Affinage

IKBKE

Inhibitor of nuclear factor kappa-B kinase subunit epsilon · UniProt Q14164

Length
716 aa
Mass
80.5 kDa
Annotated
2026-06-10
89 papers in source corpus 34 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1999 Medium

    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

    PMID:10421793

    Open questions at the time
    • Did not establish endogenous physiological context
    • Did not resolve upstream activation mechanism
  2. 2000 Medium

    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

    PMID:10759890

    Open questions at the time
    • Direct phosphosite on I-TRAF not mapped
    • Physiological stimulus driving this in vivo unclear
  3. 2002 High

    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

    PMID:11839743

    Open questions at the time
    • Upstream kinase or trigger of Ser172 phosphorylation not defined
    • Structural basis of specificity not resolved
  4. 2005 Medium

    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

    PMID:16199137

    Open questions at the time
    • Direct vs indirect IRF3 phosphorylation not shown here
    • Endogenous TLR receptor specificity not delineated
  5. 2006 Medium

    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

    PMID:16840782

    Open questions at the time
    • Direct in vitro phosphorylation of p65 by IKBKE not demonstrated
    • Selectivity for constitutive over induced signaling mechanism unexplained
  6. 2007 High

    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

    PMID:17574021

    Open questions at the time
    • Full oncogenic substrate set not defined at this stage
    • Determinants of amplification dependency unresolved
  7. 2007 High

    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

    PMID:17599067

    Open questions at the time
    • Molecular mechanism of ULD-dependent activation not resolved
    • Whether ULD mediates ubiquitin binding unaddressed
  8. 2010 High

    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

    PMID:20170763

    Open questions at the time
    • In vivo stoichiometry of each site not determined
    • Hierarchy/ordering of multisite phosphorylation unknown
  9. 2011 High

    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

    PMID:21908616

    Open questions at the time
    • Subcellular context of AKT phosphorylation not defined
    • Relative contribution vs canonical PI3K route in vivo unquantified
  10. 2013 Medium

    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

    PMID:23691078

    Open questions at the time
    • E3 ligase mediating FOXO3a degradation not identified
    • Generality across cell types untested
  11. 2013 High

    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

    PMID:23396211

    Open questions at the time
    • Direct adipose substrate of IKBKE not defined here
    • TBK1 vs IKBKE contribution to phenotype not separated
  12. 2014 High

    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

    PMID:24562310

    Open questions at the time
    • Direct phosphorylation target driving HK-II relocation unidentified
    • IKBKE-specific vs TBK1 contribution unresolved
  13. 2016 Medium

    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

    PMID:27287717

    Open questions at the time
    • Tyrosine kinase responsible for IKBKE phosphorylation in cells not pinned down
    • Structural effect of tyrosine phosphorylation unclear
  14. 2017 High

    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

    PMID:28481329

    Open questions at the time
    • E3 ligase/lysosomal targeting machinery for YAP not identified
    • Cross-talk with Hippo core kinases not delineated
  15. 2017 High

    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

    PMID:29255173

    Open questions at the time
    • Mammalian orthologous receptor not identified in this study
    • ALLO-1 phosphosite mapping incomplete
  16. 2017 Medium

    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

    PMID:22330135

    Open questions at the time
    • Functional consequence of induced IKBKE not quantified here
    • Other transcriptional regulators not assessed
  17. 2018 Medium

    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

    PMID:30289335 PMID:30504235 PMID:30814890

    Open questions at the time
    • TSC1 phosphosite not mapped (Low-confidence finding)
    • Direct vs indirect autophagy regulation incompletely separated
  18. 2018 Medium

    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

    PMID:30529153

    Open questions at the time
    • IKBKE phosphosite targeted by PLK4 not defined
    • Generality beyond glioblastoma untested
  19. 2020 Medium

    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

    PMID:32324216

    Open questions at the time
    • Direct IKBKE substrate in this axis unidentified
    • Mechanistic link from Hippo to c-MYC incompletely defined
  20. 2022 High

    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

    PMID:35066576 PMID:35391917

    Open questions at the time
    • TPL2 axis is Low-confidence and phosphosite unmapped
    • Snail phosphosite not specified
  21. 2023 Medium

    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

    PMID:34544426 PMID:37811994

    Open questions at the time
    • TEAD2/YAP1 finding is Low-confidence with limited direct phosphorylation evidence
    • Stimulus regulating SERPINB1-IKBKE turnover unclear
  22. 2024 High

