Affinage

Showing IKBKB — IKKB is a alias.

IKBKB

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

Length
756 aa
Mass
86.6 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IKBKB (IKK-beta/IKK2) is the principal catalytic serine/threonine kinase of the multiprotein IKK signalsome that drives canonical NF-κB activation by phosphorylating IκBα and IκBβ in a cytokine-inducible manner, triggering their degradation and releasing RelA for nuclear translocation (PMID:9346484). It is the dominant catalytic isoform: the IKK1/IKK2 heterodimer is the most kinetically efficient configuration for IκBα phosphorylation, its activity is gated by activation-loop phosphorylation at Ser177/Ser181, and germline loss causes embryonic lethality from hepatic apoptosis with only partial compensation by IKK-alpha (PMID:10229185, PMID:10823818). Beyond IκB, IKK2 amplifies NF-κB output by directly phosphorylating RelA/p65 at Ser536 to promote coactivator recruitment and transcription (PMID:12759443, PMID:15489227), and it extends into NF-κB-independent signaling by phosphorylating TSC1 (at Ser487/Ser511) to activate mTOR and angiogenesis (PMID:17693255), by associating with p85 S6K1 to drive H2O2-induced p53-dependent death (PMID:22955948), and by activating a TPL2-JNK survival axis downstream of EBV LMP1 (PMID:32019925). Its activity is set by upstream kinases including PDK1 (Ser181) (PMID:16207722) and constrained by PP2A-mediated dephosphorylation (PMID:19607706) and Ro52-mediated monoubiquitination that targets active IKK2 to autophagosomes (PMID:19675099, PMID:20627395). Tissue-restricted genetic studies establish non-redundant roles in epidermal and intestinal immune homeostasis (PMID:12075355, PMID:17322906), peripheral B-cell survival (PMID:12707341), hepatic and myeloid-driven metabolic control of insulin resistance (PMID:15685173, PMID:15685170), skeletal muscle homeostasis (PMID:17080195), and hypothalamic NF-κB control of GnRH and aging (PMID:23636330), while constitutive IKK2 activity contributes to pancreatitis and Kras-driven and lymphoid malignancy (PMID:17525799, PMID:22264792, PMID:25107905). In humans, both loss-of-function and gain-of-function IKBKB mutations cause combined immunodeficiency, directly linking IKK2 kinase activity and complex assembly to immune cell signaling (PMID:24369075, PMID:25139357, PMID:30337470).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1997 High

    Established that IKK2 is a catalytic kinase subunit physically driving cytokine-induced NF-κB activation, defining the core of the canonical pathway.

    Evidence Biochemical purification of the IKK signalsome from HeLa cells with in vitro kinase assays and dominant-negative mutants

    PMID:9346484

    Open questions at the time
    • Did not resolve isoform-specific contributions of IKK1 vs IKK2
    • Upstream activating kinases not yet defined
  2. 1999 High

    Demonstrated IKK2 is non-redundant in vivo for NF-κB-dependent hepatocyte survival, showing IKK-alpha cannot fully compensate.

    Evidence Germline knockout mice with kinase activity and NF-κB assays in KO fibroblasts

    PMID:10229185

    Open questions at the time
    • Embryonic lethality precluded analysis of adult tissue-specific roles
    • Mechanism of partial IKK-alpha compensation unresolved
  3. 2000 High

    Quantified the biochemical basis for IKK2 dominance by showing the IKK1/IKK2 heterodimer is the most efficient IκBα kinase and that activation-loop phosphorylation governs activity.

    Evidence Recombinant baculoviral expression and in vitro kinetic characterization with phosphomimetic mutants

    PMID:10823818

    Open questions at the time
    • Kinetics on peptide substrate may not reflect full-length IκB or in-cell regulation
    • Did not address substrates beyond IκBα
  4. 2003 High

    Extended IKK2 function beyond IκB to direct phosphorylation of RelA/p65 at Ser536, showing it shapes NF-κB transcriptional output, not just nuclear entry.

    Evidence IKK-alpha/IKK-beta KO MEFs with phospho-specific Western blot and reporter assays under LPS stimulation

    PMID:12759443

    Open questions at the time
    • Relative in vivo contribution of multiple Ser536 kinases not resolved
    • Promoter-context dependence not addressed
  5. 2004 High

    Clarified the transcriptional consequence of Ser536 phosphorylation by linking it to coactivator (TAF II 31) versus corepressor (AES) recruitment at target promoters.

    Evidence RNAi, in vitro kinase assays, and reconstitution of p65-deficient fibroblasts with phosphomimetic/blocking mutants plus reporter assays

    PMID:15489227

    Open questions at the time
    • Multiple kinases (IKKε, TBK1) also phosphorylate Ser536, complicating IKK2-specific attribution
    • Genome-wide target scope not defined
  6. 2005 Medium

    Defined upstream and counter-regulatory inputs on IKK2 activity: PDK1 phosphorylates Ser181 to promote survival signaling, and converging Raf-1/MEKK-1 and Bcl-2 inputs activate IKK2.

