{"gene":"IKBKE","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1999,"finding":"IKK-i (IKBKE) is a lipopolysaccharide-inducible kinase that phosphorylates IκB-α preferentially at Ser36 (and Ser32) and significantly stimulates NF-κB activation upon overexpression.","method":"Suppression subtractive hybridization isolation, overexpression in cell lines, in vitro kinase assay on IκB-α","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay with site-specific substrate, but single lab, foundational characterization paper","pmids":["10421793"],"is_preprint":false},{"year":2000,"finding":"IKK-i (IKBKE) phosphorylates I-TRAF/TANK in vitro, causing TRAF2 to be released from the I-TRAF/TRAF2 complex, and NF-κB activation by IKK-i is mediated through this phosphorylation-dependent liberation of TRAF2.","method":"Yeast two-hybrid screening (identified IKK-i / I-TRAF interaction), co-immunoprecipitation, in vitro kinase assay, dominant-negative rescue experiments","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction confirmed by yeast two-hybrid and co-IP, in vitro kinase assay, dominant-negative epistasis; single lab","pmids":["10759890"],"is_preprint":false},{"year":2002,"finding":"Recombinant human IKBKE (IKK-i) is phosphorylated on Ser172 in its activation loop, and this phosphorylation is necessary for kinase activity; IKK-i and TBK1 have distinct peptide substrate specificities from IKK-2 and distinct ATP-binding site properties.","method":"Recombinant protein purification, phosphopeptide mapping, site-directed mutagenesis of Ser172, in vitro kinase assays, ATP analog profiling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro with purified recombinant enzyme, mutagenesis of activation-loop Ser172, multiple orthogonal methods in a single rigorous study","pmids":["11839743"],"is_preprint":false},{"year":2005,"finding":"IKK-i (IKBKE) activates both NF-κB and IRF3 pathways, leading to interferon-β and other cytokine production; kinase-dead IKK-i does not block TNFα-mediated NF-κB activation, indicating IKK-i acts upstream of IKK2 downstream of TLR signaling rather than in the TNFα pathway. STAT1, Tyk2, and JAK1 serve as secondary mediators downstream of IFN-β produced by IKK-i.","method":"Tetracycline-inducible stable cell lines expressing wild-type or kinase-inactive IKK-i, cytokine production assays, luciferase reporter assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible expression system with kinase-dead controls, reporter assays, multiple cytokine readouts; single lab","pmids":["16199137"],"is_preprint":false},{"year":2006,"finding":"IKBKE (IKK-i/IKKε) phosphorylates p65/RelA at Ser536 to sustain constitutive (but not cytokine-induced) NF-κB activity in cancer cells; knockdown of IKBKE or expression of S536A p65 suppresses HeLa cell proliferation.","method":"RNA interference knockdown, site-directed mutagenesis of p65-S536, NF-κB reporter assays, cell proliferation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of phospho-site combined with RNAi knockdown and functional proliferation readout; single lab","pmids":["16840782"],"is_preprint":false},{"year":2007,"finding":"IKBKE is amplified and overexpressed in breast cancer and functions as an oncogene; it activates the NF-κB pathway in both cell lines and breast tumors; suppression of IKBKE in amplified lines induces cell death.","method":"Library of activated kinases screen, whole-genome structural analysis (copy-number), shRNA knockdown, NF-κB reporter assay, transformation assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — integrated genomic approach with functional validation by kinase library screen, copy-number analysis, RNAi knockdown + cell-death readout, NF-κB reporter; multiple orthogonal methods, widely replicated","pmids":["17574021"],"is_preprint":false},{"year":2007,"finding":"TBK1 and IKBKE contain a ubiquitin-like domain (ULD) adjacent to their kinase domains; deletion or mutation of the ULD impairs kinase activation, blocks IRF3 phosphorylation and nuclear translocation, and abolishes IFN-β and RANTES promoter activation.","method":"Domain deletion and point mutagenesis, reconstitution in TBK1/IKBKE double-deficient cells, IRF3 phosphorylation assay, luciferase reporter, nuclear localization imaging","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis with reconstitution in null cells, multiple functional readouts (IRF3 phosphorylation, nuclear translocation, promoter activation); single lab but multiple orthogonal methods","pmids":["17599067"],"is_preprint":false},{"year":2008,"finding":"Paramyxoviral V proteins from Rubulavirus act as alternative substrates for TBK1/IKBKE; they are directly phosphorylated by TBK1/IKKε, which leads to their degradation and thereby inhibits IRF3-mediated antiviral gene induction.","method":"Cell survival assay for IRF3 inhibitors, in vitro phosphorylation assay, mutant PIV5 (V protein cannot inhibit IKKε) functional comparison","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro phosphorylation demonstrated, functional viral mutant validation; single lab","pmids":["18362155"],"is_preprint":false},{"year":2010,"finding":"IKBKE (IKKε) directly phosphorylates IRF-3 at Ser-386, Ser-396, and Ser-402 in its C-terminal regulatory domain, as determined by systematic mass spectrometry of co-expressed phosphorylated IRF-3.","method":"Co-expression of IRF-3 C-terminal domain with IKK-i, anion-exchange chromatography fractionation, nanoESI-MS intact mass analysis, LC-MS/MS phosphoproteomics with Orbitrap","journal":"Journal of proteomics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mass spectrometric identification of phosphorylation sites from co-expression reconstitution system; multiple MS methods orthogonally confirming phospho-residues","pmids":["20170763"],"is_preprint":false},{"year":2011,"finding":"IKBKE directly phosphorylates Akt at Thr308 and Ser473 independent of PI3K, PDK1, mTORC2, and the Akt pleckstrin homology domain, constituting a PI3K-independent Akt activation pathway.","method":"In vitro kinase assay, PI3K inhibitor treatment, PDK1 and mTORC2 knockdown, PH-domain-targeting inhibitor (perifosine/triciribine) versus kinase-domain-targeting inhibitors (MK-2206, GSK690693), transformation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro direct phosphorylation assay plus multiple inhibitor and knockdown approaches distinguishing PI3K-dependent vs. -independent routes; single lab, multiple orthogonal methods","pmids":["21908616"],"is_preprint":false},{"year":2013,"finding":"IKBKE directly phosphorylates FOXO3a at Ser644, promoting its nuclear-to-cytoplasmic translocation and degradation. An Akt-nonphosphorylatable FOXO3a-A3 mutant is still inhibited by IKBKE, and FOXO3a-S644A largely abrogates IKBKE's inhibitory effect on FOXO3a function.","method":"Site-directed mutagenesis (FOXO3a-S644A, FOXO3a-A3), in vitro kinase assay, subcellular fractionation and nuclear-cytoplasmic translocation assay, overexpression/knockdown studies","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of phospho-site combined with kinase assay and functional translocation/degradation readouts; single lab","pmids":["23691078"],"is_preprint":false},{"year":2013,"finding":"Amlexanox is a selective small-molecule inhibitor of IKBKE and TBK1; in obese mice it elevates energy expenditure through increased thermogenesis, producing weight loss and improved insulin sensitivity by targeting these kinases.","method":"In vitro kinase inhibition assay, mouse high-fat diet model, metabolic phenotyping (thermogenesis, weight, insulin sensitivity)","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct kinase inhibition confirmed in vitro; in vivo mechanistic validation in mouse model with multiple metabolic readouts; widely replicated in subsequent studies","pmids":["23396211"],"is_preprint":false},{"year":2014,"finding":"TBK1 and IKKε (IKBKE) are essential for TLR-induced rapid increases in glycolytic flux in dendritic cells by promoting association of the glycolytic enzyme HK-II with mitochondria, thereby supporting anabolic demands of DC activation.","method":"Pharmacological inhibition of TBK1/IKKε, metabolic flux measurements, HK-II mitochondrial association assay (subcellular fractionation), DC activation phenotyping","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct kinase inhibition linked to specific HK-II localization change and metabolic flux measurement; replicated with multiple TLR agonists and orthogonal readouts","pmids":["24562310"],"is_preprint":false},{"year":2016,"finding":"Mutant EGFR (but not wild-type EGFR) directly interacts with IKBKE and phosphorylates it on Y153 and Y179; the Y153F/Y179F unphosphorylatable IKBKE mutant loses kinase activity and fails to activate AKT.","method":"Co-immunoprecipitation, site-directed mutagenesis (Y153F/Y179F), in vitro kinase assay, phospho-specific antibody for Y153 in clinical NSCLC specimens, shRNA knockdown","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, mutagenesis loss-of-function, kinase assay; single lab","pmids":["27287717"],"is_preprint":false},{"year":2017,"finding":"Virus-activated IKKε phosphorylates YAP at Ser403, triggering lysosomal degradation of YAP and thereby relieving YAP-mediated inhibition of IRF3 dimerization and nuclear translocation during antiviral responses.","method":"In vitro kinase assay, site-directed mutagenesis of YAP-Ser403, lysosome inhibitor treatment, IRF3 dimerization and nuclear localization assays, viral infection models, YAP-deficient mice","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct phosphorylation by in vitro kinase assay, mutagenesis of the phospho-site, lysosomal degradation mechanism defined, in vivo validation; multiple orthogonal methods","pmids":["28481329"],"is_preprint":false},{"year":2017,"finding":"In C. elegans, the TBK1/IKKε family kinase IKKE-1 interacts with the allophagy receptor ALLO-1, and IKKE-1-dependent phosphorylation of ALLO-1 is required for paternal organelle (mitochondrial) clearance by selective autophagy.","method":"Genetic screens, co-immunoprecipitation, phosphorylation assay, live imaging, loss-of-function mutations in ikke-1","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, direct phosphorylation, genetic epistasis with phenotypic readout (mitochondrial clearance), live imaging; orthogonal methods in a single rigorous study","pmids":["29255173"],"is_preprint":false},{"year":2017,"finding":"IKBKE is a