    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

    PMID:37937644 PMID:38242271 PMID:38324694 PMID:39193925 PMID:39262777

    Open questions at the time
    • Redundancy boundaries between TBK1 and IKBKE incompletely partitioned
    • FoxA1 and HMGA1a phosphosite occupancy in vivo not fully quantified
  23. 2025 Medium

    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)

    PMID:41319264

    Open questions at the time
    • TNFR1/RIPK1 finding is a preprint awaiting peer review
    • Crosstalk between K33 and K48 ubiquitination of IKBKE unresolved
  24. 2026 High

    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

    PMID:41699675

    Open questions at the time
    • Conservation across cancer types beyond pancreatic untested
    • Interplay with IKBKE's NF-κB survival roles not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 11 GO:0016740 transferase activity 4 GO:0140657 ATP-dependent activity 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 7 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-9612973 Autophagy 4 R-HSA-1430728 Metabolism 2 R-HSA-5357801 Programmed Cell Death 2
Partners
AKTFOXA1IRF3RNF114STINGTAX1BP1TSC1YAP1
Complex memberships
TNFR1 complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 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. Suppression subtractive hybridization isolation, overexpression in cell lines, in vitro kinase assay on IκB-α International immunology Medium 10421793
2000 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. Yeast two-hybrid screening (identified IKK-i / I-TRAF interaction), co-immunoprecipitation, in vitro kinase assay, dominant-negative rescue experiments Genes to cells Medium 10759890
2002 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. Recombinant protein purification, phosphopeptide mapping, site-directed mutagenesis of Ser172, in vitro kinase assays, ATP analog profiling The Journal of biological chemistry High 11839743
2005 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. Tetracycline-inducible stable cell lines expressing wild-type or kinase-inactive IKK-i, cytokine production assays, luciferase reporter assays Cellular signalling Medium 16199137
2006 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. RNA interference knockdown, site-directed mutagenesis of p65-S536, NF-κB reporter assays, cell proliferation assays The Journal of biological chemistry Medium 16840782
2007 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. Library of activated kinases screen, whole-genome structural analysis (copy-number), shRNA knockdown, NF-κB reporter assay, transformation assay Cell High 17574021
2007 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. Domain deletion and point mutagenesis, reconstitution in TBK1/IKBKE double-deficient cells, IRF3 phosphorylation assay, luciferase reporter, nuclear localization imaging The EMBO journal High 17599067
2008 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. Cell survival assay for IRF3 inhibitors, in vitro phosphorylation assay, mutant PIV5 (V protein cannot inhibit IKKε) functional comparison The Journal of biological chemistry Medium 18362155
2010 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. 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 of proteomics High 20170763
2011 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. 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 The Journal of biological chemistry High 21908616
2013 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. Site-directed mutagenesis (FOXO3a-S644A, FOXO3a-A3), in vitro kinase assay, subcellular fractionation and nuclear-cytoplasmic translocation assay, overexpression/knockdown studies PloS one Medium 23691078
2013 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. In vitro kinase inhibition assay, mouse high-fat diet model, metabolic phenotyping (thermogenesis, weight, insulin sensitivity) Nature medicine High 23396211
2014 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. Pharmacological inhibition of TBK1/IKKε, metabolic flux measurements, HK-II mitochondrial association assay (subcellular fractionation), DC activation phenotyping Nature immunology High 24562310
2016 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. Co-immunoprecipitation, site-directed mutagenesis (Y153F/Y179F), in vitro kinase assay, phospho-specific antibody for Y153 in clinical NSCLC specimens, shRNA knockdown Cancer research Medium 27287717
2017 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. 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 Nature immunology High 28481329
2017 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. Genetic screens, co-immunoprecipitation, phosphorylation assay, live imaging, loss-of-function mutations in ikke-1 Nature cell biology High 29255173
