Affinage

IKBKB

Inhibitor of nuclear factor kappa-B kinase subunit beta · UniProt O14920

Round 2 corrected
Length
756 aa
Mass
86.6 kDa
Annotated
2026-04-28
130 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IKBKB (IKKβ/IKK2) is the principal catalytic serine/threonine kinase of the canonical NF-κB signaling pathway, functioning within a trimeric IKK complex with IKKα and the regulatory subunit NEMO/IKKγ to phosphorylate IκBα (Ser32/36) and IκBβ (Ser19/23), triggering their proteasomal degradation and NF-κB nuclear translocation (PMID:9346484, PMID:9346485, PMID:9751060). Activation requires phosphorylation of Ser177/Ser181 in its activation loop by upstream kinases TAK1 and PDK1, while negative regulation is achieved through C-terminal autophosphorylation, PP2A-mediated dephosphorylation, PHD1-catalyzed prolyl hydroxylation at Pro191, Ro52-mediated monoubiquitination directing autophagosomal degradation, and S-glutathionylation (PMID:10195894, PMID:11460167, PMID:16207722, PMID:17114296, PMID:19675099, PMID:29622764). Beyond IκB, IKKβ directly phosphorylates p65/RelA at Ser536 to enhance transactivation, phosphorylates FOXO3a to promote its degradation, and phosphorylates the innate immune adaptors MAVS and STING to initiate IRF3 recruitment in antiviral defense (PMID:10521409, PMID:15084260, PMID:25636800). Homozygous loss-of-function IKBKB mutations in humans cause combined immunodeficiency with impaired TCR, BCR, and TLR responses, while gain-of-function mutations drive constitutive NF-κB activation and immune dysregulation (PMID:24369075, PMID:30337470).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1997 High

    Identification of IKKβ as a catalytic subunit of the IKK signalsome resolved the long-sought kinase that phosphorylates IκBs to activate NF-κB, establishing the enzyme's core biochemical function.

    Evidence Biochemical purification from HeLa cells, molecular cloning, in vitro kinase assays, and dominant-negative mutagenesis by three independent groups

    PMID:9346241 PMID:9346484 PMID:9346485

    Open questions at the time
    • Upstream activation mechanism unknown
    • Relative contributions of IKKα vs IKKβ unresolved
    • Physiological substrates beyond IκBα/β not identified
  2. 1998 High

    Discovery of NEMO/IKKγ as a regulatory subunit that preferentially binds IKKβ explained how cytokine signals are transduced to the catalytic core of the IKK complex.

    Evidence Antibody-based purification of the IKK complex, co-immunoprecipitation, dominant-negative truncation mutants

    PMID:9751060

    Open questions at the time
    • Mechanism by which NEMO transmits upstream signals unknown
    • Stoichiometry of the native complex undefined
  3. 1999 High

    Mapping of the activation-loop phosphorylation sites (Ser177/181) and the C-terminal autophosphorylation-based negative feedback defined the intrinsic on/off switch of IKKβ catalytic activity.

    Evidence Site-directed mutagenesis of activation loop serines, in vitro kinase assays with TNF/IL-1 stimulation

    PMID:10195894

    Open questions at the time
    • Identity of the upstream kinase performing activation-loop phosphorylation not yet established
    • Structural basis of autoinhibition unknown
  4. 1999 High

    Genetic ablation of IKKβ in mice (embryonic lethal at E14.5 with liver apoptosis) demonstrated it is the dominant kinase for canonical NF-κB activation in vivo, expanding beyond IκB phosphorylation to direct phosphorylation of p65 at Ser536 and linking IKKβ to the PI3K/Akt survival axis.

    Evidence Homozygous knockout mice, MEF NF-κB assays, in vitro kinase assays on GST-p65, co-immunoprecipitation of Akt–IKK

    PMID:10229185 PMID:10485711 PMID:10521409

    Open questions at the time
    • Tissue-specific functions not addressed by global KO
    • Whether p65 Ser536 phosphorylation is IKKβ-exclusive or shared with IKKα uncertain
  5. 2001 High

    Reconstitution of the TAK1–TAB1/TAB2 complex as the upstream kinase that phosphorylates IKKβ in a K63-polyubiquitin-dependent manner connected ubiquitin signaling to IKK activation and completed the IL-1/TLR→TRAF6→TAK1→IKKβ cascade.

    Evidence Biochemical purification (TRIKA2), in vitro kinase cascade reconstitution, ubiquitination assays

    PMID:11460167

    Open questions at the time
    • Alternative upstream kinases (e.g., PDK1) not yet placed in the hierarchy
    • Mechanism of NEMO-mediated ubiquitin sensing unresolved
  6. 2004 High

    Discovery that IKKβ directly phosphorylates FOXO3a to promote its ubiquitin-dependent degradation, independent of Akt, revealed a non-NF-κB oncogenic function by which IKKβ drives cell proliferation and tumorigenesis.

    Evidence Co-immunoprecipitation, in vitro kinase assay, proteasome inhibitor rescue, tumor xenograft

    PMID:15084260

    Open questions at the time
    • Phosphorylation sites on FOXO3a not fully mapped
    • Contribution of IKKα to FOXO3a regulation not excluded
  7. 2005 High

    PDK1 was shown to directly phosphorylate IKKβ at Ser181 independently of Akt, establishing a second upstream kinase input, and IKKβ was placed in the MAVS/RIG-I antiviral signaling complex, broadening its role to innate immunity.