direct transcriptional target of STAT3; constitutively active STAT3 increases IKBKE mRNA and protein levels, and tobacco components (nicotine, NNK) induce IKBKE expression through STAT3 binding to STAT3-response elements in the IKBKE promoter.","method":"Ectopic STAT3 expression, STAT3 inhibition, IKBKE promoter characterization with ChIP and luciferase reporter, RT-PCR and Western blot","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming STAT3 binding to IKBKE promoter, luciferase reporter, mutagenesis of STAT3-response elements; single lab","pmids":["22330135"],"is_preprint":false},{"year":2018,"finding":"PLK4 physically interacts with IKBKE, phosphorylates it, and thereby increases NF-κB transcriptional activity in glioblastoma, contributing to TMZ chemoresistance.","method":"Co-immunoprecipitation, in vitro kinase assay, shRNA knockdown, NF-κB reporter assay, xenograft mouse model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP interaction confirmed, in vitro phosphorylation demonstrated, functional NF-κB readout; single lab","pmids":["30529153"],"is_preprint":false},{"year":2018,"finding":"IKBKE functions as a positive regulator of autophagy in breast cancer cells; its activity is required for ERBB2 and PI3K-AKT-MTOR pathway-dependent autophagy, and IKBKE-dependent autophagy is necessary for breast cancer cell proliferation.","method":"Activated kinase library screen, autophagy flux assays, kinase-dead IKBKE controls, ERBB2/PI3K pathway inhibitor epistasis, shRNA knockdown with proliferation readout","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase library screen, kinase-dead controls, epistasis with oncogenic pathway inhibitors; single lab, multiple methods","pmids":["30289335"],"is_preprint":false},{"year":2018,"finding":"IKBKE inhibits TSC1 through direct interaction and phosphorylation of TSC1, leading to TSC1 destabilization and consequent mTOR/S6K pathway activation in colorectal cancer cells.","method":"Co-immunoprecipitation of IKBKE and TSC1, IKBKE knockdown with S6K activity measurement, Western blot for TSC1 levels","journal":"Turkish journal of biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP and knockdown approach, single lab, limited mechanistic validation of direct phosphorylation","pmids":["30814890"],"is_preprint":false},{"year":2018,"finding":"IKBKE/TBK1 phosphorylates the oncogenic gene regulator YB-1, which then binds to the MYC promoter to enhance MYC transcription, sustaining MYC-dependent survival in AML cells.","method":"Proteomic analysis of IKBKE/TBK1-sensitive AML cells, shRNA knockdown, phosphorylation analysis of YB-1, ChIP assay for YB-1 on MYC promoter, gene expression profiling","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics identified YB-1 phosphorylation, ChIP confirmed YB-1-MYC promoter binding, functional shRNA knockdown; single lab, multiple orthogonal approaches","pmids":["30504235"],"is_preprint":false},{"year":2020,"finding":"IKBKE activity enhances androgen receptor (AR) levels in prostate cancer by inhibiting the Hippo pathway, reducing c-MYC at cis-regulatory elements in the AR gene, and this regulation is validated in patient-derived explants.","method":"siRNA knockdown, pharmacological inhibition, xenograft model, patient-derived explants, ChIP for c-MYC at AR gene regulatory elements, gene expression analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP mechanistic evidence, patient-derived explant validation, multiple cancer models; single lab","pmids":["32324216"],"is_preprint":false},{"year":2021,"finding":"IKBKE interacts with and directly phosphorylates NIK in the NF-κB pathway to suppress osteoclast differentiation; IKBKE knockout promotes osteoclastogenesis.","method":"Co-immunoprecipitation of IKKε and NIK, qPCR/immunoblot for NF-κB pathway components, IKKε knockout mouse model with osteoclast differentiation assays","journal":"International journal of biological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP for interaction, knockout model, but direct phosphorylation assay not described in abstract; single lab","pmids":["33867851"],"is_preprint":false},{"year":2022,"finding":"IKBKE directly phosphorylates the EMT transcription factor Snail, blocking β-TRCP1-mediated Snail ubiquitination and degradation, thereby stabilizing Snail to promote breast cancer invasion and metastasis.","method":"Direct in vitro kinase assay, co-immunoprecipitation, ubiquitination assay, murine mammary tumor model (PyVMT), in vitro invasion/migration assays, in vivo lung metastasis","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct kinase assay, co-IP, ubiquitination mechanism, in vitro and in vivo models; single lab but multiple orthogonal methods","pmids":["35066576"],"is_preprint":false},{"year":2022,"finding":"IKBKE drives constitutive ERK1/2 activation in tumor cells by physically interacting with and phosphorylating the MAP3K TPL2, which then activates MEK1.","method":"Co-immunoprecipitation of IKBKE with TPL2 and MEK1, in vitro kinase assay, IKBKE silencing with MAPK Western blot, RT-PCR","journal":"EXCLI journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP interaction shown, in vitro kinase assay, but single lab, limited validation","pmids":["35391917"],"is_preprint":false},{"year":2023,"finding":"SERPINB1 catalyzes K48-linked polyubiquitination of IKBKE and degrades it through the proteasome pathway; inhibition of IKBKE by SERPINB1 induces autophagy to decrease type I interferon signaling.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linkage specificity), proteasome inhibitor treatment, autophagy assays, antiviral readouts","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, K48-ubiquitination assay with linkage specificity, proteasome pathway confirmed; single lab","pmids":["37811994"],"is_preprint":false},{"year":2023,"finding":"IKKε (IKBKE) interacts with TEAD2 and YAP1 and accelerates their nuclear translocation; IKBKE promotes glioblastoma progression via a regulatory feedback circuit: IKBKE↑→YAP1↑→miR-let-7b/i↓→IKBKE↑.","method":"Co-immunoprecipitation (IKBKE with TEAD2 and YAP1), nuclear fractionation, miRNA overexpression/knockdown, in vivo subcutaneous and intracranial tumor models","journal":"Journal of translational medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP for interaction, functional nuclear translocation assay; single lab, limited mechanistic depth on direct phosphorylation","pmids":["34544426"],"is_preprint":false},{"year":2024,"finding":"TBK1 and IKBKE function redundantly to phosphorylate the selective autophagy receptor TAX1BP1; this phosphorylation promotes TAX1BP1 lysosomal localization/degradation and controls its function in clearing MAVS aggregates (aggrephagy) to limit RLR signaling.","method":"Genetic knockout of TBK1 and IKBKE, in vitro kinase assay for TAX1BP1 phosphorylation, lysosome localization assay, MAVS aggregate clearance assay (SDD-AGE), VSV infection model","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay, genetic KO, lysosome localization, MAVS aggrephagy functional readout; multiple orthogonal methods in single study","pmids":["39193925"],"is_preprint":false},{"year":2024,"finding":"IKBKE directly binds and phosphorylates FoxA1 to reduce its DNA binding and complex formation, leading to elevated hepatocellular malignancies; nonphosphorylatable Foxa1 knock-in mice delay liver tumorigenesis, and Ikbke knockout delays DEN-induced liver tumor development.","method":"CRISPR-based kinome screening, direct co-IP of IKBKE and FoxA1, in vitro kinase assay, Foxa1 knock-in mice (phospho-mimic and non-phosphorylatable), Ikbke knockout in DEN tumor model, DNA-binding assay","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPR kinome screen, in vitro kinase assay, co-IP, multiple knock-in and knockout mouse models with tumor phenotype; multiple orthogonal methods","pmids":["38324694"],"is_preprint":false},{"year":2024,"finding":"IKKε (IKBKE) confers non-IFN STING responses (NF-κB and MAPK) in macrophages via a conserved STING-binding mechanism shared with TBK1, and can sustain these responses in the absence of TBK1.","method":"Genetic knockout of IKKε and TBK1, biochemical STING-binding assays, Western blot for NF-κB and MAPK activation, macrophage functional assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and biochemical approaches, TBK1-deficient background epistasis; single lab","pmids":["39262777"],"is_preprint":false},{"year":2024,"finding":"IKBKE phosphorylates HMGA1a at Ser36 and/or Ser44, inhibiting its degradation and regulating its nuclear translocation; nuclear HMGA1a then binds the ZEB2 promoter to promote ZEB2 expression and EMT in glioblastoma.","method":"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis of HMGA1a phospho-sites, nuclear/cytoplasmic fractionation, ChIP on ZEB2 promoter, invasion/migration assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct phosphorylation at defined sites, co-IP, ChIP, functional EMT readout; single lab","pmids":["38242271"],"is_preprint":false},{"year":2024,"finding":"A truncated, kinase-dead IKBKE variant (p.Cys626Tyr, dominant-negative) causes impaired STING phosphorylation and IFN-β induction upon HSV-2 or dsDNA stimulation; rescue by wild-type IKBKE restores IFNB1 induction, establishing a nonredundant role for IKBKE in cGAS/STING-dependent antiviral immunity.","method":"Patient variant identification, STING phosphorylation Western blot, IFNB1 luciferase reporter, stem cell-derived microglia infection, wild-type IKBKE rescue experiment","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human LOF variant with dominant-negative activity, rescue experiment, stem cell-derived primary cell model; single patient but multiple assays","pmids":["37937644"],"is_preprint":false},{"year":2025,"finding":"The E3 ligase RNF114 catalyzes K33-linked ubiquitination of IKBKE at Lys490; the autophagy receptor CALCOCO2/NDP52 recognizes K33-ubiquitinated IKBKE and delivers it to phagophores for degradation, a mechanism exploited by picornavirus VP2 to suppress innate immunity.","method":"Co-immunoprecipitation, ubiquitination assay (K33-linkage specificity, Lys490 site-directed mutagenesis), autophagy flux assay, VP2 overexpression, siRNA knockdown of RNF114/CALCOCO2","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, linkage-specific ubiquitination assay, site mutagenesis; single lab but multiple orthogonal methods","pmids":["41319264"],"is_preprint":false},{"year":2025,"finding":"IKBKE/IKKε