2017 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. Ectopic STAT3 expression, STAT3 inhibition, IKBKE promoter characterization with ChIP and luciferase reporter, RT-PCR and Western blot Oncogene Medium 22330135
2018 PLK4 physically interacts with IKBKE, phosphorylates it, and thereby increases NF-κB transcriptional activity in glioblastoma, contributing to TMZ chemoresistance. Co-immunoprecipitation, in vitro kinase assay, shRNA knockdown, NF-κB reporter assay, xenograft mouse model Cancer letters Medium 30529153
2018 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. Activated kinase library screen, autophagy flux assays, kinase-dead IKBKE controls, ERBB2/PI3K pathway inhibitor epistasis, shRNA knockdown with proliferation readout Autophagy Medium 30289335
2018 IKBKE inhibits TSC1 through direct interaction and phosphorylation of TSC1, leading to TSC1 destabilization and consequent mTOR/S6K pathway activation in colorectal cancer cells. Co-immunoprecipitation of IKBKE and TSC1, IKBKE knockdown with S6K activity measurement, Western blot for TSC1 levels Turkish journal of biology Low 30814890
2018 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. 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 Blood advances Medium 30504235
2020 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. siRNA knockdown, pharmacological inhibition, xenograft model, patient-derived explants, ChIP for c-MYC at AR gene regulatory elements, gene expression analysis Nucleic acids research Medium 32324216
2021 IKBKE interacts with and directly phosphorylates NIK in the NF-κB pathway to suppress osteoclast differentiation; IKBKE knockout promotes osteoclastogenesis. Co-immunoprecipitation of IKKε and NIK, qPCR/immunoblot for NF-κB pathway components, IKKε knockout mouse model with osteoclast differentiation assays International journal of biological sciences Low 33867851
2022 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. Direct in vitro kinase assay, co-immunoprecipitation, ubiquitination assay, murine mammary tumor model (PyVMT), in vitro invasion/migration assays, in vivo lung metastasis Cell death and differentiation High 35066576
2022 IKBKE drives constitutive ERK1/2 activation in tumor cells by physically interacting with and phosphorylating the MAP3K TPL2, which then activates MEK1. Co-immunoprecipitation of IKBKE with TPL2 and MEK1, in vitro kinase assay, IKBKE silencing with MAPK Western blot, RT-PCR EXCLI journal Low 35391917
2023 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. Co-immunoprecipitation, ubiquitination assay (K48-linkage specificity), proteasome inhibitor treatment, autophagy assays, antiviral readouts Journal of virology Medium 37811994
2023 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↑. Co-immunoprecipitation (IKBKE with TEAD2 and YAP1), nuclear fractionation, miRNA overexpression/knockdown, in vivo subcutaneous and intracranial tumor models Journal of translational medicine Low 34544426
2024 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. 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 Autophagy High 39193925
2024 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. 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 Science advances High 38324694
2024 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. Genetic knockout of IKKε and TBK1, biochemical STING-binding assays, Western blot for NF-κB and MAPK activation, macrophage functional assays iScience Medium 39262777
2024 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. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis of HMGA1a phospho-sites, nuclear/cytoplasmic fractionation, ChIP on ZEB2 promoter, invasion/migration assays Cellular signalling Medium 38242271
2024 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. Patient variant identification, STING phosphorylation Western blot, IFNB1 luciferase reporter, stem cell-derived microglia infection, wild-type IKBKE rescue experiment JCI insight Medium 37937644
2025 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. Co-immunoprecipitation, ubiquitination assay (K33-linkage specificity, Lys490 site-directed mutagenesis), autophagy flux assay, VP2 overexpression, siRNA knockdown of RNF114/CALCOCO2 Autophagy Medium 41319264
2025 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. IKBKE/TBK1 functional knockouts in melanoma cells, RIPK1 phosphorylation (S25) Western blot, TNFR1 complex immunoprecipitation, T cell and NK cell co-culture cytotoxicity assays bioRxivpreprint Medium
2026 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. 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 of experimental & clinical cancer research High 41699675