    Evidence In vitro kinase assay with site-specific antibodies, IKKα-KO MEFs; co-immunoprecipitation of IKKβ with MAVS/Cardif, siRNA knockdown

    PMID:16177806 PMID:16207722

    Open questions at the time
    • Whether PDK1 and TAK1 act in parallel or sequentially unclear
    • Relative contribution of IKKβ vs TBK1/IKKε to MAVS signaling unknown
  8. 2006 High

    Two distinct negative regulatory mechanisms were elucidated: NEMO-mediated recruitment of IKKβ to K63-polyubiquitinated RIP1 at TNF-R1 defined the activation docking mechanism, while PHD1-catalyzed hydroxylation of Pro191 in the activation loop provided an oxygen-sensing brake on IKKβ activity under normoxia.

    Evidence RIP1 K377R and NEMO ubiquitin-binding mutagenesis; PHD siRNA knockdown, P191A mutagenesis, NF-κB reporter assays

    PMID:16603398 PMID:17114296

    Open questions at the time
    • Whether PHD1 hydroxylation and activation-loop phosphorylation are mutually exclusive not tested
    • Structural basis of NEMO–ubiquitin–IKKβ ternary interaction unknown at atomic resolution
  9. 2009 Medium

    Multiple post-translational negative feedback loops were characterized: PP2A dephosphorylates IKKβ to terminate signaling, Ro52-mediated monoubiquitination targets active IKKβ for autophagic degradation, and S-glutathionylation inhibits IKKβ activation under oxidative stress.

    Evidence PP2A activity assays with phospho-IKKβ; in vitro ubiquitination reconstitution with Ro52/UbcH5B, autophagosome translocation assays; IKKβ-SSG immunoprecipitation and kinase assays

    PMID:19607706 PMID:19675099 PMID:20627395 PMID:29622764

    Open questions at the time
    • Relative importance of autophosphorylation, PP2A, Ro52-autophagy, and glutathionylation in different cell types not compared
    • In vivo validation of Ro52-autophagy pathway lacking
  10. 2013 High

    Homozygous loss-of-function IKBKB mutations in humans were shown to cause combined immunodeficiency (SCID-like), and hypothalamic IKKβ/NF-κB was found to suppress GnRH and promote systemic ageing, extending IKKβ biology to neuroendocrine and ageing processes.

    Evidence Homozygosity mapping plus whole-gene sequencing with immune cell functional assays; hypothalamus-specific conditional KO/constitutively active IKKβ mice with lifespan analysis

    PMID:23636330 PMID:24369075

    Open questions at the time
    • Genotype–phenotype spectrum of human IKBKB deficiency incompletely defined
    • Mechanism linking hypothalamic IKKβ to neurogenesis not fully elucidated
  11. 2014 High

    Structural basis of constitutive IKKβ activation was revealed: somatic K171E/T mutations disrupt a cationic pocket that normally requires activation-loop phosphorylation, mimicking permanent activation; a human gain-of-function V203I mutation was validated by knock-in mouse, establishing genotype-to-phenotype causation for hyperactive IKKβ alleles.

    Evidence TALEN knock-in in B lymphoid cells, kinase activity assays, structural modeling; CRISPR knock-in mouse for V203I with matched human phenotype

    PMID:25107905 PMID:30337470

    Open questions at the time
    • Full crystal structure of human IKKβ in active vs inactive states not resolved at the time
    • Spectrum of oncogenic IKBKB mutations across cancer types not systematically surveyed
  12. 2015 High

    IKKβ was shown to directly phosphorylate conserved serine/threonine clusters on MAVS and STING, enabling IRF3 recruitment in antiviral signaling, establishing IKKβ as a kinase for innate immune adaptor priming beyond NF-κB.

    Evidence In vitro kinase reconstitution, phosphorylation-site mutagenesis, co-immunoprecipitation, structural analysis

    PMID:25636800

    Open questions at the time
    • Precise division of labor between IKKβ and TBK1 at MAVS/STING phosphosites in vivo not resolved
    • Whether this function operates in all cell types or is myeloid-specific unclear
  13. 2020 High

    A non-canonical IKKβ→TPL2→JNK signaling axis was discovered downstream of EBV LMP1, distinct from canonical NF-κB, revealing that IKKβ can activate JNK through an intermediary kinase and that this pathway is essential for EBV-transformed B cell survival.

    Evidence Kinase-dead TAK1 constructs, IKK2 inhibition/KO, TPL2 KO, JNK activation assays, EBV-transformed B cell survival assays

    PMID:32019925

    Open questions at the time
    • Generalizability of IKKβ–TPL2–JNK axis beyond EBV context not tested
    • Direct IKKβ-TPL2 phosphorylation event not biochemically reconstituted

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full structural dynamics of the IKKα/IKKβ/NEMO holocomplex, the complete substrate repertoire of IKKβ beyond known targets, whether tissue-specific IKKβ functions (hypothalamic ageing, keratinocyte homeostasis, hepatocyte survival) share common downstream effectors, and the therapeutic window for IKKβ inhibition given its dual roles in immunity and oncogenesis.
  • No high-resolution cryo-EM or crystal structure of the complete native IKK holocomplex
  • Systematic phosphoproteomics of IKKβ substrates not performed
  • Context-dependent balance between pro-survival and pro-apoptotic NF-κB outputs not mechanistically resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016740 transferase activity 7
Localization
GO:0005829 cytosol 3 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 14 R-HSA-168256 Immune System 8 R-HSA-1643685 Disease 4 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 1
Partners
CHUKFOXO3IKBKGMAP3K7MAVSPDPK1TMEM173TRIM21
Complex memberships
IKK complex (IKKα/IKKβ/NEMO)