    Evidence Kinase screens, in vitro phosphorylation, site-specific and dominant-negative mutants, IKKα-KO MEFs, and ventricular myocyte overexpression

    PMID:12167626 PMID:16207722

    Open questions at the time
    • PDK1-IKK2 link based on a single lab with limited mutagenesis
    • Physiological context of Bcl-2-IKK2 coupling beyond myocytes unclear
  7. 2005 High

    Established IKK2 as a central node coupling inflammation to metabolic disease, with distinct hepatocyte- versus myeloid-intrinsic contributions to insulin resistance.

    Evidence Hepatocyte-constitutive-active, hepatocyte-KO, and myeloid-KO mouse models with IκBα superrepressor rescue, cytokine neutralization, and salicylate pharmacology

    PMID:15685170 PMID:15685173

    Open questions at the time
    • Direct metabolic substrates of IKK2 distinct from NF-κB cytokine output not defined
    • Relative cross-tissue weighting in human disease not addressed
  8. 2005 Medium

    Identified phosphatase and adaptor control of IKK2: PP2A constitutively inactivates IKK2 and is itself suppressed by UVB to sustain signaling, while NIBP potentiates IKK complex phosphorylation.

    Evidence PP2A activity assays with modeling, IL-1/UVB stimulation, and yeast two-hybrid plus Co-IP/knockdown for NIBP

    PMID:15951441 PMID:19607706

    Open questions at the time
    • NIBP interaction validated in a single lab without reciprocal in vivo evidence
    • PP2A regulation studied via modeling-experiment integration in limited cell contexts
  9. 2007 High

    Uncovered the first major NF-κB-independent substrate axis by showing IKK2 phosphorylates TSC1 (Ser487/Ser511) to suppress the TSC complex and activate mTOR, linking inflammation to growth and angiogenesis.

    Evidence Co-IP, in vitro kinase assays with phosphosite identification, mutant overexpression, in vivo tumor models, and tumor IHC

    PMID:17693255

    Open questions at the time
    • Quantitative contribution of TSC1 phosphorylation to mTOR activity in normal tissues unresolved
  10. 2007 High

    Demonstrated tissue-intrinsic IKK2 requirements for epithelial immune homeostasis in intestine and the sufficiency of IKK2 activation to drive pancreatitis.

    Evidence Intestinal epithelial and pancreatic acinar conditional gain/loss-of-function mouse models with infection, cytokine blockade, and cerulein challenge

    PMID:17322906 PMID:17525799

    Open questions at the time
    • Downstream IKK2-dependent gene programs only partially mapped
    • TNF identified as effector but full mediator network undefined
  11. 2008 High

    Dissected hepatic IKK isoform logic, showing IKK2 alone is dispensable for hepatocyte canonical NF-κB after TNF but redundant with IKK1, which maintains the bile-blood barrier.

    Evidence Combined and single hepatocyte-specific conditional KO of IKK1, IKK2, and NEMO with LPS challenge and histology

    PMID:15776110 PMID:18606991

    Open questions at the time
    • Molecular basis of IKK1/IKK2 redundancy in hepatocytes not defined
    • Substrate-level explanation for NEMO vs IKK2 divergence unresolved
  12. 2009 Medium

    Defined a degradative off-switch in which Ro52, with UbcH5B, monoubiquitinates active IKK2 to dampen NF-κB and route it to autophagosomes.

    Evidence Co-IP, in vitro ubiquitination, monoubiquitin fusions, autophagy inhibition, and localization imaging

    PMID:19675099 PMID:20627395

    Open questions at the time
    • Both reports from the same lab
    • Physiological triggers controlling Ro52-IKK2 engagement unclear
  13. 2012 Medium

    Broadened IKK2 effector outputs beyond IκB to FOXO3 cytosolic sequestration, p85-S6K1-driven oxidative death, and Kras-NF-κB feedforward loops sustaining tumorigenesis.

    Evidence Co-IP, knockdown/overexpression, subcellular fractionation, kinase assays, and conditional pancreatic IKK2 inactivation in KrasG12D mice

    PMID:22264792 PMID:22313691 PMID:22327365 PMID:22955948

    Open questions at the time
    • FOXO3 and S6K1 interactions rest on single-lab Co-IP without structural detail
    • Direct vs indirect nature of several effector links not fully separated
  14. 2013 High

    Revealed a systemic physiological role for hypothalamic IKK-β/NF-κB in suppressing GnRH to drive aging, identifying it as a modulator of lifespan and neurogenesis.