is recruited to the TNFR1 complex downstream of TNF signaling and is required for pro-survival RIPK1 S25 phosphorylation; genetic knockout of IKKε prevents this checkpoint, increasing RIPK1 activation and sensitizing tumor cells to CD8 T cell and NK cell killing.","method":"IKBKE/TBK1 functional knockouts in melanoma cells, RIPK1 phosphorylation (S25) Western blot, TNFR1 complex immunoprecipitation, T cell and NK cell co-culture cytotoxicity assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined phosphorylation site, complex immunoprecipitation, functional cytotoxicity assay; preprint, single lab","pmids":[],"is_preprint":true},{"year":2026,"finding":"IKBKE directly phosphorylates GSDME at Thr6, hindering caspase-3-mediated GSDME cleavage and thereby suppressing pyroptosis and contributing to gemcitabine chemoresistance in pancreatic cancer; co-IP and GST pulldown confirmed IKBKE-GSDME interaction.","method":"Co-IP, GST pulldown, in vitro kinase assay, phosphorylation mass spectrometry, site-directed mutagenesis of Thr6, caspase-3 cleavage assay, GSDME pyroptosis assay, patient-derived organoids, xenograft model","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay, mass spectrometry identification of Thr6 phosphosite, mutagenesis functional validation, cleavage assay, multiple model systems; single lab but comprehensive multi-method approach","pmids":["41699675"],"is_preprint":false}],"current_model":"IKBKE (IKKε) is a serine/threonine kinase that requires Ser172 activation-loop autophosphorylation and an intact ubiquitin-like domain for activity; it phosphorylates a broad substrate network including IκB-α (Ser36), p65/RelA (Ser536), IRF3 (Ser386/396/402), YAP (Ser403), Akt (Thr308/Ser473), FOXO3a (Ser644), Snail, FoxA1, HMGA1a, YB-1, TAX1BP1, GSDME (Thr6), TSC1, and RIPK1 (S25 via TNFR1 complex), activating NF-κB, IRF3/IFN, AKT/mTOR, Hippo, and autophagy pathways while also being subject to RNF114-mediated K33-ubiquitination and proteasomal or autophagic degradation; collectively these activities place IKBKE at the intersection of innate antiviral immunity, inflammatory signaling, metabolic regulation (glycolysis and thermogenesis in adipose tissue), and oncogenic transformation in multiple cancers."},"narrative":{"mechanistic_narrative":"IKBKE (IKKε) is a serine/threonine kinase that sits at the intersection of innate antiviral immunity, inflammatory signaling, and oncogenic transformation, originally identified as an LPS-inducible kinase that phosphorylates IκB-α at Ser36/Ser32 to stimulate NF-κB activation [PMID:10421793]. Its catalytic activity requires autophosphorylation of activation-loop Ser172 and an intact ubiquitin-like domain adjacent to the kinase domain, the latter being essential for IRF3 phosphorylation, nuclear translocation, and IFN-β/RANTES promoter induction [PMID:11839743, PMID:17599067]. In immunity, IKBKE directly phosphorylates IRF3 at Ser386/Ser396/Ser402 to drive interferon-β production [PMID:16199137, PMID:20170763], engages STING to confer non-IFN NF-κB and MAPK responses, and is essential and nonredundant for cGAS/STING-dependent antiviral immunity, as a dominant-negative human variant abolishes STING phosphorylation and IFNB1 induction [PMID:39262777, PMID:37937644]. IKBKE also tunes antiviral signaling by phosphorylating YAP at Ser403 to relieve YAP-mediated inhibition of IRF3, and phosphorylates the selective autophagy receptor TAX1BP1 to control MAVS aggregate clearance [PMID:28481329, PMID:39193925]. As an amplified oncogene in breast cancer, IKBKE activates NF-κB through p65/RelA Ser536 phosphorylation and is required for tumor cell survival and proliferation [PMID:16840782, PMID:17574021]. Its oncogenic reach extends through a PI3K-independent route to AKT activation (Thr308/Ser473), FOXO3a Ser644 phosphorylation driving its nuclear export and degradation, stabilization of the EMT factor Snail by blocking β-TRCP1-mediated degradation, and phosphorylation of FoxA1 to reduce its DNA binding and promote hepatocellular tumorigenesis [PMID:21908616, PMID:23691078, PMID:35066576, PMID:38324694]. IKBKE additionally regulates autophagy, glycolytic flux in dendritic cells, and adipose thermogenesis, the last being therapeutically exploitable via the IKBKE/TBK1 inhibitor amlexanox [PMID:23396211, PMID:24562310, PMID:30289335]. IKBKE protein levels are controlled by ubiquitin-dependent turnover, including RNF114-mediated K33-linked ubiquitination at Lys490 routing it to autophagic degradation and SERPINB1-driven K48-linked proteasomal degradation [PMID:37811994, PMID:41319264].","teleology":[{"year":1999,"claim":"Established IKBKE as a catalytically active, inducible kinase feeding into NF-κB, defining its first substrate and pathway link.","evidence":"Suppression subtractive hybridization, overexpression, and in vitro kinase assay on IκB-α","pmids":["10421793"],"confidence":"Medium","gaps":["Did not establish endogenous physiological context","Did not resolve upstream activation mechanism"]},{"year":2000,"claim":"Connected IKBKE to NF-κB activation through phosphorylation of the adaptor I-TRAF/TANK, liberating TRAF2 as a signaling mechanism.","evidence":"Yeast two-hybrid, co-IP, in vitro kinase assay, and dominant-negative rescue","pmids":["10759890"],"confidence":"Medium","gaps":["Direct phosphosite on I-TRAF not mapped","Physiological stimulus driving this in vivo unclear"]},{"year":2002,"claim":"Defined the molecular requirement for IKBKE activity by identifying activation-loop Ser172 autophosphorylation and a substrate specificity distinct from canonical IKK2.","evidence":"Recombinant protein, phosphopeptide mapping, Ser172 mutagenesis, ATP analog profiling","pmids":["11839743"],"confidence":"High","gaps":["Upstream kinase or trigger of Ser172 phosphorylation not defined","Structural basis of specificity not resolved"]},{"year":2005,"claim":"Positioned IKBKE as a dual NF-κB and IRF3 activator downstream of TLR but not TNFα signaling, clarifying its pathway placement.","evidence":"Tet-inducible wild-type/kinase-dead cell lines, cytokine and luciferase reporter assays","pmids":["16199137"],"confidence":"Medium","gaps":["Direct vs indirect IRF3 phosphorylation not shown here","Endogenous TLR receptor specificity not delineated"]},{"year":2006,"claim":"Identified p65/RelA Ser536 as a direct route by which IKBKE sustains constitutive NF-κB activity supporting cancer cell proliferation.","evidence":"RNAi knockdown, p65-S536A mutagenesis, NF-κB reporter and proliferation assays","pmids":["16840782"],"confidence":"Medium","gaps":["Direct in vitro phosphorylation of p65 by IKBKE not demonstrated","Selectivity for constitutive over induced signaling mechanism unexplained"]},{"year":2007,"claim":"Established IKBKE as an amplified breast cancer oncogene whose suppression is lethal in amplified lines, linking its NF-κB activity to transformation.","evidence":"Activated kinase library screen, copy-number analysis, shRNA, NF-κB reporter, transformation assay","pmids":["17574021"],"confidence":"High","gaps":["Full oncogenic substrate set not defined at this stage","Determinants of amplification dependency unresolved"]},{"year":2007,"claim":"Defined the ubiquitin-like domain as essential for kinase activation and downstream IRF3/IFN output, explaining a structural requirement for function.","evidence":"Domain deletion/mutagenesis with reconstitution in TBK1/IKBKE-null cells, IRF3 and promoter readouts","pmids":["17599067"],"confidence":"High","gaps":["Molecular mechanism of ULD-dependent activation not resolved","Whether ULD mediates ubiquitin binding unaddressed"]},{"year":2010,"claim":"Mapped the precise IRF3 C-terminal phosphosites (Ser386/396/402) targeted by IKBKE, establishing the molecular basis of IRF3 activation.","evidence":"Co-expression reconstitution with nanoESI-MS and LC-MS/MS phosphoproteomics","pmids":["20170763"],"confidence":"High","gaps":["In vivo stoichiometry of each site not determined","Hierarchy/ordering of multisite phosphorylation unknown"]},{"year":2011,"claim":"Revealed a PI3K-independent mechanism of AKT activation via direct IKBKE phosphorylation of Thr308 and Ser473, expanding its oncogenic repertoire.","evidence":"In vitro kinase assay, PI3K/PDK1/mTORC2 perturbation, PH- vs kinase-domain inhibitors, transformation assay","pmids":["21908616"],"confidence":"High","gaps":["Subcellular context of AKT phosphorylation not defined","Relative contribution vs canonical PI3K route in vivo unquantified"]},{"year":2013,"claim":"Showed IKBKE inactivates the tumor-suppressor FOXO3a through Ser644 phosphorylation independent of AKT, driving its export and degradation.","evidence":"FOXO3a-S644A and Akt-nonphosphorylatable mutants, in vitro kinase assay, fractionation","pmids":["23691078"],"confidence":"Medium","gaps":["E3 ligase mediating FOXO3a degradation not identified","Generality across cell types untested"]},{"year":2013,"claim":"Identified amlexanox as a selective IKBKE/TBK1 inhibitor that drives thermogenesis and improves metabolic phenotype, linking the kinase to energy homeostasis and providing a chemical tool.","evidence":"In vitro kinase inhibition and high-fat-diet mouse metabolic phenotyping","pmids":["23396211"],"confidence":"High","gaps":["Direct adipose substrate of IKBKE not defined here","TBK1 vs IKBKE contribution to phenotype not separated"]},{"year":2014,"claim":"Linked IKBKE/TBK1 to immunometabolism by promoting HK-II–mitochondria association and glycolytic flux during dendritic cell activation.","evidence":"Pharmacological inhibition, metabolic flux, subcellular fractionation, DC phenotyping","pmids":["24562310"],"confidence":"High","gaps":["Direct phosphorylation target driving HK-II relocation unidentified","IKBKE-specific vs TBK1 contribution unresolved"]},{"year":2016,"claim":"Established mutant EGFR as an upstream activator that tyrosine-phosphorylates IKBKE (Y153/Y179) to enable AKT activation in lung cancer.","evidence":"Co-IP, Y153F/Y179F mutagenesis, in vitro kinase assay, phospho-antibody in NSCLC specimens","pmids":["27287717"],"confidence":"Medium","gaps":["Tyrosine kinase responsible for IKBKE phosphorylation in cells not pinned down","Structural effect of tyrosine phosphorylation unclear"]},{"year":2017,"claim":"Defined a feedback mechanism in antiviral immunity whereby IKBKE phosphorylates YAP at Ser403 to drive its lysosomal degradation and relieve YAP suppression of IRF3.","evidence":"In