Source papers

Stage 0 corpus · 89 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKɛ supports the anabolic demands of dendritic cell activation. Nature immunology 903 24562310
2007 Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell 514 17574021
2013 An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice. Nature medicine 381 23396211
1999 IKK-i, a novel lipopolysaccharide-inducible kinase that is related to IkappaB kinases. International immunology 318 10421793
2017 YAP antagonizes innate antiviral immunity and is targeted for lysosomal degradation through IKKɛ-mediated phosphorylation. Nature immunology 167 28481329
2017 Inhibition of IKKɛ and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes. Cell metabolism 137 28683283
2006 IKK-i/IKKepsilon controls constitutive, cancer cell-associated NF-kappaB activity via regulation of Ser-536 p65/RelA phosphorylation. The Journal of biological chemistry 134 16840782
2014 Targeting an IKBKE cytokine network impairs triple-negative breast cancer growth. The Journal of clinical investigation 126 25365225
2002 IKK-i and TBK-1 are enzymatically distinct from the homologous enzyme IKK-2: comparative analysis of recombinant human IKK-i, TBK-1, and IKK-2. The Journal of biological chemistry 120 11839743
2004 Histamine H1 receptor antagonist blocks histamine-induced proinflammatory cytokine production through inhibition of Ca2+-dependent protein kinase C, Raf/MEK/ERK and IKK/I kappa B/NF-kappa B signal cascades. Biochemical pharmacology 110 15652235
2007 Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genes. The EMBO journal 105 17599067
2000 NF-kappaB activation through IKK-i-dependent I-TRAF/TANK phosphorylation. Genes to cells : devoted to molecular & cellular mechanisms 93 10759890
2008 Select paramyxoviral V proteins inhibit IRF3 activation by acting as alternative substrates for inhibitor of kappaB kinase epsilon (IKKe)/TBK1. The Journal of biological chemistry 85 18362155
2011 IKBKE protein activates Akt independent of phosphatidylinositol 3-kinase/PDK1/mTORC2 and the pleckstrin homology domain to sustain malignant transformation. The Journal of biological chemistry 78 21908616
2020 Short-term exposure to air pollution (PM2.5) induces hypothalamic inflammation, and long-term leads to leptin resistance and obesity via Tlr4/Ikbke in mice. Scientific reports 66 32576879
2016 Suppressor of IKKɛ is an essential negative regulator of pathological cardiac hypertrophy. Nature communications 66 27249321
2010 IKBKE is over-expressed in glioma and contributes to resistance of glioma cells to apoptosis via activating NF-κB. The Journal of pathology 65 21171089
2012 IKBKE is induced by STAT3 and tobacco carcinogen and determines chemosensitivity in non-small cell lung cancer. Oncogene 63 22330135
2017 Amlexanox, a selective inhibitor of IKBKE, generates anti-tumoral effects by disrupting the Hippo pathway in human glioblastoma cell lines. Cell death & disease 58 29048430
2010 A candidate gene study of the type I interferon pathway implicates IKBKE and IL8 as risk loci for SLE. European journal of human genetics : EJHG 58 21179067
2020 Co-delivery of IKBKE siRNA and cabazitaxel by hybrid nanocomplex inhibits invasiveness and growth of triple-negative breast cancer. Science advances 56 32832636
2018 PLK4 is a determinant of temozolomide sensitivity through phosphorylation of IKBKE in glioblastoma. Cancer letters 53 30529153
2017 The autophagy receptor ALLO-1 and the IKKE-1 kinase control clearance of paternal mitochondria in Caenorhabditis elegans. Nature cell biology 51 29255173
2019 Advances in IKBKE as a potential target for cancer therapy. Cancer medicine 48 31733040
2005 IKK-i signals through IRF3 and NFkappaB to mediate the production of inflammatory cytokines. Cellular signalling 45 16199137
2011 MicroRNAs 296 and 298 are imprinted and part of the GNAS/Gnas cluster and miR-296 targets IKBKE and Tmed9. RNA (New York, N.Y.) 40 22114321
2013 IKBKE phosphorylation and inhibition of FOXO3a: a mechanism of IKBKE oncogenic function. PloS one 37 23691078
2022 IKBKE phosphorylates and stabilizes Snail to promote breast cancer invasion and metastasis. Cell death and differentiation 34 35066576
2015 MicroRNAs let-7b/i suppress human glioma cell invasion and migration by targeting IKBKE directly. Biochemical and biophysical research communications 34 25656572
2014 Hematopoietic IKBKE limits the chronicity of inflammasome priming and metaflammation. Proceedings of the National Academy of Sciences of the United States of America 34 25540417