    Evidence Viral hypothalamic IKK-β activation/inhibition, transgenic mice, GnRH measurement, and lifespan/neurogenesis assays

    PMID:23636330

    Open questions at the time
    • Direct molecular link from NF-κB to GnRH repression not defined
    • Neuronal-specific IKK2 substrates unidentified
  15. 2014 High

    Established human IKBKB disease causation through loss-of-function mutations causing combined immunodeficiency via failed complex assembly and impaired IκBα phosphorylation.

    Evidence Whole-exome sequencing, Co-IP for complex formation, IκBα phospho-blots, and NF-κB translocation in patient cells

    PMID:24369075 PMID:25139357

    Open questions at the time
    • Genotype-phenotype range across mutation types incompletely mapped
  16. 2014 High

    Defined structural determinants of IKK2 catalysis by showing K171 mutations disrupt activation-loop phosphate coordination to yield constitutive, oncogenic kinase activity.

    Evidence Biochemical kinase assays, structural modeling, and TALEN knock-in in B lymphoid cells

    PMID:25107905

    Open questions at the time
    • No high-resolution structure of the mutant confirming the proposed cationic pocket
  17. 2018 High

    Demonstrated that gain-of-function IKBKB mutation causes human immune disease through enhanced NF-κB signaling, formally proving causation in vivo.

    Evidence Whole-exome sequencing, patient-cell NF-κB assays, and CRISPR/Cas9 knock-in mice recapitulating phenotype

    PMID:30337470

    Open questions at the time
    • Mechanism by which V203I enhances activity at the structural level not resolved
  18. 2020 High

    Expanded IKK2 signaling repertoire to NF-κB-independent outputs: a TPL2-JNK survival axis downstream of EBV LMP1 and SNARE-dependent calreticulin exposure for immunogenic cell death.

    Evidence Co-IP, kinase assays, genetic rescue in EBV-transformed B cells, and TLR4/IKK2/SNARE dissection with CALR surface assays

    PMID:32019925 PMID:32354736

    Open questions at the time
    • Direct IKK2 substrate in the SNARE/exocytosis pathway not identified
    • Generality of IKK2-TPL2-JNK axis beyond EBV context unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How IKK2 substrate selection is partitioned between canonical IκB/NF-κB signaling and the growing set of NF-κB-independent substrates (TSC1, S6K1, TPL2, FOXO3) in a context-dependent manner remains unresolved.
  • No unifying model for substrate switching
  • Stoichiometry and structural basis of non-canonical substrate engagement undefined
  • In vivo relevance of several effector axes outside disease models untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016740 transferase activity 4 GO:0140110 transcription regulator activity 3
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1430728 Metabolism 2
Partners
FOXO3IKBKAIKBKGNIBPNIKRPS6KB1TRIM21TSC1
Complex memberships
IKK signalsome (IKK complex)