vitro kinase assay, YAP-S403 mutagenesis, lysosome inhibition, IRF3 dimerization assays, YAP-deficient mice","pmids":["28481329"],"confidence":"High","gaps":["E3 ligase/lysosomal targeting machinery for YAP not identified","Cross-talk with Hippo core kinases not delineated"]},{"year":2017,"claim":"Demonstrated a conserved role for the IKBKE family in selective autophagy via phosphorylation of the allophagy receptor ALLO-1 for paternal organelle clearance.","evidence":"C. elegans genetic screens, co-IP, phosphorylation assay, live imaging, ikke-1 loss-of-function","pmids":["29255173"],"confidence":"High","gaps":["Mammalian orthologous receptor not identified in this study","ALLO-1 phosphosite mapping incomplete"]},{"year":2017,"claim":"Placed IKBKE downstream of STAT3 transcriptionally, explaining how oncogenic and tobacco-driven signaling upregulates IKBKE expression.","evidence":"Ectopic/inhibited STAT3, ChIP on IKBKE promoter, luciferase reporter, expression analysis","pmids":["22330135"],"confidence":"Medium","gaps":["Functional consequence of induced IKBKE not quantified here","Other transcriptional regulators not assessed"]},{"year":2018,"claim":"Connected IKBKE to multiple oncogenic outputs: positive regulation of ERBB2/PI3K-AKT-driven autophagy, TSC1 destabilization activating mTOR, and YB-1 phosphorylation enhancing MYC transcription.","evidence":"Kinase library screen, autophagy flux/kinase-dead controls, co-IP, ChIP on MYC promoter, S6K activity","pmids":["30289335","30814890","30504235"],"confidence":"Medium","gaps":["TSC1 phosphosite not mapped (Low-confidence finding)","Direct vs indirect autophagy regulation incompletely separated"]},{"year":2018,"claim":"Identified PLK4 as an upstream kinase that phosphorylates IKBKE to boost NF-κB activity and TMZ chemoresistance in glioblastoma.","evidence":"Co-IP, in vitro kinase assay, shRNA, NF-κB reporter, xenograft","pmids":["30529153"],"confidence":"Medium","gaps":["IKBKE phosphosite targeted by PLK4 not defined","Generality beyond glioblastoma untested"]},{"year":2020,"claim":"Linked IKBKE to androgen receptor regulation in prostate cancer through Hippo pathway inhibition and c-MYC occupancy at AR regulatory elements.","evidence":"siRNA, inhibitor, xenograft, patient-derived explants, ChIP for c-MYC at AR locus","pmids":["32324216"],"confidence":"Medium","gaps":["Direct IKBKE substrate in this axis unidentified","Mechanistic link from Hippo to c-MYC incompletely defined"]},{"year":2022,"claim":"Defined IKBKE-driven Snail stabilization (blocking β-TRCP1 degradation) and TPL2-MEK1-ERK activation as mechanisms promoting invasion/metastasis and constitutive ERK signaling.","evidence":"In vitro kinase assay, co-IP, ubiquitination assay, PyVMT model, invasion/metastasis assays","pmids":["35066576","35391917"],"confidence":"High","gaps":["TPL2 axis is Low-confidence and phosphosite unmapped","Snail phosphosite not specified"]},{"year":2023,"claim":"Established two degradation routes for IKBKE—SERPINB1-mediated K48 proteasomal turnover and IKBKE-TEAD2/YAP1 nuclear circuits—linking IKBKE protein control to interferon and tumor signaling.","evidence":"Co-IP, K48-linkage ubiquitination assay, proteasome inhibition, nuclear fractionation, miRNA perturbation, tumor models","pmids":["37811994","34544426"],"confidence":"Medium","gaps":["TEAD2/YAP1 finding is Low-confidence with limited direct phosphorylation evidence","Stimulus regulating SERPINB1-IKBKE turnover unclear"]},{"year":2024,"claim":"Consolidated IKBKE's roles in innate immune regulation (TAX1BP1 phosphorylation controlling MAVS aggrephagy; STING-binding non-IFN responses; nonredundant cGAS/STING antiviral immunity via a human dominant-negative variant) and oncogenic transcription factor control (FoxA1 DNA-binding inhibition driving liver tumorigenesis; HMGA1a phosphorylation driving ZEB2/EMT).","evidence":"Genetic knockouts, in vitro kinase assays, STING-binding assays, MAVS SDD-AGE, patient variant rescue, knock-in/knockout mouse tumor models, ChIP","pmids":["39193925","39262777","37937644","38324694","38242271"],"confidence":"High","gaps":["Redundancy boundaries between TBK1 and IKBKE incompletely partitioned","FoxA1 and HMGA1a phosphosite occupancy in vivo not fully quantified"]},{"year":2025,"claim":"Identified RNF114-mediated K33-ubiquitination (Lys490) routing IKBKE to NDP52-dependent autophagic degradation and a TNFR1-complex role in pro-survival RIPK1 S25 phosphorylation, expanding IKBKE regulation and its impact on cell-death checkpoints.","evidence":"Co-IP, K33-linkage ubiquitination assay with Lys490 mutagenesis, autophagy flux, TNFR1 complex IP, RIPK1 S25 readout, immune cytotoxicity assays (one preprint)","pmids":["41319264"],"confidence":"Medium","gaps":["TNFR1/RIPK1 finding is a preprint awaiting peer review","Crosstalk between K33 and K48 ubiquitination of IKBKE unresolved"]},{"year":2026,"claim":"Defined IKBKE phosphorylation of GSDME at Thr6 as a brake on caspase-3-mediated cleavage that suppresses pyroptosis and confers chemoresistance, linking IKBKE to programmed cell death control.","evidence":"Co-IP, GST pulldown, in vitro kinase assay, MS phosphosite mapping, Thr6 mutagenesis, cleavage and pyroptosis assays, organoids, xenograft","pmids":["41699675"],"confidence":"High","gaps":["Conservation across cancer types beyond pancreatic untested","Interplay with IKBKE's NF-κB survival roles not integrated"]},{"year":null,"claim":"How the diverse IKBKE substrate network is selected and prioritized in different tissue and disease contexts, and what governs the choice between its activating phosphorylation outputs versus its own ubiquitin-dependent degradation, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model explaining multisubstrate specificity","Context-dependent partitioning of immune vs oncogenic vs metabolic roles undefined","Hierarchy of competing degradation pathways (K48 vs K33) unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,8,9,10,14,23,27,28,30,34]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,8,9]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10,30]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[26,30]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,3,8,14,27,29,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,9,19,24]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,23,28,34]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[15,18,27,32]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[33,34]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[11,12]}],"complexes":["TNFR1 complex"],"partners":["IRF3","YAP1","AKT","TAX1BP1","STING","TSC1","FOXA1","RNF114"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14164","full_name":"Inhibitor of nuclear factor kappa-B kinase subunit epsilon","aliases":["Inducible I kappa-B kinase","IKK-i"],"length_aa":716,"mass_kda":80.5,"function":"Serine/threonine kinase that plays an essential role in regulating inflammatory responses to viral infection, through the activation of the type I IFN, NF-kappa-B and STAT signaling. Also involved in TNFA and inflammatory cytokines, like Interleukin-1, signaling. Following activation of viral RNA sensors, such as RIG-I-like receptors, associates with DDX3X and phosphorylates interferon regulatory factors (IRFs), IRF3 and IRF7, as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRF3 leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNB. In order to establish such an antiviral state, IKBKE forms several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including IPS1/MAVS, TANK, AZI2/NAP1 or TBKBP1/SINTBAD can be recruited to the IKBKE-containing-complexes. Activated by polyubiquitination in response to TNFA and interleukin-1, regulates the NF-kappa-B signaling pathway through, at least, the phosphorylation of CYLD. 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. In addition, is also required for the induction of a subset of ISGs which displays antiviral activity, may be through the phosphorylation of STAT1 at 'Ser-708'. Phosphorylation of STAT1 at 'Ser-708' also seems to promote the assembly and DNA binding of ISGF3 (STAT1:STAT2:IRF9) complexes compared to GAF (STAT1:STAT1) complexes, in this way regulating the balance between type I and type II IFN responses. Protects cells against DNA damage-induced cell death. Also plays an important role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity. Phosphorylates AKT1","subcellular_location":"Cytoplasm; Nucleus; Nucleus, PML body","url":"https://www.uniprot.org/uniprotkb/Q14164/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IKBKE","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IKBKE","total_profiled":1310},"omim":[{"mim_id":"620004","title":"NMRA-LIKE REDOX SENSOR 1; NMRAL1","url":"https://www.omim.org/entry/620004"},{"mim_id":"619410","title":"TUBULIN TYROSINE LIGASE-LIKE 12; TTLL12","url":"https://www.omim.org/entry/619410"},{"mim_id":"612374","title":"STIMULATOR OF INTERFERON RESPONSE cGAMP INTERACTOR 1; STING1","url":"https://www.omim.org/entry/612374"},{"mim_id":"611656","title":"SUPPRESSOR OF IKBKE 1; SIKE1","url":"https://www.omim.org/entry/611656"},{"mim_id":"609916","title":"5-@AZACYTIDINE-INDUCED PROTEIN 2; AZI2","url":"https://www.omim.org/entry/609916"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":22.7}],"url":"https://www.proteinatlas.org/search/IKBKE"},"hgnc":{"alias_symbol":["IKKE","IKK-i","KIAA0151"],"prev_symbol":[]},"alphafold":{"accession":"Q14164","domains":[{"cath_id":"3.30.200.20","chopping":"1-86","consensus_level":"high","plddt":90.6779,"start":1,"end":86},{"cath_id":"1.10.510.10","chopping":"91-303","consensus_level":"medium","plddt":90.7564,"start":91,"end":303},{"cath_id":"3.10.20.90","chopping":"314-381","consensus_level":"high","plddt":95.4075,"start":314,"end":381},{"cath_id":"1.20.1270.420","chopping":"408-473_495-654","consensus_level":"medium","plddt":92.9405,"start":408,"end":654}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14164","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14164-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14164-F1-predicted_aligned_error_v6.png","plddt_mean":88.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IKBKE","jax_strain_url":"https://www.jax.org/strain/search?query=IKBKE"},"sequence":{"accession":"Q14164","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14164.