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 IKK-2 (IKBKB) was identified as a catalytic subunit of the IKK signalsome complex purified from HeLa cells; it phosphorylates IκBα and IκBβ on specific serine residues, and dominant-negative mutants block RelA nuclear translocation and NF-κB-dependent reporter activity, establishing IKK-2 as essential for NF-κB activation. Protein purification from HeLa cells, in vitro kinase assay, dominant-negative mutagenesis, NF-κB reporter assay Science High 9346484
1997 IKKβ was molecularly cloned and characterized as a serine kinase 52% identical to IKKα; it forms heterodimers with IKKα through leucine zipper motifs, interacts with NIK, phosphorylates IκBα Ser32/36 and IκBβ Ser19/23, and a catalytically inactive IKKβ mutant blocks cytokine-induced NF-κB activation. Molecular cloning, co-immunoprecipitation, in vitro kinase assay, dominant-negative overexpression Science High 9346485
1997 The IKK complex contains two kinase subunits IKKα and IKKβ; both catalytic activities contribute to IκB phosphorylation and NF-κB activation, with IKKα–IKKβ interaction mediated via leucine zipper motifs and helix-loop-helix motifs involved in regulatory subunit interactions. Molecular cloning, co-immunoprecipitation, in vitro kinase assay Cell High 9346241
1999 Phosphorylation of Ser177 and Ser181 in the activation loop of IKKβ is essential for IKK activation by TNF and IL-1; once activated, IKKβ autophosphorylates a C-terminal serine cluster that decreases IKK activity, providing a negative feedback mechanism. IKKα activation-loop phosphorylation is not required for proinflammatory IKK activation. Site-directed mutagenesis of activation loop serines, in vitro kinase assay, TNF/IL-1 stimulation Science High 10195894
1999 IKKβ was identified as essential for mouse embryonic liver development; IKK-β-deficient mice die at ~E14.5 from liver degeneration and apoptosis. Embryonic fibroblasts from these mice have greatly reduced basal and cytokine-induced NF-κB and IKK activity, demonstrating IKKβ is the dominant kinase for canonical NF-κB signaling in vivo. Gene knockout (homozygous), embryonic lethality phenotyping, NF-κB reporter assay in MEFs, kinase assay Immunity High 10229185
1999 IKKβ phosphorylates the p65 NF-κB subunit on Ser536 in its C-terminal transactivation domain in vitro and in TNF-α-stimulated cells, suggesting dual roles for the IKK complex: IκB degradation and direct p65 transactivation. In vitro kinase assay with GST-p65, site-directed mutagenesis, TNF-α stimulation, in vivo phosphorylation mapping Journal of Biological Chemistry High 10521409
1998 IKK-γ (NEMO) was identified as a third regulatory subunit of the IKK complex that interacts preferentially with IKKβ and is required for activation of the IKK complex by proinflammatory stimuli; a C-terminal truncation of IKK-γ that retains IKKβ binding acts as a dominant negative. Antibody-based purification of IKK complex, co-immunoprecipitation, dominant-negative expression Nature High 9751060
2000 The recombinant IKK1/IKK2 heterodimer has the highest catalytic efficiency (kcat/Km = 47.50 h⁻¹ μM⁻¹) toward an IκBα peptide substrate compared with IKK2 homodimer or IKK1 homodimer; ADP is a competitive inhibitor with Ki of 0.77 μM that may physiologically regulate kinase activity. Baculoviral expression and purification of recombinant heterodimer and homodimers, enzyme kinetics (Km for ATP and IκBα peptide, kcat, competitive inhibition analysis) Journal of Biological Chemistry High 10823818
2000 IKK1 and IKK2 double-deficient mice die at E12 with complete loss of NF-κB activity and an additional defect in neurulation with enhanced apoptosis in the neuroepithelium; MEFs from double-deficient embryos fail to activate NF-κB in response to any inducer, demonstrating that IKK1 and IKK2 together are essential for all NF-κB activation in vivo. Double-gene knockout mouse, genetic cross with κB-lacZ reporter mice, NF-κB activity assay in MEFs Genes & Development High 10898787
2001 TAK1 (in complex with TAB1 and TAB2) phosphorylates and activates IKK in a manner dependent on TRAF6 and the K63-linked polyubiquitin-synthesizing enzyme Ubc13/Uev1A, placing TAK1 as an upstream kinase of IKKβ in the IL-1/LPS NF-κB pathway. Biochemical purification (TRIKA2), in vitro kinase reconstitution, ubiquitination assay Nature High 11460167
1999 IKKβ is activated downstream of Akt/PI3K in PDGF signaling; Akt transiently associates with IKK in vivo upon PDGF stimulation and induces IKK activation, defining a Ras/PI3K/Akt/IKK/NF-κB anti-apoptotic pathway. Co-immunoprecipitation (Akt–IKK association), dominant-negative constructs, NF-κB reporter assay Nature High 10485711
2004 IKKβ physically interacts with and phosphorylates FOXO3a, promoting its cytoplasmic localization and proteasomal degradation via ubiquitin-dependent proteolysis, independent of Akt, thus promoting cell proliferation and tumorigenesis. Co-immunoprecipitation, in vitro kinase assay, proteasome inhibitor rescue, constitutively active IKKβ expression, tumor xenograft Cell High 15084260