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 IKK-beta (IKK-2/IKBKB) was identified as a catalytic subunit of the large IKK signalsome complex purified from HeLa cells. It phosphorylates IκBα and IκBβ in a cytokine-inducible manner, and dominant-negative mutants of IKK-2 blocked RelA nuclear translocation and NF-κB-dependent reporter activity, establishing IKK-2 as a critical kinase in the NF-κB signaling pathway. Biochemical purification of IKK signalsome from HeLa cells; in vitro kinase assay; dominant-negative mutant overexpression; NF-κB reporter assay Science High 9346484
1999 IKK-beta-deficient mice die at ~E14.5 due to liver degeneration and apoptosis. IKK-beta-deficient embryonic fibroblasts show reduced basal NF-κB activity and impaired cytokine-induced NF-κB activation, and the IKK complex has greatly reduced basal and cytokine-inducible kinase activity. IKK-alpha can only partially compensate for loss of IKK-beta in vivo. Germline gene knockout in mice; kinase activity assays on IKK complex from KO fibroblasts; NF-κB activity assays Immunity High 10229185
2000 The recombinant IKK1/IKK2 heterodimer has the highest catalytic efficiency (kcat/Km = 47.50 h⁻¹ μM⁻¹) for phosphorylating an IκBα peptide substrate among all IKK isoforms tested. IKK2 homodimer is more active than IKK1 homodimer. Activation loop phosphorylation (mimicked by S177E/S181E mutation) regulates kinase activity; ADP acts as a competitive inhibitor with Ki = 0.77 μM. Baculoviral expression, purification, and in vitro kinetic characterization of recombinant IKK1/IKK2 heterodimer, homodimers, and constitutively active mutant; IκBα peptide substrate kinase assay The Journal of biological chemistry High 10823818
2002 Epidermis-specific deletion of IKK2 inhibits NF-κB activation in keratinocytes and causes a severe TNF-mediated, αβ T-cell-independent inflammatory skin disease, demonstrating that IKK2-mediated NF-κB activity in epidermal keratinocytes is required for maintaining skin immune homeostasis. Cre/loxP conditional knockout of IKK2 in epidermal keratinocytes; histological and immunological analysis of skin phenotype Nature High 12075355
2003 IKK-beta plays an essential role in LPS-induced phosphorylation of RelA/p65 at serine 536, promoting NF-κB transcriptional activity. IKK-alpha only partially contributes to this phosphorylation. This phosphorylation is independent of the PI3K/Akt pathway. Mouse embryonic fibroblasts lacking IKK-alpha or IKK-beta; Western blot for p65 Ser536 phosphorylation; reporter assays; LPS stimulation Journal of immunology High 12759443
2003 IKK-beta is required for peripheral B cell survival and proliferation. Conditional deletion of IKKbeta in B cells dramatically reduces all peripheral B cell subsets due to cell survival defects, impairs mitogenic responses to LPS, anti-CD40, and anti-IgM, and blocks canonical NF-κB signaling, resulting in failure to mount effective antibody responses. Conditional KO mice with floxed Ikkbeta allele; flow cytometry; B cell survival and proliferation assays; NF-κB signaling assays Journal of immunology High 12707341
2004 Multiple kinases including IKK-alpha, IKKbeta, IKKε, and TBK1 can phosphorylate p65 at Ser536. IKKε and TBK1 phosphorylate Ser536 in vivo and in vitro. Ser536 phosphorylation promotes IL-8 transcription mediated by TAF(II)31 recruitment to the promoter; absence of phosphorylation favors binding of the corepressor AES to p65. RNA interference; chromatographic fractionation; dominant-negative mutants; in vitro kinase assay; reconstitution in p65-deficient fibroblasts with phosphomimetic/phosphoblocking mutants; reporter assays The Journal of biological chemistry High 15489227
2005 IKK-beta is activated in liver by obesity/high-fat diet, and selective hepatocyte-specific constitutive activation of IKK-beta (LIKK mice) causes a type 2 diabetes phenotype with hyperglycemia, hepatic insulin resistance, and systemic insulin resistance via production of proinflammatory cytokines (IL-6, IL-1β, TNF-α). IκBα superrepressor expression in hepatocytes reversed both LIKK and HFD-induced phenotypes. Salicylate inhibition of IKK-beta or IL-6 neutralization improved insulin resistance. Transgenic mice with constitutively active IKK-beta in hepatocytes; IκBα superrepressor transgenic mice; cytokine neutralization; salicylate pharmacology; glucose/insulin tolerance tests Nature medicine High 15685173