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14164/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14164"}},"corpus_meta":[{"pmid":"24562310","id":"PMC_24562310","title":"TLR-driven 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signaling axis].","date":"2025","source":"Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica","url":"https://pubmed.ncbi.nlm.nih.gov/40686170","citation_count":1,"is_preprint":false},{"pmid":"41378297","id":"PMC_41378297","title":"IKBKE modulates autophagy and progestin resistance in endometrial cancer.","date":"2025","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41378297","citation_count":0,"is_preprint":false},{"pmid":"41623554","id":"PMC_41623554","title":"Phorbol Myristate Acetate Inhibits Senecavirus A Replication by Activating IKBKE-Mediated IFN Pathway and NF-κB Signal.","date":"2026","source":"Transboundary and emerging diseases","url":"https://pubmed.ncbi.nlm.nih.gov/41623554","citation_count":0,"is_preprint":false},{"pmid":"41571553","id":"PMC_41571553","title":"CXCL14 Promotes Ovarian Cancer Progression and Autophagy Through the IKBKE/NF-κB Pathway.","date":"2026","source":"The journal of gene 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muscle","date":"2025-10-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.16.682884","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.20.655064","title":"Inhibition of TBK1/IKKe mediated RIPK1 phosphorylation sensitizes tumors to immune cell killing","date":"2025-05-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.20.655064","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46863,"output_tokens":8589,"usd":0.134712,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18391,"output_tokens":7180,"usd":0.135728,"stage2_stop_reason":"end_turn"},"total_usd":0.27044,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"IKK-i (IKBKE) is a lipopolysaccharide-inducible kinase that phosphorylates IκB-α preferentially at Ser36 (and Ser32) and significantly stimulates NF-κB activation upon overexpression.\",\n      \"method\": \"Suppression subtractive hybridization isolation, overexpression in cell lines, in vitro kinase assay on IκB-α\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay with site-specific substrate, but single lab, foundational characterization paper\",\n      \"pmids\": [\"10421793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IKK-i (IKBKE) phosphorylates I-TRAF/TANK in vitro, causing TRAF2 to be released from the I-TRAF/TRAF2 complex, and NF-κB activation by IKK-i is mediated through this phosphorylation-dependent liberation of TRAF2.\",\n      \"method\": \"Yeast two-hybrid screening (identified IKK-i / I-TRAF interaction), co-immunoprecipitation, in vitro kinase assay, dominant-negative rescue experiments\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction confirmed by yeast two-hybrid and co-IP, in vitro kinase assay, dominant-negative epistasis; single lab\",\n      \"pmids\": [\"10759890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Recombinant human IKBKE (IKK-i) is phosphorylated on Ser172 in its activation loop, and this phosphorylation is necessary for kinase activity; IKK-i and TBK1 have distinct peptide substrate specificities from IKK-2 and distinct ATP-binding site properties.\",\n      \"method\": \"Recombinant protein purification, phosphopeptide mapping, site-directed mutagenesis of Ser172, in vitro kinase assays, ATP analog profiling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro with purified recombinant enzyme, mutagenesis of activation-loop Ser172, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"11839743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IKK-i (IKBKE) activates both NF-κB and IRF3 pathways, leading to interferon-β and other cytokine production; kinase-dead IKK-i does not block TNFα-mediated NF-κB activation, indicating IKK-i acts upstream of IKK2 downstream of TLR signaling rather than in the TNFα pathway. STAT1, Tyk2, and JAK1 serve as secondary mediators downstream of IFN-β produced by IKK-i.\",\n      \"method\": \"Tetracycline-inducible stable cell lines expressing wild-type or kinase-inactive IKK-i, cytokine production assays, luciferase reporter assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible expression system with kinase-dead controls, reporter assays, multiple cytokine readouts; single lab\",\n      \"pmids\": [\"16199137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IKBKE (IKK-i/IKKε) phosphorylates p65/RelA at Ser536 to sustain constitutive (but not cytokine-induced) NF-κB activity in cancer cells; knockdown of IKBKE or expression of S536A p65 suppresses HeLa cell proliferation.\",\n      \"method\": \"RNA interference knockdown, site-directed mutagenesis of p65-S536, NF-κB reporter assays, cell proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of phospho-site combined with RNAi knockdown and functional proliferation readout; single lab\",\n      \"pmids\": [\"16840782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IKBKE is amplified and overexpressed in breast cancer and functions as an oncogene; it activates the NF-κB pathway in both cell lines and breast tumors; suppression of IKBKE in amplified lines induces cell death.\",\n      \"method\": \"Library of activated kinases screen, whole-genome structural analysis (copy-number), shRNA knockdown, NF-κB reporter assay, transformation assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — integrated genomic approach with functional validation by kinase library screen, copy-number analysis, RNAi knockdown + cell-death readout, NF-κB reporter; multiple orthogonal methods, widely replicated\",\n      \"pmids\": [\"17574021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TBK1 and IKBKE contain a ubiquitin-like domain (ULD) adjacent to their kinase domains; deletion or mutation of the ULD impairs kinase activation, blocks IRF3 phosphorylation and nuclear translocation, and abolishes IFN-β and RANTES promoter activation.\",\n      \"method\": \"Domain deletion and point mutagenesis, reconstitution in TBK1/IKBKE double-deficient cells, IRF3 phosphorylation assay, luciferase reporter, nuclear localization imaging\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with reconstitution in null cells, multiple functional readouts (IRF3 phosphorylation, nuclear translocation, promoter activation); single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17599067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Paramyxoviral V proteins from Rubulavirus act as alternative substrates for TBK1/IKBKE; they are directly phosphorylated by TBK1/IKKε, which leads to their degradation and thereby inhibits IRF3-mediated antiviral gene induction.\",\n      \"method\": \"Cell survival assay for IRF3 inhibitors, in vitro phosphorylation assay, mutant PIV5 (V protein cannot inhibit IKKε) functional comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro phosphorylation demonstrated, functional viral mutant validation; single lab\",\n      \"pmids\": [\"18362155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IKBKE (IKKε) directly phosphorylates IRF-3 at Ser-386, Ser-396, and Ser-402 in its C-terminal regulatory domain, as determined by systematic mass spectrometry of co-expressed phosphorylated IRF-3.\",\n      \"method\": \"Co-expression of IRF-3 C-terminal domain with IKK-i, anion-exchange chromatography fractionation, nanoESI-MS intact mass analysis, LC-MS/MS phosphoproteomics with Orbitrap\",\n      \"journal\": \"Journal of proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mass spectrometric identification of phosphorylation sites from co-expression reconstitution system; multiple MS methods orthogonally confirming phospho-residues\",\n      \"pmids\": [\"20170763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IKBKE directly phosphorylates Akt at Thr308 and Ser473 independent of PI3K, PDK1, mTORC2, and the Akt pleckstrin homology domain, constituting a PI3K-independent Akt activation pathway.\",\n      \"method\": \"In vitro kinase assay, PI3K inhibitor treatment, PDK1 and mTORC2 knockdown, PH-domain-targeting inhibitor (perifosine/triciribine) versus kinase-domain-targeting inhibitors (MK-2206, GSK690693), transformation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro direct phosphorylation assay plus multiple inhibitor and knockdown approaches distinguishing PI3K-dependent vs. -independent routes; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"21908616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IKBKE directly phosphorylates FOXO3a at Ser644, promoting its nuclear-to-cytoplasmic translocation and degradation. An Akt-nonphosphorylatable FOXO3a-A3 mutant is still inhibited by IKBKE, and FOXO3a-S644A largely abrogates IKBKE's inhibitory effect on FOXO3a function.\",\n      \"method\": \"Site-directed mutagenesis (FOXO3a-S644A, FOXO3a-A3), in vitro kinase assay, subcellular fractionation and nuclear-cytoplasmic translocation assay, overexpression/knockdown studies\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of phospho-site combined with kinase assay and functional translocation/degradation readouts; single lab\",\n      \"pmids\": [\"23691078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Amlexanox is a selective small-molecule inhibitor of IKBKE and TBK1; in obese mice it elevates energy expenditure through increased thermogenesis, producing weight loss and improved insulin sensitivity by targeting these kinases.\",\n      \"method\": \"In vitro kinase inhibition assay, mouse high-fat diet model, metabolic phenotyping (thermogenesis, weight, insulin sensitivity)\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct kinase inhibition confirmed in vitro; in vivo mechanistic validation in mouse model with multiple metabolic readouts; widely replicated in subsequent studies\",\n      \"pmids\": [\"23396211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TBK1 and IKKε (IKBKE) are essential for TLR-induced rapid increases in glycolytic flux in dendritic cells by promoting association of the glycolytic enzyme HK-II with mitochondria, thereby supporting anabolic demands of DC activation.\",\n      \"method\": \"Pharmacological inhibition of TBK1/IKKε, metabolic flux measurements, HK-II mitochondrial association assay (subcellular fractionation), DC activation phenotyping\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct kinase inhibition linked to specific HK-II localization change and metabolic flux measurement; replicated with multiple TLR agonists and orthogonal readouts\",\n      \"pmids\": [\"24562310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mutant EGFR (but not wild-type EGFR) directly interacts with IKBKE and phosphorylates it on Y153 and Y179; the Y153F/Y179F unphosphorylatable IKBKE mutant loses kinase activity and fails to activate AKT.