2006 PHD-1 (prolyl hydroxylase-1) negatively regulates IKKβ activity through hydroxylation of a conserved LxxLAP motif in IKKβ's activation loop (Pro191); hypoxia reduces PHD-mediated hydroxylation, increasing IKKβ activity and NF-κB activation. Pro191Ala mutagenesis abolishes hypoxic inducibility. siRNA knockdown of PHDs, site-directed mutagenesis (P191A), NF-κB reporter assay, PHD overexpression PNAS High 17114296
2006 IKK-γ (NEMO) recruits IKK to TNF-R1 signaling through binding to K63-linked polyubiquitin chains on RIP1 (ubiquitinated at Lys-377); mutations in NEMO that disrupt polyubiquitin binding abolish IKK and NF-κB activation, establishing IKKβ-complex activation via NEMO–ubiquitin docking. RIP1 K377R mutagenesis, NEMO ubiquitin-binding mutants, co-immunoprecipitation, IKK activity assay Molecular Cell High 16603398
2005 NIBP (NIK- and IKKβ-binding protein) physically interacts with NIK and IKKβ (but not IKKα or IKKγ), potentiates TNF-α-induced NF-κB activation by increasing phosphorylation of the IKK complex, and its siRNA knockdown reduces NF-κB activation and Bcl-xL expression in neurons. Yeast two-hybrid screen, co-immunoprecipitation, NF-κB reporter assay, siRNA knockdown Journal of Biological Chemistry Medium 15951441
2005 PDK1 directly phosphorylates IKKβ at Ser181 in the activation loop, leading to NF-κB nuclear translocation and anti-apoptotic gene expression; IKKα is not required for this pathway, and Akt does not participate in PDK1-dependent IKKβ activation. In vitro kinase assay, phospho-specific antibodies, siRNA knockdown, IKKα-knockout MEFs, constitutively active IKKβ rescue Journal of Biological Chemistry High 16207722
2002 Epidermis-specific deletion of IKK2 in keratinocytes inhibits NF-κB activation but does not cause keratinocyte hyperproliferation; instead, mice develop severe TNF-mediated inflammatory skin disease, revealing that IKK2-mediated NF-κB in keratinocytes maintains skin immune homeostasis. Cre/loxP conditional knockout (keratinocyte-specific), histopathology, cytokine analysis, TNF blockade rescue Nature High 12075355
2009 Ro52 (an E3 ubiquitin ligase) interacts more strongly with phosphomimetic IKKβ than wild-type IKKβ and, in cooperation with UbcH5B (E2), monoubiquitinates IKKβ; this monoubiquitination suppresses IKKβ-induced NF-κB signaling and reduces Tax oncoprotein levels, providing a negative feedback mechanism. Co-immunoprecipitation, in vitro ubiquitination assay with purified components, NF-κB reporter assay Journal of Biochemistry Medium 19675099
2010 Ro52-mediated monoubiquitination of active IKKβ promotes its translocation to autophagosomes; autophagy inhibitors block this Ro52-dependent downregulation of IKKβ-induced NF-κB signaling, identifying autophagy-mediated degradation as a novel mechanism for IKKβ inactivation. Subcellular fractionation/immunofluorescence (IKKβ translocation to autophagosomes), autophagy inhibitors, NF-κB reporter assay Molecular Immunology Medium 20627395
2009 Constitutively active PP2A (phosphatase) dephosphorylates IKKβ to allow IκBα resynthesis after IL-1 stimulation; UVB radiation inhibits PP2Ac activity, preventing IKKβ dephosphorylation and causing persistent IKKβ activation and IκBα degradation, converting NF-κB from a survival factor to a pro-apoptotic factor. Mathematical modeling combined with PP2A activity assays, phospho-IKKβ measurement, siRNA and pharmacological inhibitors BMC Systems Biology Medium 19607706
2010 In RSV infection, the RIG-I/MAVS/TRAF6 signaling axis activates IKKβ, which then phosphorylates p65 at Ser536 to drive NF-κB-dependent proinflammatory gene expression; NOX2 NADPH oxidase acts upstream to regulate IKKβ activation in this pathway. siRNA knockdown of RIG-I, MAVS, TRAF6, IKKβ; pharmacological IKKβ inhibitor; NOX2 silencing; phospho-p65 Ser536 immunoblot Journal of Virology Medium 20410276
2013 A homozygous frameshift duplication in IKBKB (c.1292dupG) causes loss of IKK2 expression in humans, resulting in SCID characterized by impaired responses to TCR, BCR, TLR, cytokine receptor stimulation, and mitogen activation across multiple immune cell types, despite normal lymphocyte counts. Homozygosity mapping, whole-gene sequencing, functional immune cell assays (T cell, B cell, TLR activation), Western blot (loss of IKK2 protein) New England Journal of Medicine High 24369075
2014 A homozygous nonsense mutation IKBKB R286X in humans abolishes IKK2 expression, prevents IKKα/NEMO complex formation by the truncated protein, and causes impaired IκBα phosphorylation and NF-κB nuclear translocation in B cells, resulting in combined immunodeficiency. Whole-exome sequencing, co-immunoprecipitation (complex formation), IκBα phosphorylation assay, NF-κB nuclear translocation assay Blood High 25139357
2018 A heterozygous gain-of-function de novo IKBKB missense mutation (V203I) causes constitutively enhanced NF-κB signaling and combined T and B cell functional defects in humans; the precise orthologous Ikbkb knock-in mouse recapitulates the same cellular and biochemical phenotype, proving causation. Whole-exome sequencing, CRISPR/Cas9 knock-in mouse model, NF-κB activity assay, T/B cell functional assays Journal of Experimental Medicine High 30337470