2005 IKK-beta in myeloid cells activates NF-κB to produce inflammatory mediators that cause systemic insulin resistance. Myeloid-specific IKK-beta knockout mice (Ikbkb∆mye) are protected from high-fat diet, obesity, or aging-induced insulin resistance, whereas hepatocyte-specific knockout (Ikbkb∆hep) retains liver insulin sensitivity but develops peripheral insulin resistance. Conditional KO mice with myeloid-specific or hepatocyte-specific deletion of Ikbkb; high-fat diet and aging models; insulin sensitivity assays Nature medicine High 15685170
2005 PDK1 directly phosphorylates IKKbeta at Ser181 in the activation loop, leading to NF-κB nuclear translocation and NF-κB-dependent anti-apoptotic gene expression. This is independent of Akt and IKKα, and constitutively active IKKbeta rescues cells from PDK1 knockdown-mediated TRAIL sensitization. Kinase screen; in vitro phosphorylation assay; site-specific mutants; IKKα-KO MEFs; siRNA knockdown; NF-κB reporter assay The Journal of biological chemistry Medium 16207722
2005 IKK-beta is required for Bcl-2-mediated NF-κB activation in ventricular myocytes. Bcl-2 increases IKK-beta kinase activity (requiring the BH4 domain), and catalytically inactive IKK-beta (but not IKK-alpha) blocks Bcl-2-mediated IκBα phosphorylation and NF-κB activation. This mechanism involves Raf-1/MEKK-1-mediated activation of IKK-beta. Overexpression of Bcl-2 mutants in ventricular myocytes; kinase activity assay; dominant-negative IKK-beta/alpha; IKKbeta-null MEFs; kinase-defective Raf-1/MEKK-1 mutants The Journal of biological chemistry Medium 12167626
2005 NIBP (NIK and IKKbeta-binding protein) physically interacts with NIK and IKK-beta but not IKK-alpha or IKK-gamma. NIBP overexpression potentiates TNF-α-induced NF-κB activation through increased phosphorylation of the IKK complex, IκBα, and p65, while NIBP knockdown reduces TNF-α-induced NF-κB activation. Yeast two-hybrid screen; co-immunoprecipitation; overexpression and siRNA knockdown; NF-κB reporter assay; Western blot for IKK complex phosphorylation The Journal of biological chemistry Medium 15951441
2007 IKKbeta physically interacts with TSC1 and phosphorylates it at Ser487 and Ser511, suppressing the TSC1/TSC2 tumor suppressor complex, which activates the mTOR pathway and enhances tumor angiogenesis via VEGF production. Co-immunoprecipitation; in vitro kinase assay with site-specific phosphorylation; mutant TSC1 overexpression; in vivo tumor models; IHC of tumor specimens for Ser511 phosphorylation Cell High 17693255
2007 IEC-intrinsic IKKbeta-dependent gene expression controls intestinal immune homeostasis. IEC-specific IKKbeta deletion reduces epithelial TSLP expression, impairs CD4+ Th2 responses to Trichuris infection, and leads to exacerbated DC-derived IL-12/23p40 and TNF-α and CD4+ T cell-derived IFN-γ and IL-17, causing severe intestinal inflammation. Cre/loxP conditional KO of IKKbeta in intestinal epithelial cells; parasite infection model; cytokine blockade experiments; T cell transfer Nature High 17322906
2007 Constitutive activation of IKK2 in pancreatic acinar cells is sufficient to induce acute pancreatitis in vivo, including edema, inflammatory infiltrates, necrosis, elevated serum lipase, and fibrosis. Dominant-negative IKK2 ameliorated cerulein-induced pancreatitis. TNF-α was identified as a critical effector of IKK2-induced pancreatitis. Tetracycline-inducible acinar cell-specific expression of constitutively active or dominant-negative IKK2 in transgenic mice; cerulein pancreatitis model; TNF-α inhibition The Journal of clinical investigation High 17525799
2008 IKK1 and IKK2 display distinct collaborative and redundant functions in the liver. Combined conditional ablation of both IKK1 and IKK2 (but not each alone) sensitizes hepatocytes to TNF-induced failure and causes spontaneous fatal cholangitis with inflammatory bile duct destruction. IKK2 alone does not mediate canonical NF-κB in hepatocytes upon TNF stimulation (unlike NEMO), but combined IKK1+IKK2 ablation uncovered redundancy in canonical NF-κB and IKK1-specific functions maintaining bile-blood barrier. Conditional (hepatocyte-specific) combined KO of IKK1, IKK2, or NEMO; LPS challenge; histological analysis; NF-κB activation assays Proceedings of the National Academy of Sciences of the United States of America High 18606991