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (Y153F/Y179F), in vitro kinase assay, phospho-specific antibody for Y153 in clinical NSCLC specimens, shRNA knockdown\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, mutagenesis loss-of-function, kinase assay; single lab\",\n      \"pmids\": [\"27287717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Virus-activated IKKε phosphorylates YAP at Ser403, triggering lysosomal degradation of YAP and thereby relieving YAP-mediated inhibition of IRF3 dimerization and nuclear translocation during antiviral responses.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis of YAP-Ser403, lysosome inhibitor treatment, IRF3 dimerization and nuclear localization assays, viral infection models, YAP-deficient mice\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct phosphorylation by in vitro kinase assay, mutagenesis of the phospho-site, lysosomal degradation mechanism defined, in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"28481329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In C. elegans, the TBK1/IKKε family kinase IKKE-1 interacts with the allophagy receptor ALLO-1, and IKKE-1-dependent phosphorylation of ALLO-1 is required for paternal organelle (mitochondrial) clearance by selective autophagy.\",\n      \"method\": \"Genetic screens, co-immunoprecipitation, phosphorylation assay, live imaging, loss-of-function mutations in ikke-1\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, direct phosphorylation, genetic epistasis with phenotypic readout (mitochondrial clearance), live imaging; orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"29255173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IKBKE is a direct transcriptional target of STAT3; constitutively active STAT3 increases IKBKE mRNA and protein levels, and tobacco components (nicotine, NNK) induce IKBKE expression through STAT3 binding to STAT3-response elements in the IKBKE promoter.\",\n      \"method\": \"Ectopic STAT3 expression, STAT3 inhibition, IKBKE promoter characterization with ChIP and luciferase reporter, RT-PCR and Western blot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming STAT3 binding to IKBKE promoter, luciferase reporter, mutagenesis of STAT3-response elements; single lab\",\n      \"pmids\": [\"22330135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PLK4 physically interacts with IKBKE, phosphorylates it, and thereby increases NF-κB transcriptional activity in glioblastoma, contributing to TMZ chemoresistance.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, shRNA knockdown, NF-κB reporter assay, xenograft mouse model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP interaction confirmed, in vitro phosphorylation demonstrated, functional NF-κB readout; single lab\",\n      \"pmids\": [\"30529153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IKBKE functions as a positive regulator of autophagy in breast cancer cells; its activity is required for ERBB2 and PI3K-AKT-MTOR pathway-dependent autophagy, and IKBKE-dependent autophagy is necessary for breast cancer cell proliferation.\",\n      \"method\": \"Activated kinase library screen, autophagy flux assays, kinase-dead IKBKE controls, ERBB2/PI3K pathway inhibitor epistasis, shRNA knockdown with proliferation readout\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase library screen, kinase-dead controls, epistasis with oncogenic pathway inhibitors; single lab, multiple methods\",\n      \"pmids\": [\"30289335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IKBKE inhibits TSC1 through direct interaction and phosphorylation of TSC1, leading to TSC1 destabilization and consequent mTOR/S6K pathway activation in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation of IKBKE and TSC1, IKBKE knockdown with S6K activity measurement, Western blot for TSC1 levels\",\n      \"journal\": \"Turkish journal of biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP and knockdown approach, single lab, limited mechanistic validation of direct phosphorylation\",\n      \"pmids\": [\"30814890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IKBKE/TBK1 phosphorylates the oncogenic gene regulator YB-1, which then binds to the MYC promoter to enhance MYC transcription, sustaining MYC-dependent survival in AML cells.\",\n      \"method\": \"Proteomic analysis of IKBKE/TBK1-sensitive AML cells, shRNA knockdown, phosphorylation analysis of YB-1, ChIP assay for YB-1 on MYC promoter, gene expression profiling\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics identified YB-1 phosphorylation, ChIP confirmed YB-1-MYC promoter binding, functional shRNA knockdown; single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"30504235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IKBKE activity enhances androgen receptor (AR) levels in prostate cancer by inhibiting the Hippo pathway, reducing c-MYC at cis-regulatory elements in the AR gene, and this regulation is validated in patient-derived explants.\",\n      \"method\": \"siRNA knockdown, pharmacological inhibition, xenograft model, patient-derived explants, ChIP for c-MYC at AR gene regulatory elements, gene expression analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP mechanistic evidence, patient-derived explant validation, multiple cancer models; single lab\",\n      \"pmids\": [\"32324216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IKBKE interacts with and directly phosphorylates NIK in the NF-κB pathway to suppress osteoclast differentiation; IKBKE knockout promotes osteoclastogenesis.\",\n      \"method\": \"Co-immunoprecipitation of IKKε and NIK, qPCR/immunoblot for NF-κB pathway components, IKKε knockout mouse model with osteoclast differentiation assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP for interaction, knockout model, but direct phosphorylation assay not described in abstract; single lab\",\n      \"pmids\": [\"33867851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IKBKE directly phosphorylates the EMT transcription factor Snail, blocking β-TRCP1-mediated Snail ubiquitination and degradation, thereby stabilizing Snail to promote breast cancer invasion and metastasis.\",\n      \"method\": \"Direct in vitro kinase assay, co-immunoprecipitation, ubiquitination assay, murine mammary tumor model (PyVMT), in vitro invasion/migration assays, in vivo lung metastasis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct kinase assay, co-IP, ubiquitination mechanism, in vitro and in vivo models; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"35066576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IKBKE drives constitutive ERK1/2 activation in tumor cells by physically interacting with and phosphorylating the MAP3K TPL2, which then activates MEK1.\",\n      \"method\": \"Co-immunoprecipitation of IKBKE with TPL2 and MEK1, in vitro kinase assay, IKBKE silencing with MAPK Western blot, RT-PCR\",\n      \"journal\": \"EXCLI journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP interaction shown, in vitro kinase assay, but single lab, limited validation\",\n      \"pmids\": [\"35391917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SERPINB1 catalyzes K48-linked polyubiquitination of IKBKE and degrades it through the proteasome pathway; inhibition of IKBKE by SERPINB1 induces autophagy to decrease type I interferon signaling.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linkage specificity), proteasome inhibitor treatment, autophagy assays, antiviral readouts\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, K48-ubiquitination assay with linkage specificity, proteasome pathway confirmed; single lab\",\n      \"pmids\": [\"37811994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IKKε (IKBKE) interacts with TEAD2 and YAP1 and accelerates their nuclear translocation; IKBKE promotes glioblastoma progression via a regulatory feedback circuit: IKBKE↑→YAP1↑→miR-let-7b/i↓→IKBKE↑.\",\n      \"method\": \"Co-immunoprecipitation (IKBKE with TEAD2 and YAP1), nuclear fractionation, miRNA overexpression/knockdown, in vivo subcutaneous and intracranial tumor models\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP for interaction, functional nuclear translocation assay; single lab, limited mechanistic depth on direct phosphorylation\",\n      \"pmids\": [\"34544426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TBK1 and IKBKE function redundantly to phosphorylate the selective autophagy receptor TAX1BP1; this phosphorylation promotes TAX1BP1 lysosomal localization/degradation and controls its function in clearing MAVS aggregates (aggrephagy) to limit RLR signaling.\",\n      \"method\": \"Genetic knockout of TBK1 and IKBKE, in vitro kinase assay for TAX1BP1 phosphorylation, lysosome localization assay, MAVS aggregate clearance assay (SDD-AGE), VSV infection model\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay, genetic KO, lysosome localization, MAVS aggrephagy functional readout; multiple orthogonal methods in single study\",\n      \"pmids\": [\"39193925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IKBKE directly binds and phosphorylates FoxA1 to reduce its DNA binding and complex formation, leading to elevated hepatocellular malignancies; nonphosphorylatable Foxa1 knock-in mice delay liver tumorigenesis, and Ikbke knockout delays DEN-induced liver tumor development.\",\n      \"method\": \"CRISPR-based kinome screening, direct co-IP of IKBKE and FoxA1, in vitro kinase assay, Foxa1 knock-in mice (phospho-mimic and non-phosphorylatable), Ikbke knockout in DEN tumor model, DNA-binding assay\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPR kinome screen, in vitro kinase assay, co-IP, multiple knock-in and knockout mouse models with tumor phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"38324694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IKKε (IKBKE) confers non-IFN STING responses (NF-κB and MAPK) in macrophages via a conserved STING-binding mechanism shared with TBK1, and can sustain these responses in the absence of TBK1.