2014 Somatic K171E and K171T mutations in IKBKB produce constitutively active IKKβ that does not require activation-loop phosphorylation; Lys171 forms part of a cationic pocket that interacts with the activation-loop phosphate in the active wild-type kinase, and disruption of this pocket by charge-reversal mutations mimics permanent phosphorylation. TALEN-based knock-in mutagenesis in B lymphoid cells, kinase activity assays, predictive structural modeling, biochemical studies Journal of Biological Chemistry High 25107905
2015 MAVS and STING harbor conserved serine/threonine clusters phosphorylated by IKK (and/or TBK1) upon viral stimulation; phosphorylated MAVS/STING then bind a positively charged surface of IRF3 to recruit it for TBK1-mediated activation, establishing IKKβ as a kinase in the innate antiviral adaptor phosphorylation cascade. In vitro kinase assay, mutagenesis of phosphorylation sites, co-immunoprecipitation, structural analysis Science High 25636800
2005 Cardif (MAVS) interacts with RIG-I and recruits IKKα, IKKβ and IKKε via its C-terminal region to activate NF-κB and IRF3 in antiviral signaling; Cardif knockdown inhibits RIG-I-dependent antiviral responses. Co-immunoprecipitation, siRNA knockdown, NF-κB/IFN-β reporter assay Nature High 16177806
2008 In TNF-α signaling to S6K1-mediated insulin resistance, IKK2 (but not IKK1) is required for TNF-α-induced phosphorylation of S6K1 at Thr389; in IKK2-null cells, TNF-α fails to activate S6K1, which normally phosphorylates IRS-1 at multiple serine residues to inhibit insulin signaling. IKK1/IKK2 null cells, in vitro S6K1 kinase assay on IRS-1, phospho-specific antibodies, RNAi Journal of Biological Chemistry Medium 18952604
2005 TNF-α treatment causes rapid IKK2-dependent depletion of HDAC1 protein through proteasomal degradation, without affecting other class I HDACs; this selectively increases transcription from NF-κB-associated and unassociated gene promoters, revealing a new epigenetic mechanism downstream of IKKβ. Pharmacological IKK2 inhibition, proteasome inhibitors, Western blot for HDAC levels, transcription reporter assay EMBO Reports Medium 16374504
2009 In IFN-γ signaling, IKKβ is required to activate newly synthesized IRF1 (enabling ISRE-driven chemokine gene expression) and to activate p65 NF-κB at κB sites in the ip-10 promoter; this IFN-γ-specific IKKβ activation of IRF1 and p65 is distinct from classical IL-1β-driven canonical NF-κB and represents a novel IKKβ function. IKKβ-specific siRNA/inhibitors, IRF1/p65 activity assays, promoter analysis in MEFs Journal of Interferon & Cytokine Research Medium 19929594
2013 Hypothalamic IKKβ/NF-κB activation suppresses GnRH production; genetic or pharmacological prevention of hypothalamic IKKβ activation in mice retards ageing and extends lifespan, while GnRH treatment rescues IKKβ-mediated ageing phenotypes by restoring neurogenesis. Hypothalamic-specific IKKβ knockout and constitutively active IKKβ expression, GnRH measurement, neurogenesis assay, lifespan analysis Nature High 23636330
2015 NKILA lncRNA binds directly to NF-κB/IκB complex and masks phosphorylation motifs of IκB, thereby inhibiting IKK-induced IκB phosphorylation; unlike DNA, NKILA forms a stable ternary complex with NF-κB/IκB, acting as a direct cytoplasmic IKKβ substrate competitor. RNA-protein binding assay, IκB phosphorylation assay in presence of NKILA, IKK kinase assay Cancer Cell Medium 25759022
2015 Cysteine-46 of IKKβ is an essential residue for kinase activity; C46A transgenic mice show increased inflammatory responses in a delayed-type hypersensitivity model, and the IKKβ inhibitor dihydromyricetin loses its anti-inflammatory effect in C46A mice, identifying Cys46 as a drug-binding site. In vitro kinase assay with C46A mutant IKKβ, C46A transgenic mouse model, DTH in vivo assay Oncotarget Medium 26378659
2020 IKK2 and its co-factor NEMO activate oncogenic JNK signaling downstream of EBV LMP1 via a novel pathway: TAK1 (independent of its kinase activity) mediates LMP1 signaling complex formation, NEMO ubiquitination and IKK2 activation; IKK2 then induces TPL2 kinase, which transmits JNK activation. This IKK2–TPL2–JNK axis is LMP1-specific and is required for EBV-transformed B cell survival. Kinase-dead TAK1 constructs, IKK2 inhibition/KO, TPL2 KO, JNK activation assays, EBV-transformed B cell survival assays Nature Communications High 32019925
2018 IKK-β-mediated SNARE-dependent vesicle exocytosis downstream of TLR4 signaling is required for calreticulin surface exposure (a damage-associated molecular pattern) in paclitaxel-induced immunogenic cell death in ovarian cancer cells. TLR4 and IKK2 inhibition/knockdown, SNARE inhibition, calreticulin surface exposure assay, tumor vaccination assay in vivo Cancer Immunology Research Medium 32354736
2018 GSSG (glutathione disulfide) induces S-glutathionylation of IKKβ (IKKβ-SSG), which prevents TNF-α-triggered IKKβ activation and NF-κB signaling, sensitizing hepatocytes to TNF-α-mediated cytotoxicity; HFD-fed mice show increased hepatic IKKβ-SSG and decreased IKKβ activation. Immunoprecipitation of IKKβ-SSG, IKKβ kinase activity assay, NF-κB reporter, glutaredoxin inhibitor, in vivo HFD mouse model Experimental & Molecular Medicine Medium 29622764