2018 Aphthous ulcer drug inhibits prostate tumor metastasis by targeting IKKɛ/TBK1/NF-κB signaling. Theranostics 33 30279728
2017 IKBKE Is Required during KRAS-Induced Pancreatic Tumorigenesis. Cancer research 33 28069799
2025 Ginseng exosomes modulate M1/M2 polarisation by activating autophagy and target IKK/IкB/NF-кB to alleviate inflammatory bowel disease. Journal of nanobiotechnology 32 40065319
2016 IKBKE Is a Substrate of EGFR and a Therapeutic Target in Non-Small Cell Lung Cancer with Activating Mutations of EGFR. Cancer research 32 27287717
2018 Activated kinase screening identifies the IKBKE oncogene as a positive regulator of autophagy. Autophagy 31 30289335
2017 IL-17 axis accelerates the inflammatory progression of obese in mice via TBK1 and IKBKE pathway. Immunology letters 30 28237848
2001 Expression and regulation of inducible IkappaB kinase (IKK-i) in human fibroblast-like synoviocytes. Cellular immunology 30 11902829
2020 IKBKE activity enhances AR levels in advanced prostate cancer via modulation of the Hippo pathway. Nucleic acids research 29 32324216
2002 Chlamydia pneumoniae activates IKK/I kappa B-mediated signaling, which is inhibited by 4-HNE and following primary exposure. Atherosclerosis 29 12208473
2019 Dual TBK1/IKKɛ inhibitor amlexanox attenuates the severity of hepatotoxin-induced liver fibrosis and biliary fibrosis in mice. Journal of cellular and molecular medicine 28 31821710
2017 IKBKE regulates cell proliferation and epithelial-mesenchymal transition of human malignant glioma via the Hippo pathway. Oncotarget 28 28548934
2013 Contribution of IKBKE and IFIH1 gene variants to SLE susceptibility. Genes and immunity 27 23535865
2020 Macrophages confer resistance to BET inhibition in triple-negative breast cancer by upregulating IKBKE. Biochemical pharmacology 26 32603665
2019 IKBKE enhances TMZ-chemoresistance through upregulation of MGMT expression in glioblastoma. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 23 31865606
2018 The kinases IKBKE and TBK1 regulate MYC-dependent survival pathways through YB-1 in AML and are targets for therapy. Blood advances 23 30504235
2017 Brief Report: Blockade of TANK-Binding Kinase 1/IKKɛ Inhibits Mutant Stimulator of Interferon Genes (STING)-Mediated Inflammatory Responses in Human Peripheral Blood Mononuclear Cells. Arthritis & rheumatology (Hoboken, N.J.) 23 28426911
2022 Sanguinarine Inhibition of TNF-α-Induced CCL2, IKBKE/NF-κB/ERK1/2 Signaling Pathway, and Cell Migration in Human Triple-Negative Breast Cancer Cells. International journal of molecular sciences 22 35955463
2020 Lentiviral delivery of combinatorial CAR/CRISPRi circuit into human primary T cells is enhanced by TBK1/IKKɛ complex inhibitor BX795. Journal of translational medicine 20 32967676
2022 A co-crystal berberine-ibuprofen improves obesity by inhibiting the protein kinases TBK1 and IKKɛ. Communications biology 17 35962183
2015 IKBKE Upregulation is Positively Associated with Squamous Cell Carcinoma of the Lung In Vivo and Malignant Transformation of Human Bronchial Epithelial Cells In Vitro. Medical science monitor : international medical journal of experimental and clinical research 17 26025939
2024 Phosphorylation of the selective autophagy receptor TAX1BP1 by TBK1 and IKBKE/IKKi promotes ATG8-family protein-dependent clearance of MAVS aggregates. Autophagy 16 39193925
2017 MiR-98 Promotes Apoptosis of Glioma Cells via Suppressing IKBKE/NF-κB Pathway. Technology in cancer research & treatment 13 29333957
2024 IKKɛ induces STING non-IFN immune responses via a mechanism analogous to TBK1. iScience 12 39262777
2021 IKKe in osteoclast inhibits the progression of methylprednisolone-induced osteonecrosis. International journal of biological sciences 12 33867851
2024 Atypical inflammatory kinase IKBKE phosphorylates and inactivates FoxA1 to promote liver tumorigenesis. Science advances 11 38324694
2021 Amlexanox Enhances Temozolomide-Induced Antitumor Effects in Human Glioblastoma Cells by Inhibiting IKBKE and the Akt-mTOR Signaling Pathway. ACS omega 11 33644550
2023 SERPINB1 promotes Senecavirus A replication by degrading IKBKE and regulating the IFN pathway via autophagy. Journal of virology 10 37811994
2017 IKBKE promotes glioblastoma progression by establishing the regulatory feedback loop of IKBKE/YAP1/miR-Let-7b/i. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 10 28677425
2010 Systematic characterization by mass spectrometric analysis of phosphorylation sites in IRF-3 regulatory domain activated by IKK-i. Journal of proteomics 10 20170763
2023 An IKBKE variant conferring functional cGAS/STING pathway deficiency and susceptibility to recurrent HSV-2 meningitis. JCI insight 9 37937644
