hydroxylated by PHD1/EGLN2, loss of hydroxylation under hypoxic conditions results in activation of NF-kappa-B.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily. UniProt O14920 O-phospho-L-serine at 177 177 EQUAL O-phospho-L-serine at 181 181 EQUAL 1 EQUAL 756 EQUAL Reactome DB_ID: 168108 1 UniProt:Q9Y6K9 IKBKG IKBKG FIP3 IKBKG NEMO FUNCTION Regulatory subunit of the IKK core complex which phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor (PubMed:9751060, PubMed:14695475, PubMed:20724660). Its binding to scaffolding polyubiquitin plays a key role in IKK activation by multiple signaling receptor pathways (PubMed:16547522, PubMed:18287044, PubMed:19033441, PubMed:21606507, PubMed:27777308, PubMed:19185524, PubMed:33567255). Can recognize and bind both 'Lys-63'-linked and linear polyubiquitin upon cell stimulation, with a much higher affinity for linear polyubiquitin (PubMed:16547522, PubMed:18287044, PubMed:27777308, PubMed:19033441, PubMed:21606507, PubMed:19185524). Could be implicated in NF-kappa-B-mediated protection from cytokine toxicity. Essential for viral activation of IRF3 (PubMed:19854139). Involved in TLR3- and IFIH1-mediated antiviral innate response; this function requires 'Lys-27'-linked polyubiquitination (PubMed:20724660).FUNCTION (Microbial infection) Also considered to be a mediator for HTLV-1 Tax oncoprotein activation of NF-kappa-B.SUBUNIT Homodimer; disulfide-linked (PubMed:18164680). 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 (PubMed:9751060, PubMed:9891086, PubMed:11080499, PubMed:18462684, PubMed:17977820, PubMed:32935379). The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (PubMed:9751060, PubMed:9891086, PubMed:11080499). The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (By similarity). Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (PubMed:11971985). Interacts with COPS3, CYLD, NALP2, TRPC4AP and PIDD1 (PubMed:15456791, PubMed:16360037, PubMed:12917691, PubMed:11418127). Interacts with ATM; the complex is exported from the nucleus (PubMed:16497931). Interacts with TRAF6 (PubMed:17728323). Interacts with IKBKE (PubMed:23453969). Interacts with TANK; the interaction is enhanced by IKBKE and TBK1 (PubMed:12133833). Part of a ternary complex consisting of TANK, IKBKB and IKBKG (PubMed:12133833). Interacts with ZFAND5 (PubMed:14754897). Interacts with RIPK2 (PubMed:18079694). Interacts with TNIP1 and TNFAIP3; TNIP1 facilitates the TNFAIP3-mediated de-ubiquitination of IKBKG (PubMed:11389905, PubMed:22099304). Interacts with TNFAIP3; the interaction is induced by TNF stimulation and by polyubiquitin (PubMed:11389905, PubMed:22099304). Binds (via UBAN region) polyubiquitin; binds both 'Lys-63'-linked and linear polyubiquitin, with higher affinity for linear ubiquitin (PubMed:16547522, PubMed:19033441, PubMed:21606507, PubMed:19185524). Interacts with NLRP10 (PubMed:22672233). Interacts with TANK; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with USP10; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with ZC3H12A; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with TRIM29; this interaction induces IKBKG/NEMO ubiquitination and proteolytic degradation (PubMed:27695001). Interacts with TRIM13; this interaction leads to IKBKG/NEMO ubiquitination (PubMed:25152375). Interacts with ARFIP2 (PubMed:26296658). Interacts with RIPK1 (By similarity). Interacts with (ubiquitinated) BCL10; interaction with polyubiquitinated BCL10 via both 'Lys-63'-linked and linear ubiquitin is required for TCR-induced NF-kappa-B activation (PubMed:18287044, PubMed:27777308). Interacts with MARCHF2; during the late stages of macrophage viral and bacterial infection; the interaction leads to ubiquitination and degradation of IKBKG/NEMO (PubMed:32935379).SUBUNIT (Microbial infection) Interacts with Molluscum contagiosum virus protein MC005; this interaction inhibits NF-kappa-B activation.SUBUNIT (Microbial infection) Interacts with HTLV-1 Tax oncoprotein; the interaction activates IKBKG.SUBUNIT (Microbial infection) Interacts with Shigella flexneri ipah9.8; the interaction promotes TNIP1-dependent 'Lys-27'-linked polyubiquitination of IKBKG which perturbs NF-kappa-B activation during bacterial infection.SUBUNIT (Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 virus protein ORF9B (via N-terminus); the interaction inhibits polyubiquitination through 'Lys-63' and NF-kappa-B activation.TISSUE SPECIFICITY Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.DOMAIN The leucine-zipper domain and the CCHC NOA-type zinc-fingers constitute the UBAN region and are essential for polyubiquitin binding and for the activation of IRF3.PTM Phosphorylation at Ser-68 attenuates aminoterminal homodimerization.PTM Polyubiquitinated on Lys-285 through 'Lys-63'; the ubiquitination is mediated by NOD2 and RIPK2 and probably plays a role in signaling by facilitating interactions with ubiquitin domain-containing proteins and activates the NF-kappa-B pathway. Polyubiquitinated on Lys-399 through 'Lys-63'; the ubiquitination is mediated by BCL10, MALT1 and TRAF6 and probably plays a role in signaling by facilitating interactions with ubiquitin domain-containing proteins and activates the NF-kappa-B pathway. Monoubiquitinated on Lys-277 and Lys-309; promotes nuclear export. Polyubiquitinated through 'Lys-27' by TRIM23; involved in antiviral innate and inflammatory responses. Linear polyubiquitinated on Lys-111, Lys-143, Lys-226, Lys-246, Lys-264, Lys-277, Lys-285, Lys-292, Lys-302, Lys-309 and Lys-326; the head-to-tail polyubiquitination is mediated by the LUBAC complex and plays a key role in NF-kappa-B