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 1953 16177806
1997 A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature 1833 9252186
1997 IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science (New York, N.Y.) 1783 9346484
2001 TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 1723 11460167
1999 NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature 1608 10485711
2015 Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science (New York, N.Y.) 1601 25636800
1997 The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell 1554 9346241
2000 Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 1526 11057907
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2000 The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). The Journal of biological chemistry 1179 10722755
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
1997 IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science (New York, N.Y.) 1013 9346485
2006 Regulation and function of IKK and IKK-related kinases. Science's STKE : signal transduction knowledge environment 988 17047224
1996 Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity. Cell 878 8601309
2006 Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Molecular cell 849 16603398
2004 A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nature cell biology 841 14743216
1998 IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature 794 9751060
2004 IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 784 15084260
2015 A cytoplasmic NF-κB interacting long noncoding RNA blocks IκB phosphorylation and suppresses breast cancer metastasis. Cancer cell 780 25759022
2001 Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. The Journal of biological chemistry 779 11606564
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
1999 IkappaB kinases phosphorylate NF-kappaB p65 subunit on serine 536 in the transactivation domain. The Journal of biological chemistry 727 10521409
2009 The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nature immunology 726 19820708
1999 Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation. Science (New York, N.Y.) 722 10195894
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2013 Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature 676 23636330
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proceedings of the National Academy of Sciences of the United States of America 653 17114296
2009 Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Molecular cell 649 20005846
1996 Mapping of the inducible IkappaB phosphorylation sites that signal its ubiquitination and degradation. Molecular and cellular biology 636 8657102
2009 Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. Cancer cell 595 19345327
1999 Embryonic lethality, liver degeneration, and impaired NF-kappa B activation in IKK-beta-deficient mice. Immunity 475 10229185
2012 KrasG12D-induced IKK2/β/NF-κB activation by IL-1α and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer cell 427 22264792
2007 Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis. Nature 422 17322906
2002 TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 389 12075355
2003 Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance. International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity 350 14704745
2006 Targeted ablation of IKK2 improves skeletal muscle strength, maintains mass, and promotes regeneration. The Journal of clinical investigation 261 17080195
2008 S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-(alpha) signaling through IKK2. The Journal of biological chemistry 243 18952604
2008 IkappaB kinase beta (IKKbeta/IKK2/IKBKB)--a key molecule in signaling to the transcription factor NF-kappaB. Cytokine & growth factor reviews 196 18308615
2000 Complete lack of NF-kappaB activity in IKK1 and IKK2 double-deficient mice: additional defect in neurulation. Genes & development 155 10898787
2003 IKK beta is required for peripheral B cell survival and proliferation. Journal of immunology (Baltimore, Md. : 1950) 153 12707341
1998 Role of IKK1 and IKK2 in lipopolysaccharide signaling in human monocytic cells. The Journal of biological chemistry 153 9804806
2020 Paclitaxel Induces Immunogenic Cell Death in Ovarian Cancer via TLR4/IKK2/SNARE-Dependent Exocytosis. Cancer immunology research 151 32354736
2005 Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury. The Journal of clinical investigation 150 15776110
2013 Deficiency of innate and acquired immunity caused by an IKBKB mutation. The New England journal of medicine 147 24369075
2004 Targeting NF-kappaB activation via pharmacologic inhibition of IKK2-induced apoptosis of human acute myeloid leukemia cells. Blood 134 15454494
2010 miR-218 inhibits the invasive ability of glioma cells by direct downregulation of IKK-β. Biochemical and biophysical research communications 121 20933503
2012 Reduced cell proliferation by IKK2 depletion in a mouse lung-cancer model. Nature cell biology 115 22327365
2005 NIBP, a novel NIK and IKK(beta)-binding protein that enhances NF-(kappa)B activation. The Journal of biological chemistry 104 15951441
2006 FDC-specific functions of p55TNFR and IKK2 in the development of FDC networks and of antibody responses. Immunity 101 16413924
2010 Respiratory syncytial virus-mediated NF-kappa B p65 phosphorylation at serine 536 is dependent on RIG-I, TRAF6, and IKK beta. Journal of virology 100 20410276
2008 IKK-2 is required for TNF-alpha-induced invasion and proliferation of human mesenchymal stem cells. Journal of molecular medicine (Berlin, Germany) 94 18600306
2010 Downregulation of active IKK beta by Ro52-mediated autophagy. Molecular immunology 92 20627395
2001 Tumor necrosis factor alpha-induced activation of downstream NF-kappaB site of the promoter mediates epithelial ICAM-1 expression and monocyte adhesion. Involvement of PKCalpha, tyrosine kinase, and IKK2, but not MAPKs, pathway. Cellular signalling 90 11483407