2009 Ro52 (an E3 ubiquitin ligase) interacts with phosphorylated/active IKKbeta and, cooperating with the E2 enzyme UbcH5B, monoubiquitinates IKKbeta. This monoubiquitination down-regulates IKKbeta-induced NF-κB signaling and promotes translocation of active IKKbeta to autophagosomes for degradation. Co-immunoprecipitation; in vitro ubiquitination assay; NF-κB reporter assay; monoubiquitin fusion protein; autophagy inhibitor treatment; subcellular localization imaging Journal of biochemistry; Molecular immunology Medium 19675099 20627395
2009 PP2A constitutively dephosphorylates and inactivates IKKbeta; UVB irradiation inhibits PP2Ac activity, preventing IKKbeta dephosphorylation and causing persistent IKKbeta activation that phosphorylates newly synthesized IκBα, sustaining NF-κB activation. Mathematical modeling combined with experimental validation; PP2A activity assays; IKKbeta phosphorylation kinetics; IL-1 and UVB stimulation of cells BMC systems biology Medium 19607706
2009 IKK-beta is required in B cells for NF-κB activation and in response to LPS in monocytic cells. A dominant-negative IKK2 mutant, but not wild-type IKK1 or IKK2, inhibited LPS-induced κB-dependent transcription in a dose-dependent manner in human monocytic cells. Dominant-negative IKK2 overexpression in monocytic cells; κB-dependent reporter assay The Journal of biological chemistry Medium 9804806
2009 IKK-beta is required for activation of both IRF1 and p65 subunit of NF-κB in response to IFN-γ, revealing a novel role for IKKbeta in IFN-γ-dependent chemokine (ip-10) gene expression independent of classical NF-κB activation. IKKbeta-deficient MEFs; ChIP; reporter assays; IFN-γ and IL-1β stimulation Journal of interferon & cytokine research Medium 19929594
2012 IKKbeta directly phosphorylates and activates TSC1 suppression to activate mTOR. In lung cancer, IKK2 promotes tumor proliferation via NF-κB target gene Timp1, which activates the Erk signaling pathway through its receptor CD63. IKK2 depletion reduced tumor proliferation and prolonged survival in a lentiviral lung cancer model. Lentiviral shRNA knockdown of Ikbkb in mouse lung cancer model; xenograft and lentiviral tumor models; identification of Timp1 as NF-κB target mediator Nature cell biology Medium 22327365
2012 IKK-beta directly interacts with and sequesters FOXO3 in the cytosol, preventing FOXO3 nuclear localization and thereby promoting chemoresistance to cisplatin in MDA-MB-231 breast cancer cells. Co-immunoprecipitation; overexpression and RNAi knockdown; subcellular fractionation; apoptosis assays Cellular signalling Medium 22313691
2012 KrasG12D activates AP-1 to induce IL-1α, which in turn activates IKK2/β-NF-κB; NF-κB then induces IL-1α and p62 as feedforward loops sustaining NF-κB activity. Pancreas-targeted IKK2/β inactivation inhibited NF-κB and PDAC development in KrasG12D mice. Conditional pancreatic IKK2 inactivation in KrasG12D mouse models; analysis of IL-1α/p62 feedforward loops; gene expression and NF-κB activity assays Cancer cell High 22264792
2012 IKK-beta contributes to H2O2-induced cell death independent of NF-κB, via p85 S6K1. IKK-beta associates with p85 (but not p70) S6K1, which is required for H2O2-induced p85 S6K1 activation, leading to Mdm2 Ser166 phosphorylation and p53 accumulation. Co-immunoprecipitation; kinase activity assay; siRNA knockdown; phospho-specific Western blot; cell death assays Cell death and differentiation Medium 22955948
2013 Hypothalamic IKK-β and NF-κB inhibit GnRH production to mediate aging-related GnRH decline. Prevention of hypothalamic IKK-β and NF-κB activation retards aging and extends lifespan in mice. GnRH treatment amends aging-impaired neurogenesis. Conditional IKK-β activation/inhibition in hypothalamus using viral vectors; GnRH measurement; lifespan and neurogenesis assays; transgenic mouse models Nature High 23636330