\",\n      \"method\": \"Genetic knockout of IKKε and TBK1, biochemical STING-binding assays, Western blot for NF-κB and MAPK activation, macrophage functional assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and biochemical approaches, TBK1-deficient background epistasis; single lab\",\n      \"pmids\": [\"39262777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IKBKE phosphorylates HMGA1a at Ser36 and/or Ser44, inhibiting its degradation and regulating its nuclear translocation; nuclear HMGA1a then binds the ZEB2 promoter to promote ZEB2 expression and EMT in glioblastoma.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis of HMGA1a phospho-sites, nuclear/cytoplasmic fractionation, ChIP on ZEB2 promoter, invasion/migration assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phosphorylation at defined sites, co-IP, ChIP, functional EMT readout; single lab\",\n      \"pmids\": [\"38242271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A truncated, kinase-dead IKBKE variant (p.Cys626Tyr, dominant-negative) causes impaired STING phosphorylation and IFN-β induction upon HSV-2 or dsDNA stimulation; rescue by wild-type IKBKE restores IFNB1 induction, establishing a nonredundant role for IKBKE in cGAS/STING-dependent antiviral immunity.\",\n      \"method\": \"Patient variant identification, STING phosphorylation Western blot, IFNB1 luciferase reporter, stem cell-derived microglia infection, wild-type IKBKE rescue experiment\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human LOF variant with dominant-negative activity, rescue experiment, stem cell-derived primary cell model; single patient but multiple assays\",\n      \"pmids\": [\"37937644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The E3 ligase RNF114 catalyzes K33-linked ubiquitination of IKBKE at Lys490; the autophagy receptor CALCOCO2/NDP52 recognizes K33-ubiquitinated IKBKE and delivers it to phagophores for degradation, a mechanism exploited by picornavirus VP2 to suppress innate immunity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K33-linkage specificity, Lys490 site-directed mutagenesis), autophagy flux assay, VP2 overexpression, siRNA knockdown of RNF114/CALCOCO2\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, linkage-specific ubiquitination assay, site mutagenesis; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41319264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IKBKE/IKKε is recruited to the TNFR1 complex downstream of TNF signaling and is required for pro-survival RIPK1 S25 phosphorylation; genetic knockout of IKKε prevents this checkpoint, increasing RIPK1 activation and sensitizing tumor cells to CD8 T cell and NK cell killing.\",\n      \"method\": \"IKBKE/TBK1 functional knockouts in melanoma cells, RIPK1 phosphorylation (S25) Western blot, TNFR1 complex immunoprecipitation, T cell and NK cell co-culture cytotoxicity assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined phosphorylation site, complex immunoprecipitation, functional cytotoxicity assay; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"IKBKE directly phosphorylates GSDME at Thr6, hindering caspase-3-mediated GSDME cleavage and thereby suppressing pyroptosis and contributing to gemcitabine chemoresistance in pancreatic cancer; co-IP and GST pulldown confirmed IKBKE-GSDME interaction.\",\n      \"method\": \"Co-IP, GST pulldown, in vitro kinase assay, phosphorylation mass spectrometry, site-directed mutagenesis of Thr6, caspase-3 cleavage assay, GSDME pyroptosis assay, patient-derived organoids, xenograft model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay, mass spectrometry identification of Thr6 phosphosite, mutagenesis functional validation, cleavage assay, multiple model systems; single lab but comprehensive multi-method approach\",\n      \"pmids\": [\"41699675\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IKBKE (IKKε) is a serine/threonine kinase that requires Ser172 activation-loop autophosphorylation and an intact ubiquitin-like domain for activity; it phosphorylates a broad substrate network including IκB-α (Ser36), p65/RelA (Ser536), IRF3 (Ser386/396/402), YAP (Ser403), Akt (Thr308/Ser473), FOXO3a (Ser644), Snail, FoxA1, HMGA1a, YB-1, TAX1BP1, GSDME (Thr6), TSC1, and RIPK1 (S25 via TNFR1 complex), activating NF-κB, IRF3/IFN, AKT/mTOR, Hippo, and autophagy pathways while also being subject to RNF114-mediated K33-ubiquitination and proteasomal or autophagic degradation; collectively these activities place IKBKE at the intersection of innate antiviral immunity, inflammatory signaling, metabolic regulation (glycolysis and thermogenesis in adipose tissue), and oncogenic transformation in multiple cancers.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IKBKE (IKKε) is a serine/threonine kinase that sits at the intersection of innate antiviral immunity, inflammatory signaling, and oncogenic transformation, originally identified as an LPS-inducible kinase that phosphorylates IκB-α at Ser36/Ser32 to stimulate NF-κB activation [#0]. Its catalytic activity requires autophosphorylation of activation-loop Ser172 and an intact ubiquitin-like domain adjacent to the kinase domain, the latter being essential for IRF3 phosphorylation, nuclear translocation, and IFN-β/RANTES promoter induction [#2, #6]. In immunity, IKBKE directly phosphorylates IRF3 at Ser386/Ser396/Ser402 to drive interferon-β production [#3, #8], engages STING to confer non-IFN NF-κB and MAPK responses, and is essential and nonredundant for cGAS/STING-dependent antiviral immunity, as a dominant-negative human variant abolishes STING phosphorylation and IFNB1 induction [#29, #31]. IKBKE also tunes antiviral signaling by phosphorylating YAP at Ser403 to relieve YAP-mediated inhibition of IRF3, and phosphorylates the selective autophagy receptor TAX1BP1 to control MAVS aggregate clearance [#14, #27]. As an amplified oncogene in breast cancer, IKBKE activates NF-κB through p65/RelA Ser536 phosphorylation and is required for tumor cell survival and proliferation [#4, #5]. Its oncogenic reach extends through a PI3K-independent route to AKT activation (Thr308/Ser473), FOXO3a Ser644 phosphorylation driving its nuclear export and degradation, stabilization of the EMT factor Snail by blocking β-TRCP1-mediated degradation, and phosphorylation of FoxA1 to reduce its DNA binding and promote hepatocellular tumorigenesis [#9, #10, #23, #28]. IKBKE additionally regulates autophagy, glycolytic flux in dendritic cells, and adipose thermogenesis, the last being therapeutically exploitable via the IKBKE/TBK1 inhibitor amlexanox [#11, #12, #18]. IKBKE protein levels are controlled by ubiquitin-dependent turnover, including RNF114-mediated K33-linked ubiquitination at Lys490 routing it to autophagic degradation and SERPINB1-driven K48-linked proteasomal degradation [#25, #32].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established IKBKE as a catalytically active, inducible kinase feeding into NF-κB, defining its first substrate and pathway link.\",\n      \"evidence\": \"Suppression subtractive hybridization, overexpression, and in vitro kinase assay on IκB-α\",\n      \"pmids\": [\"10421793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish endogenous physiological context\", \"Did not resolve upstream activation mechanism\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Connected IKBKE to NF-κB activation through phosphorylation of the adaptor I-TRAF/TANK, liberating TRAF2 as a signaling mechanism.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, in vitro kinase assay, and dominant-negative rescue\",\n      \"pmids\": [\"10759890\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphosite on I-TRAF not mapped\", \"Physiological stimulus driving this in vivo unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the molecular requirement for IKBKE activity by identifying activation-loop Ser172 autophosphorylation and a substrate specificity distinct from canonical IKK2.\",\n      \"evidence\": \"Recombinant protein, phosphopeptide mapping, Ser172 mutagenesis, ATP analog profiling\",\n      \"pmids\": [\"11839743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream kinase or trigger of Ser172 phosphorylation not defined\", \"Structural basis of specificity not resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Positioned IKBKE as a dual NF-κB and IRF3 activator downstream of TLR but not TNFα signaling, clarifying its pathway placement.\",\n      \"evidence\": \"Tet-inducible wild-type/kinase-dead cell lines, cytokine and luciferase reporter assays\",\n      \"pmids\": [\"16199137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect IRF3 phosphorylation not shown here\", \"Endogenous TLR receptor specificity not delineated\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified p65/RelA Ser536 as a direct route by which IKBKE sustains constitutive NF-κB activity supporting cancer cell proliferation.\",\n      \"evidence\": \"RNAi knockdown, p65-S536A mutagenesis, NF-κB reporter and proliferation assays\",\n      \"pmids\": [\"16840782\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct in vitro phosphorylation of p65 by IKBKE not demonstrated\", \"Selectivity for constitutive over induced signaling mechanism unexplained\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established IKBKE as an amplified breast cancer oncogene whose suppression is lethal in amplified lines, linking its NF-κB activity to transformation.\",\n      \"evidence\": \"Activated kinase library screen, copy-number analysis, shRNA, NF-κB reporter, transformation assay\",\n      \"pmids\": [\"17574021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full oncogenic substrate set not defined at this stage\", \"Determinants of amplification dependency unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the ubiquitin-like domain as essential for kinase activation and downstream IRF3/IFN output, explaining a structural requirement for function.\",\n      \"evidence\": \"Domain deletion/mutagenesis with reconstitution in TBK1/IKBKE-null cells, IRF3 and promoter readouts\",\n      \"pmids\": [\"17599067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of ULD-dependent activation not resolved\", \"Whether ULD mediates ubiquitin binding unaddressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapped the precise IRF3 C-terminal phosphosites (Ser386/396/402) targeted by IKBKE, establishing the molecular basis of IRF3 activation.