2011 Constitutive IKK2 activation in intestinal epithelial cells induces intestinal tumors in mice. The Journal of clinical investigation 89 21701067
2013 miR-451 inhibits cell proliferation in human hepatocellular carcinoma through direct suppression of IKK-β. Carcinogenesis 83 23740840
2010 Conditional ablation of Ikkb inhibits melanoma tumor development in mice. The Journal of clinical investigation 81 20530876
2008 IKK1 and IKK2 cooperate to maintain bile duct integrity in the liver. Proceedings of the National Academy of Sciences of the United States of America 79 18606991
2005 3-Phosphoinositide-dependent protein kinase-1-mediated IkappaB kinase beta (IkkB) phosphorylation activates NF-kappaB signaling. The Journal of biological chemistry 78 16207722
2004 Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 3: Orally active anti-inflammatory agents. Bioorganic & medicinal chemistry letters 75 15225718
2008 Pharmacological IKK2 inhibition blocks liver steatosis and initiation of non-alcoholic steatohepatitis. Gut 73 18408102
2018 Selective IKK2 inhibitor IMD0354 disrupts NF-κB signaling to suppress corneal inflammation and angiogenesis. Angiogenesis 69 29332242
2003 AS602868, a pharmacological inhibitor of IKK2, reveals the apoptotic potential of TNF-alpha in Jurkat leukemic cells. Oncogene 68 14603259
2018 IKK2/NF-κB signaling protects neurons after traumatic brain injury. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 67 29187362
2014 miR-200c regulates IL8 expression by targeting IKBKB: a potential mediator of inflammation in leiomyoma pathogenesis. PloS one 67 24755559
2009 Ro52-mediated monoubiquitination of IKK{beta} down-regulates NF-{kappa}B signalling. Journal of biochemistry 66 19675099
2018 Gain-of-function IKBKB mutation causes human combined immune deficiency. The Journal of experimental medicine 64 30337470
2006 Validation of the anti-inflammatory properties of small-molecule IkappaB Kinase (IKK)-2 inhibitors by comparison with adenoviral-mediated delivery of dominant-negative IKK1 and IKK2 in human airways smooth muscle. Molecular pharmacology 60 16687566
2013 LPS-mediated endothelial activation in pulmonary endothelial cells: role of Nox2-dependent IKK-β phosphorylation. American journal of physiology. Lung cellular and molecular physiology 58 23333803
2014 A nonsense mutation in IKBKB causes combined immunodeficiency. Blood 57 25139357
2000 Characterization of the recombinant IKK1/IKK2 heterodimer. Mechanisms regulating kinase activity. The Journal of biological chemistry 57 10823818
2013 Apigenin potentiates the growth inhibitory effects by IKK-β-mediated NF-κB activation in pancreatic cancer cells. Toxicology letters 54 24148603
2006 Rosmarinic acid as a downstream inhibitor of IKK-beta in TNF-alpha-induced upregulation of CCL11 and CCR3. British journal of pharmacology 51 16604092
2009 The IKK2/NF-{kappa}B pathway suppresses MYC-induced lymphomagenesis. Blood 48 19628709
2006 IkappaB kinase-2-independent and -dependent inflammation in airway disease models: relevance of IKK-2 inhibition to the clinic. Molecular pharmacology 45 16517756
2004 Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 2: Improvement of in vitro activity. Bioorganic & medicinal chemistry letters 45 15225717
2007 Targeting NF-kappaB pathway with an IKK2 inhibitor induces inhibition of multiple myeloma cell growth. British journal of haematology 43 17542984
2018 Concentrated Ambient PM2.5-Induced Inflammation and Endothelial Dysfunction in a Murine Model of Neural IKK2 Deficiency. Environmental health perspectives 42 29410383
2018 The p55TNFR-IKK2-Ripk3 axis orchestrates arthritis by regulating death and inflammatory pathways in synovial fibroblasts. Nature communications 42 29434332
2007 Use of molecular imaging to quantify response to IKK-2 inhibitor treatment in murine arthritis. Arthritis and rheumatism 42 17195214
2004 A novel series of potent and selective IKK2 inhibitors. Bioorganic & medicinal chemistry letters 42 14698170
2009 Mechanism of PP2A-mediated IKK beta dephosphorylation: a systems biological approach. BMC systems biology 41 19607706
2010 Discovery of a novel IKK-β inhibitor by ligand-based virtual screening techniques. Bioorganic & medicinal chemistry letters 40 21078555
2019 RPS15A promotes gastric cancer progression via activation of the Akt/IKK-β/NF-κB signalling pathway. Journal of cellular and molecular medicine 39 30661291
2009 Roles of IKK-beta, IRF1, and p65 in the activation of chemokine genes by interferon-gamma. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 39 19929594
2006 Targeting the NF-kappaB pathway through pharmacological inhibition of IKK2 prevents human cytomegalovirus replication and virus-induced inflammatory response in infected endothelial cells. Antiviral research 39 17070604
2018 Glutathione disulfide sensitizes hepatocytes to TNFα-mediated cytotoxicity via IKK-β S-glutathionylation: a potential mechanism underlying non-alcoholic fatty liver disease. Experimental & molecular medicine 37 29622764
2016 MicroRNA-16 sensitizes breast cancer cells to paclitaxel through suppression of IKBKB expression. Oncotarget 36 26993770
2004 Human cytomegalovirus stimulates cellular IKK2 activity and requires the enzyme for productive replication. Journal of virology 36 14990741
2024 miRNA-148a-containing GMSC-derived EVs modulate Treg/Th17 balance via IKKB/NF-κB pathway and treat a rheumatoid arthritis model. JCI insight 35 38652539
2019 miR-218 regulates diabetic nephropathy via targeting IKK-β and modulating NK-κB-mediated inflammation. Journal of cellular physiology 35 31549412
2016 A negative feedback loop between miR-200b and the nuclear factor-κB pathway via IKBKB/IKK-β in breast cancer cells. The FEBS journal 35 26433127