activation. Deubiquitinated by USP10 in a TANK-dependent and -independent manner, leading to the negative regulation of NF-kappa-B signaling upon DNA damage (PubMed:25861989). Ubiquitinated at Lys-326 by MARCHF2 following bacterial and viral infection which leads to its degradation (PubMed:32935379).PTM Sumoylated on Lys-277 and Lys-309 with SUMO1; the modification results in phosphorylation of Ser-85 by ATM leading to a replacement of the sumoylation by mono-ubiquitination on these residues.PTM Neddylated by TRIM40, resulting in stabilization of NFKBIA and down-regulation of NF-kappa-B activity.PTM (Microbial infection) Cleaved by hepatitis A virus (HAV) protease 3C allowing the virus to disrupt the host innate immune signaling.PTM (Microbial infection) Polyubiquitinated on Lys-309 and Lys-321 via 'Lys-27'-linked ubiquitin by Shigella flexneri E3 ubiquitin-protein ligase ipah9.8, leading to its degradation by the proteasome.PTM (Microbial infection) Polyubiquitination through 'Lys-63' is interrupted by interaction with SARS coronavirus-2/SARS-CoV-2 virus protein ORF9B which inhibits the NF-kappa-B pathway. UniProt Q9Y6K9 1 EQUAL 419 EQUAL Reactome DB_ID: 168104 1 UniProt:O15111 CHUK CHUK TCF16 CHUK IKKA 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 (PubMed:9244310, PubMed:9252186, PubMed:9346484, PubMed:18626576). 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 (PubMed:9244310, PubMed:9252186, PubMed:9346484, PubMed:18626576). These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome (PubMed:9244310, PubMed:9252186, PubMed:9346484, PubMed:18626576). 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 (PubMed:9244310, PubMed:9252186, PubMed:9346484, PubMed:18626576). 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) (PubMed:21765415). 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 (PubMed:20501937). 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 (PubMed:17434128). 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 (PubMed:12789342). Additionally, phosphorylates the CREBBP-interacting protein NCOA3. Also phosphorylates FOXO3 and may regulate this pro-apoptotic transcription factor (PubMed:15084260). Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (By similarity). Phosphorylates AMBRA1 following mitophagy induction, promoting AMBRA1 interaction with ATG8 family proteins and its mitophagic activity (PubMed:30217973).ACTIVITY REGULATION Activated when phosphorylated and inactivated when dephosphorylated.SUBUNIT 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 (PubMed:32935379). The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (PubMed:10195894, PubMed:12612076). The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65 (By similarity). Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP (PubMed:11971985). Part of a 70-90 kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14 (PubMed:9751059). Directly interacts with TRPC4AP (By similarity). May interact with TRAF2 (PubMed:19150425). Interacts with NALP2 (PubMed:15456791). May interact with MAVS/IPS1 (PubMed:16177806). Interacts with ARRB1 and ARRB2 (PubMed:15173580). Interacts with NLRC5; prevents CHUK phosphorylation and kinase activity (PubMed:20434986). Interacts with PIAS1; this interaction induces PIAS1 phosphorylation (PubMed:17540171). Interacts with ZNF268 isoform 2; the interaction is further increased in a TNF-alpha-dependent manner (PubMed:23091055). Interacts with FOXO3 (PubMed:15084260). Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation (PubMed:26334375). Interacts with LRRC14 (PubMed:27426725). Interacts with SASH1 (PubMed:23776175). Directly interacts with DDX3X after the physiological activation of the TLR7 and TLR8 pathways; this interaction enhances CHUK autophosphorylation (PubMed:30341167).SUBUNIT (Microbial infection) Interacts with InlC of Listeria monocytogenes.TISSUE SPECIFICITY Widely expressed.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.PTM Phosphorylated by MAP3K14/NIK, AKT and to a lesser extent by MEKK1, and dephosphorylated by PP2A. Autophosphorylated.PTM (Microbial infection) Acetylation of Thr-179 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the I-kappa-B signaling pathway.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily. UniProt O15111 1 EQUAL 745 EQUAL Reactome Database ID Release 81 202513 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202513 Reactome R-HSA-202513 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202513.2 GO 0008384 GO molecular function Reactome Database ID Release 81 9773797 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9773797 Reactome Database ID Release 81 5684275 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684275 Reactome R-HSA-5684275 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684275.2 22988300 Pubmed 2012 I?B kinase 2 regulates TPL-2 activation of extracellular signal-regulated kinases 1 and 2 by direct phosphorylation of TPL-2 serine 400 Roget, Karine Ben-Addi, Abduelhakem Mambole-Dema, Agnes Gantke, Thorsten Yang, Huei-Ting Janzen, Julia Morrice, N Abbott, Derek W Ley, Steven C Mol. Cell. Biol. 32:4684-90 19754427 Pubmed 2009 IRAK1-independent pathways required for the interleukin-1-stimulated activation of the Tpl2 catalytic subunit and its dissociation from ABIN2 Handoyo, Hosea Stafford, Margaret J McManus, Eamon Baltzis, Dionissios Peggie, Mark Cohen, P Biochem. J. 424:109-18 16806191 Pubmed 2006 Interleukin-1 stimulated activation of the COT catalytic subunit through the phosphorylation of Thr290 and Ser62 Stafford, Margaret J Morrice, Nick A Peggie, Mark W Cohen, P FEBS Lett. 580:4010-4