2013 Loss-of-function IKBKB mutation (c.1292dupG) in humans causes severe combined immunodeficiency with loss of IKK2 expression, resulting in impaired responses to stimulation through T-cell receptors, B-cell receptors, toll-like receptors, inflammatory cytokine receptors, and mitogens in multiple immune cell types. Homozygosity mapping; whole gene sequencing; functional immune cell stimulation assays; patient lymphocyte studies The New England journal of medicine High 24369075
2014 A nonsense mutation in IKBKB (R286X) causes combined immunodeficiency in humans. Mutant IKKβ(R286X) is unable to complex with IKKα/NEMO, leading to impaired IκBα phosphorylation and NF-κB nuclear translocation in patient B cells. Whole-exome sequencing; co-immunoprecipitation to test complex formation; Western blot for IκBα phosphorylation; immunofluorescence for NF-κB nuclear translocation Blood High 25139357
2014 IKKβ K171E and K171T mutations found in lymphomas result in constitutively active kinase even in the absence of activation loop phosphorylation. Lysine 171 normally forms part of a cationic pocket interacting with the activation loop phosphate; its mutation disrupts this interaction, causing constitutive activity and contributing to lymphomagenesis. Biochemical kinase activity assays; predictive structural modeling; TALEN-based knock-in mutagenesis in B lymphoid cells; NF-κB signaling assays The Journal of biological chemistry High 25107905
2015 Cysteine-46 (Cys-46) is an essential residue for IKK-β kinase activity. Mutation of Cys-46 to alanine (C46A) increases inflammatory responses in vivo in a DTH mouse model. Dihydromyricetin (DMY) binds Cys-46 to exert anti-inflammatory effects in WT but not C46A transgenic mice. In vitro mutagenesis of IKK-β; C46A transgenic mouse model; delayed-type hypersensitivity model; IKK-β kinase activity assay; pharmacological challenge Oncotarget Medium 26378659
2018 A de novo heterozygous gain-of-function IKBKB missense mutation (V203I) causes enhanced NF-κB signaling and combined T and B cell functional defects in humans. CRISPR/Cas9 knock-in of the orthologous codon change in mice recapitulates the human cellular and biochemical phenotype, establishing causation. Whole exome sequencing; NF-κB signaling assays in patient cells; CRISPR/Cas9 knock-in mouse model; T and B cell functional assays The Journal of experimental medicine High 30337470
2020 IKK2 mediates LMP1 (Epstein-Barr virus)-induced JNK activation independently of its canonical NF-κB function. LMP1 induces TAK1-mediated NEMO ubiquitination and IKK2 activation, which then activates TPL2 kinase to transmit JNK activation signals. This IKK2-TPL2-JNK axis mediates essential LMP1 survival signals in EBV-transformed B cells. Genetic knockdown/overexpression; co-immunoprecipitation; kinase activity assays; EBV-transformed B cell models; lymphoma cell line studies Nature communications High 32019925
2020 Paclitaxel activates IKK2 through TLR4 signaling, and IKK2 mediates SNARE-dependent vesicle exocytosis to expose calreticulin on the cell surface, contributing to immunogenic cell death (ICD) in ovarian cancer. This is mechanistically distinct from paclitaxel-induced ER stress signaling. TLR4 inhibition; IKK2 knockdown; SNARE pathway analysis; CALR surface exposure assay; tumor vaccination assay in vivo Cancer immunology research Medium 32354736
2005 Deletion of IKK2 specifically in hepatocytes does not impair NF-κB activation or increase apoptosis after TNF-α stimulation (unlike NEMO deletion which blocks NF-κB and causes massive apoptosis), but does protect from ischemia/reperfusion injury. Conditional hepatocyte-specific KO of IKK2 or NEMO; TNF-α challenge; partial hepatic I/R injury model; NF-κB activation assays The Journal of clinical investigation High 15776110
2006 Muscle-restricted deletion of IKK2 shifts muscle fiber distribution, improves muscle force, protects against denervation-induced atrophy (maintaining fiber type, size, and strength), and facilitates skeletal muscle regeneration through enhanced satellite cell activation and reduced fibrosis. Conditional muscle-specific KO of IKK2; denervation model; muscle damage/regeneration model; force measurement; protein synthesis/degradation assays The Journal of clinical investigation High 17080195