2008 Interleukin-1beta up-regulates RGS4 through the canonical IKK2/IkappaBalpha/NF-kappaB pathway in rabbit colonic smooth muscle. The Biochemical journal 35 18260825
2015 Moderate activation of IKK2-NF-kB in unstressed adult mouse liver induces cytoprotective genes and lipogenesis without apparent signs of inflammation or fibrosis. BMC gastroenterology 34 26219821
2014 Immunodeficiency associated with a nonsense mutation of IKBKB. Journal of clinical immunology 34 25216719
2013 Long-term IKK2/NF-κB signaling in pancreatic β-cells induces immune-mediated diabetes. Diabetes 34 24296718
2006 Amelioration of arthritis by intraarticular dominant negative Ikk beta gene therapy using adeno-associated virus type 5. Human gene therapy 34 16942442
2017 Transient IKK2 activation in astrocytes initiates selective non-cell-autonomous neurodegeneration. Molecular neurodegeneration 33 28193238
2013 Selective ablation of lung epithelial IKK2 impairs pulmonary Th17 responses and delays the clearance of Pneumocystis. Journal of immunology (Baltimore, Md. : 1950) 33 24078701
2005 Tumour necrosis factor-alpha depletes histone deacetylase 1 protein through IKK2. EMBO reports 32 16374504
2019 Genetic suppression of IKK2/NF-κB in astrocytes inhibits neuroinflammation and reduces neuronal loss in the MPTP-Probenecid model of Parkinson's disease. Neurobiology of disease 31 30818064
2007 Alpha-catulin, a Rho signalling component, can regulate NF-kappaB through binding to IKK-beta, and confers resistance to apoptosis. Oncogene 29 17952117
2018 Central IKK2 Inhibition Ameliorates Air Pollution-Mediated Hepatic Glucose and Lipid Metabolism Dysfunction in Mice With Type II Diabetes. Toxicological sciences : an official journal of the Society of Toxicology 28 29635361
2009 Discovery of 6-aryl-7-alkoxyisoquinoline inhibitors of IkappaB kinase-beta (IKK-beta). Journal of medicinal chemistry 28 19348415
2007 AS602868, a dual inhibitor of IKK2 and FLT3 to target AML cells. Leukemia 28 17330097
2018 The effects of IKK-beta inhibition on early NF-kappa-B activation and transcription of downstream genes. Cellular signalling 27 30543861
2014 Constitutive activation of IKK2/NF-κB impairs osteogenesis and skeletal development. PloS one 27 24618907
2005 Inhibition of IKK-2 by 2-[(aminocarbonyl)amino]-5-acetylenyl-3-thiophenecarboxamides. Bioorganic & medicinal chemistry letters 27 15911271
2020 Therapeutic potential of IKK-β inhibitors from natural phenolics for inflammation in cardiovascular diseases. Inflammopharmacology 26 31894515
2005 IKK{beta} as a target for treatment of inflammation induced bone loss. Annals of the rheumatic diseases 26 16239395
2004 IKK2 inhibitor alleviates kidney and wasting diseases in a murine model of human AIDS. The American journal of pathology 26 15039214
2021 IKK2/NF-κB Activation in Astrocytes Reduces amyloid β Deposition: A Process Associated with Specific Microglia Polarization. Cells 25 34685649
2018 Inhibition of microRNA-16 facilitates the paclitaxel resistance by targeting IKBKB via NF-κB signaling pathway in hepatocellular carcinoma. Biochemical and biophysical research communications 25 29935185
2017 2-Methoxystypandrone improves in vitro-produced bovine embryo quality through inhibition of IKBKB. Theriogenology 25 28708489
2011 IKK-β-mediated myeloid cell activation exacerbates inflammation and inhibits recovery after spinal cord injury. European journal of immunology 25 21469085
2020 A central role of IKK2 and TPL2 in JNK activation and viral B-cell transformation. Nature communications 24 32019925
2014 IKK2 inhibition attenuates laser-induced choroidal neovascularization. PloS one 24 24489934
2014 The novel IKK2 inhibitor LY2409881 potently synergizes with histone deacetylase inhibitors in preclinical models of lymphoma through the downregulation of NF-κB. Clinical cancer research : an official journal of the American Association for Cancer Research 24 25355930
2023 Microglia-specific knock-out of NF-κB/IKK2 increases the accumulation of misfolded α-synuclein through the inhibition of p62/sequestosome-1-dependent autophagy in the rotenone model of Parkinson's disease. Glia 23 37199240
2018 Design, synthesis and biological evaluation of novel thiazolidinedione derivatives as irreversible allosteric IKK-β modulators. European journal of medicinal chemistry 22 30130718
2020 Emerging role of NIK/IKK2-binding protein (NIBP)/trafficking protein particle complex 9 (TRAPPC9) in nervous system diseases. Translational research : the journal of laboratory and clinical medicine 21 32434006
2016 Overcoming adaptive resistance in mucoepidermoid carcinoma through inhibition of the IKK-β/IκBα/NFκB axis. Oncotarget 21 27682876
2015 Mutation of cysteine 46 in IKK-beta increases inflammatory responses. Oncotarget 21 26378659
2011 Hepatocyte-specific IKK-β activation enhances VLDL-triglyceride production in APOE*3-Leiden mice. Journal of lipid research 21 21357939
2023 Protocatechuic acid ameliorates lipopolysaccharide-induced kidney damage in mice via downregulation of TLR-4-mediated IKBKB/NF-κB and MAPK/Erk signaling pathways. Journal of applied toxicology : JAT 20 36807594
2021 Emergence of Enzalutamide Resistance in Prostate Cancer is Associated with BCL-2 and IKKB Dependencies. Clinical cancer research : an official journal of the American Association for Cancer Research 20 33542074
2019 Establishment of a Mouse Model of Atopic Dermatitis by Deleting Ikk2 in Dermal Fibroblasts. The Journal of investigative dermatology 20 30670308
2014 IκB kinase β (IKBKB) mutations in lymphomas that constitutively activate canonical nuclear factor κB (NFκB) signaling. The Journal of biological chemistry 20 25107905
2013 Expression and function of NIK- and IKK2-binding protein (NIBP) in mouse enteric nervous system. Neurogastroenterology and motility 20 24011459