2020 The decreased expression of IKBKE in systemic lupus erythematosus. Clinical rheumatology 9 32146614
2019 Identification of an IKBKE inhibitor with antitumor activity in cancer cells overexpressing IKBKE. Cytokine 9 30685606
2024 ALLO-1- and IKKE-1-dependent positive feedback mechanism promotes the initiation of paternal mitochondrial autophagy. Nature communications 8 38368448
2018 IKBKE inhibits TSC1 to activate the mTOR/S6K pathway for oncogenic transformation. Turkish journal of biology = Turk biyoloji dergisi 8 30814890
2021 CYT387, a potent IKBKE inhibitor, suppresses human glioblastoma progression by activating the Hippo pathway. Journal of translational medicine 7 34544426
2015 Polymorphisms of IKBKE gene are associated with major depressive disorder and panic disorder. Brain and behavior 6 25798331
2024 IKBKE promotes the ZEB2-mediated EMT process by phosphorylating HMGA1a in glioblastoma. Cellular signalling 5 38242271
2023 IKBKE regulates angiogenesis by modulating VEGF expression and secretion in glioblastoma. Tissue & cell 5 37573607
2021 Silencing IKBKE inhibits the migration and invasion of glioblastoma by promoting Snail1 degradation. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 4 34741724
2018 Single-Nucleotide Polymorphisms in NOD1, RIPK2, MICB, PLCE1, TNF, and IKBKE Genes Associated with Symptomatic Dengue in Children from Colombia. Viral immunology 4 30332343
2016 Overexpression of suppressor of IKBKE 1 is associated with vincristine resistance in colon cancer cells. Biomedical reports 4 27882221
2012 Effects of IKKɛ on oxidised low-density lipoprotein-induced injury in vascular endothelial cells. Heart, lung & circulation 4 23261326
2025 Matrix stiffness-induced IKBKE and MAPK8 signaling drives a phenotypic switch from DCIS to invasive breast cancer. Cell communication and signaling : CCS 2 40468448
2025 Picornavirus VP2 protein suppresses innate immunity through selective autophagic degradation of IKBKE/IKKε. Autophagy 2 41319264
2024 IKBKE regulates renal cell carcinoma progression and sunitinib resistance through the RRM2-AKT pathway. International journal of biological sciences 2 39664571
2022 IKBKE-driven TPL2 and MEK1 phosphorylations sustain constitutive ERK1/2 activation in tumor cells. EXCLI journal 2 35391917
2022 IKBKE and BANK1 Polymorphisms and Clinical Characteristics in Chinese Women with Systemic Lupus Erythematosus. Immunological investigations 2 35930382
2017 The expression of inhibitor of nuclear factor kappa-B kinase epsilon (IKKe) in human aortic aneurysm. Folia morphologica 2 28198528
2026 Reversing enhancer RNA-mediated IKBKE gene repression enables synthetic anticancer immunity in prostate cancer models. The Journal of clinical investigation 1 41542764
2026 MiR-423-5p Targeting IKBKE Ameliorates LPS/GPS-induced Inflammation and Cross-border Regulation of Exogenous miRNAs in Scutellaria baicalensis. International immunopharmacology 1 41558293
2025 FKBP5 inhibitor suppresses platelet activation and thrombosis by inhibiting IKBKE/PI3K/Rap1 pathway. International journal of biological macromolecules 1 40345291
2025 [Anti-endometritis effect of carbonized Scutellariae Radix in mice induced by LPS via inhibiting cell pyroptosis through IKBKE/NLRP3 signaling axis]. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica 1 40686170
2024 The impact of MCCK1, an inhibitor of IKBKE kinase, on acute B lymphocyte leukemia cells. Mathematical biosciences and engineering : MBE 1 38872531
2019 Molecular mechanism of interactions between chrysin and I-kappa-B kinase epsilon (IKKe)/tank binding kinase-1(TBK1): Cell-based assay and in silico molecular docking studies. Journal of biomolecular structure & dynamics 1 30767626
2026 CXCL14 Promotes Ovarian Cancer Progression and Autophagy Through the IKBKE/NF-κB Pathway. The journal of gene medicine 0 41571553
2026 Phorbol Myristate Acetate Inhibits Senecavirus A Replication by Activating IKBKE-Mediated IFN Pathway and NF-κB Signal. Transboundary and emerging diseases 0 41623554
2026 IKBKE downregulation increases chemosensitivity through pyroptosis mediated by the caspase-3/GSDME pathway in pancreatic cancer. Journal of experimental & clinical cancer research : CR 0 41699675
2025 IKBKE modulates autophagy and progestin resistance in endometrial cancer. Frontiers in oncology 0 41378297
2024 A novel functional IKBKE variant activating NFAT in a patient with polyarthritis and a remittent fever. Frontiers in immunology 0 39524436

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