\",\n      \"evidence\": \"Co-expression reconstitution with nanoESI-MS and LC-MS/MS phosphoproteomics\",\n      \"pmids\": [\"20170763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo stoichiometry of each site not determined\", \"Hierarchy/ordering of multisite phosphorylation unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed a PI3K-independent mechanism of AKT activation via direct IKBKE phosphorylation of Thr308 and Ser473, expanding its oncogenic repertoire.\",\n      \"evidence\": \"In vitro kinase assay, PI3K/PDK1/mTORC2 perturbation, PH- vs kinase-domain inhibitors, transformation assay\",\n      \"pmids\": [\"21908616\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subcellular context of AKT phosphorylation not defined\", \"Relative contribution vs canonical PI3K route in vivo unquantified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed IKBKE inactivates the tumor-suppressor FOXO3a through Ser644 phosphorylation independent of AKT, driving its export and degradation.\",\n      \"evidence\": \"FOXO3a-S644A and Akt-nonphosphorylatable mutants, in vitro kinase assay, fractionation\",\n      \"pmids\": [\"23691078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating FOXO3a degradation not identified\", \"Generality across cell types untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified amlexanox as a selective IKBKE/TBK1 inhibitor that drives thermogenesis and improves metabolic phenotype, linking the kinase to energy homeostasis and providing a chemical tool.\",\n      \"evidence\": \"In vitro kinase inhibition and high-fat-diet mouse metabolic phenotyping\",\n      \"pmids\": [\"23396211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct adipose substrate of IKBKE not defined here\", \"TBK1 vs IKBKE contribution to phenotype not separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked IKBKE/TBK1 to immunometabolism by promoting HK-II–mitochondria association and glycolytic flux during dendritic cell activation.\",\n      \"evidence\": \"Pharmacological inhibition, metabolic flux, subcellular fractionation, DC phenotyping\",\n      \"pmids\": [\"24562310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphorylation target driving HK-II relocation unidentified\", \"IKBKE-specific vs TBK1 contribution unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established mutant EGFR as an upstream activator that tyrosine-phosphorylates IKBKE (Y153/Y179) to enable AKT activation in lung cancer.\",\n      \"evidence\": \"Co-IP, Y153F/Y179F mutagenesis, in vitro kinase assay, phospho-antibody in NSCLC specimens\",\n      \"pmids\": [\"27287717\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tyrosine kinase responsible for IKBKE phosphorylation in cells not pinned down\", \"Structural effect of tyrosine phosphorylation unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a feedback mechanism in antiviral immunity whereby IKBKE phosphorylates YAP at Ser403 to drive its lysosomal degradation and relieve YAP suppression of IRF3.\",\n      \"evidence\": \"In vitro kinase assay, YAP-S403 mutagenesis, lysosome inhibition, IRF3 dimerization assays, YAP-deficient mice\",\n      \"pmids\": [\"28481329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase/lysosomal targeting machinery for YAP not identified\", \"Cross-talk with Hippo core kinases not delineated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated a conserved role for the IKBKE family in selective autophagy via phosphorylation of the allophagy receptor ALLO-1 for paternal organelle clearance.\",\n      \"evidence\": \"C. elegans genetic screens, co-IP, phosphorylation assay, live imaging, ikke-1 loss-of-function\",\n      \"pmids\": [\"29255173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian orthologous receptor not identified in this study\", \"ALLO-1 phosphosite mapping incomplete\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed IKBKE downstream of STAT3 transcriptionally, explaining how oncogenic and tobacco-driven signaling upregulates IKBKE expression.\",\n      \"evidence\": \"Ectopic/inhibited STAT3, ChIP on IKBKE promoter, luciferase reporter, expression analysis\",\n      \"pmids\": [\"22330135\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of induced IKBKE not quantified here\", \"Other transcriptional regulators not assessed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected IKBKE to multiple oncogenic outputs: positive regulation of ERBB2/PI3K-AKT-driven autophagy, TSC1 destabilization activating mTOR, and YB-1 phosphorylation enhancing MYC transcription.\",\n      \"evidence\": \"Kinase library screen, autophagy flux/kinase-dead controls, co-IP, ChIP on MYC promoter, S6K activity\",\n      \"pmids\": [\"30289335\", \"30814890\", \"30504235\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TSC1 phosphosite not mapped (Low-confidence finding)\", \"Direct vs indirect autophagy regulation incompletely separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified PLK4 as an upstream kinase that phosphorylates IKBKE to boost NF-κB activity and TMZ chemoresistance in glioblastoma.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, shRNA, NF-κB reporter, xenograft\",\n      \"pmids\": [\"30529153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IKBKE phosphosite targeted by PLK4 not defined\", \"Generality beyond glioblastoma untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked IKBKE to androgen receptor regulation in prostate cancer through Hippo pathway inhibition and c-MYC occupancy at AR regulatory elements.\",\n      \"evidence\": \"siRNA, inhibitor, xenograft, patient-derived explants, ChIP for c-MYC at AR locus\",\n      \"pmids\": [\"32324216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct IKBKE substrate in this axis unidentified\", \"Mechanistic link from Hippo to c-MYC incompletely defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined IKBKE-driven Snail stabilization (blocking β-TRCP1 degradation) and TPL2-MEK1-ERK activation as mechanisms promoting invasion/metastasis and constitutive ERK signaling.\",\n      \"evidence\": \"In vitro kinase assay, co-IP, ubiquitination assay, PyVMT model, invasion/metastasis assays\",\n      \"pmids\": [\"35066576\", \"35391917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TPL2 axis is Low-confidence and phosphosite unmapped\", \"Snail phosphosite not specified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established two degradation routes for IKBKE—SERPINB1-mediated K48 proteasomal turnover and IKBKE-TEAD2/YAP1 nuclear circuits—linking IKBKE protein control to interferon and tumor signaling.\",\n      \"evidence\": \"Co-IP, K48-linkage ubiquitination assay, proteasome inhibition, nuclear fractionation, miRNA perturbation, tumor models\",\n      \"pmids\": [\"37811994\", \"34544426\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TEAD2/YAP1 finding is Low-confidence with limited direct phosphorylation evidence\", \"Stimulus regulating SERPINB1-IKBKE turnover unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Consolidated IKBKE's roles in innate immune regulation (TAX1BP1 phosphorylation controlling MAVS aggrephagy; STING-binding non-IFN responses; nonredundant cGAS/STING antiviral immunity via a human dominant-negative variant) and oncogenic transcription factor control (FoxA1 DNA-binding inhibition driving liver tumorigenesis; HMGA1a phosphorylation driving ZEB2/EMT).\",\n      \"evidence\": \"Genetic knockouts, in vitro kinase assays, STING-binding assays, MAVS SDD-AGE, patient variant rescue, knock-in/knockout mouse tumor models, ChIP\",\n      \"pmids\": [\"39193925\", \"39262777\", \"37937644\", \"38324694\", \"38242271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy boundaries between TBK1 and IKBKE incompletely partitioned\", \"FoxA1 and HMGA1a phosphosite occupancy in vivo not fully quantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified RNF114-mediated K33-ubiquitination (Lys490) routing IKBKE to NDP52-dependent autophagic degradation and a TNFR1-complex role in pro-survival RIPK1 S25 phosphorylation, expanding IKBKE regulation and its impact on cell-death checkpoints.\",\n      \"evidence\": \"Co-IP, K33-linkage ubiquitination assay with Lys490 mutagenesis, autophagy flux, TNFR1 complex IP, RIPK1 S25 readout, immune cytotoxicity assays (one preprint)\",\n      \"pmids\": [\"41319264\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TNFR1/RIPK1 finding is a preprint awaiting peer review\", \"Crosstalk between K33 and K48 ubiquitination of IKBKE unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined IKBKE phosphorylation of GSDME at Thr6 as a brake on caspase-3-mediated cleavage that suppresses pyroptosis and confers chemoresistance, linking IKBKE to programmed cell death control.\",\n      \"evidence\": \"Co-IP, GST pulldown, in vitro kinase assay, MS phosphosite mapping, Thr6 mutagenesis, cleavage and pyroptosis assays, organoids, xenograft\",\n      \"pmids\": [\"41699675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation across cancer types beyond pancreatic untested\", \"Interplay with IKBKE's NF-κB survival roles not integrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse IKBKE substrate network is selected and prioritized in different tissue and disease contexts, and what governs the choice between its activating phosphorylation outputs versus its own ubiquitin-dependent degradation, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model explaining multisubstrate specificity\", \"Context-dependent partitioning of immune vs oncogenic vs metabolic roles undefined\", \"Hierarchy of competing degradation pathways (K48 vs K33) unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 8, 9, 10, 14, 23, 27, 28, 30, 34]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 8, 9]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10, 30]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [26, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 3, 8, 14, 27, 29, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 9, 19, 24]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 23, 28, 34]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [15, 18, 27, 32]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [33, 34]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [11, 12]}\n    ],\n    \"complexes\": [\"TNFR1 complex\"],\n    \"partners\": [\"IRF3\", \"YAP1\", \"AKT\", \"TAX1BP1\", \"STING\", \"TSC1\", \"FoxA1\", \"RNF114\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}