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nature medicine 1802 15685173
1997 IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science (New York, N.Y.) 1786 9346484
2005 IKK-beta links inflammation to obesity-induced insulin resistance. Nature medicine 1444 15685170
2013 Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature 685 23636330
2007 IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 545 17693255
1999 Embryonic lethality, liver degeneration, and impaired NF-kappa B activation in IKK-beta-deficient mice. Immunity 476 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 432 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 352 14704745
2003 IKK beta plays an essential role in the phosphorylation of RelA/p65 on serine 536 induced by lipopolysaccharide. Journal of immunology (Baltimore, Md. : 1950) 341 12759443
2004 Constitutive and interleukin-1-inducible phosphorylation of p65 NF-{kappa}B at serine 536 is mediated by multiple protein kinases including I{kappa}B kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF family member-associated (TANK)-binding kinase 1 (TBK1), and an unknown kinase and couples p65 to TATA-binding protein-associated factor II31-mediated interleukin-8 transcription. The Journal of biological chemistry 317 15489227
2006 Targeted ablation of IKK2 improves skeletal muscle strength, maintains mass, and promotes regeneration. The Journal of clinical investigation 262 17080195
2008 IkappaB kinase beta (IKKbeta/IKK2/IKBKB)--a key molecule in signaling to the transcription factor NF-kappaB. Cytokine & growth factor reviews 199 18308615
2011 Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB. Nature medicine 194 21642978
2020 Paclitaxel Induces Immunogenic Cell Death in Ovarian Cancer via TLR4/IKK2/SNARE-Dependent Exocytosis. Cancer immunology research 154 32354736
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
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
2002 IKK beta and phosphatidylinositol 3-kinase/Akt participate in non-pathogenic Gram-negative enteric bacteria-induced RelA phosphorylation and NF-kappa B activation in both primary and intestinal epithelial cell lines. The Journal of biological chemistry 140 12140289
2005 A selective novel low-molecular-weight inhibitor of IkappaB kinase-beta (IKK-beta) prevents pulmonary inflammation and shows broad anti-inflammatory activity. British journal of pharmacology 133 15753951
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 102 16413924
2007 Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo. The Journal of clinical investigation 101 17525799
2010 Downregulation of active IKK beta by Ro52-mediated autophagy. Molecular immunology 93 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
2014 MiR-503 targets PI3K p85 and IKK-β and suppresses progression of non-small cell lung cancer. International journal of cancer 88 24550137
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 79 16207722
2003 Discovery of novel and selective IKK-beta serine-threonine protein kinase inhibitors. Part 1. Bioorganic & medicinal chemistry letters 79 12617920
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 74 18408102
2018 Selective IKK2 inhibitor IMD0354 disrupts NF-κB signaling to suppress corneal inflammation and angiogenesis. Angiogenesis 71 29332242
2018 IKK2/NF-κB signaling protects neurons after traumatic brain injury. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 68 29187362
2014 miR-200c regulates IL8 expression by targeting IKBKB: a potential mediator of inflammation in leiomyoma pathogenesis. PloS one 68 24755559
2003 AS602868, a pharmacological inhibitor of IKK2, reveals the apoptotic potential of TNF-alpha in Jurkat leukemic cells. Oncogene 68 14603259
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 65 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
2014 A nonsense mutation in IKBKB causes combined immunodeficiency. Blood 57 25139357
2002 IKK beta is required for Bcl-2-mediated NF-kappa B activation in ventricular myocytes. The Journal of biological chemistry 57 12167626
2000 Characterization of the recombinant IKK1/IKK2 heterodimer. Mechanisms regulating kinase activity. The Journal of biological chemistry 57 10823818
2009 A novel, highly selective, tight binding IkappaB kinase-2 (IKK-2) inhibitor: a tool to correlate IKK-2 activity to the fate and functions of the components of the nuclear factor-kappaB pathway in arthritis-relevant cells and animal models. The Journal of pharmacology and experimental therapeutics 55 19168710
2007 The discovery of 2-amino-3,5-diarylbenzamide inhibitors of IKK-alpha and IKK-beta kinases. Bioorganic & medicinal chemistry letters 55 17502144
2006 Rosmarinic acid as a downstream inhibitor of IKK-beta in TNF-alpha-induced upregulation of CCL11 and CCR3. British journal of pharmacology 53 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
2010 Tumor necrosis factor stimulates matrix metalloproteinase 9 secretion from cultured human chorionic trophoblast cells through TNF receptor 1 signaling to IKBKB-NFKB and MAPK1/3 pathway. Biology of reproduction 43 20463356
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
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
2024 miRNA-148a-containing GMSC-derived EVs modulate Treg/Th17 balance via IKKB/NF-κB pathway and treat a rheumatoid arthritis model. JCI insight 39 38652539
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
2010 IKK-beta inhibitors: an analysis of drug-receptor interaction by using molecular docking and pharmacophore 3D-QSAR approaches. Journal of molecular graphics & modelling 37 20537930
2019 miR-218 regulates diabetic nephropathy via targeting IKK-β and modulating NK-κB-mediated inflammation. Journal of cellular physiology 36 31549412
2016 MicroRNA-16 sensitizes breast cancer cells to paclitaxel through suppression of IKBKB expression. Oncotarget 36 26993770
2013 Long-term IKK2/NF-κB signaling in pancreatic β-cells induces immune-mediated diabetes. Diabetes 36 24296718
2003 Fluticasone reduces IL-6 and IL-8 production of cystic fibrosis bronchial epithelial cells via IKK-beta kinase pathway. The European respiratory journal 36 12762338
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
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 35 26219821
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
2017 Aspirin Inhibits IKK-β-mediated Prostate Cancer Cell Invasion by Targeting Matrix Metalloproteinase-9 and Urokinase-Type Plasminogen Activator. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 33 28278500
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
2021 IKK2/NF-κB Activation in Astrocytes Reduces amyloid β Deposition: A Process Associated with Specific Microglia Polarization. Cells 30 34685649
2018 The effects of IKK-beta inhibition on early NF-kappa-B activation and transcription of downstream genes. Cellular signalling 28 30543861
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
2016 Activation of G-Protein-Coupled Estrogen Receptor Inhibits the Migration of Human Nonsmall Cell Lung Cancer Cells via IKK-β/NF-κB Signals. DNA and cell biology 27 27082459
2014 Constitutive activation of IKK2/NF-κB impairs osteogenesis and skeletal development. PloS one 27 24618907
2014 Rosiglitazone inhibits hepatic insulin resistance induced by chronic pancreatitis and IKK-β/NF-κB expression in liver. Pancreas 27 25036911
2011 IKK-β-mediated myeloid cell activation exacerbates inflammation and inhibits recovery after spinal cord injury. European journal of immunology 27 21469085
2020 Therapeutic potential of IKK-β inhibitors from natural phenolics for inflammation in cardiovascular diseases. Inflammopharmacology 26 31894515
2020 A central role of IKK2 and TPL2 in JNK activation and viral B-cell transformation. Nature communications 26 32019925
2017 2-Methoxystypandrone improves in vitro-produced bovine embryo quality through inhibition of IKBKB. Theriogenology 26 28708489
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
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 25 37199240
2014 IKK2 inhibition attenuates laser-induced choroidal neovascularization. PloS one 25 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
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 22 33542074
2018 Design, synthesis and biological evaluation of novel thiazolidinedione derivatives as irreversible allosteric IKK-β modulators. European journal of medicinal chemistry 22 30130718
2015 Mutation of cysteine 46 in IKK-beta increases inflammatory responses. Oncotarget 22 26378659
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
2012 IKK-β mediates chemoresistance by sequestering FOXO3; a critical factor for cell survival and death. Cellular signalling 21 22313691
2011 Hepatocyte-specific IKK-β activation enhances VLDL-triglyceride production in APOE*3-Leiden mice. Journal of lipid research 21 21357939
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
2012 IKK-β mediates hydrogen peroxide induced cell death through p85 S6K1. Cell death and differentiation 20 22955948

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