Affinage

MAP3K14

Mitogen-activated protein kinase kinase kinase 14 · UniProt Q99558

Length
947 aa
Mass
104.0 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP3K14 (NF-κB-inducing kinase, NIK) is a constitutively active serine/threonine kinase that serves as the central signaling hub for the noncanonical NF-κB pathway while also regulating canonical NF-κB, interferon responses, apoptosis, mitochondrial dynamics, and metabolic homeostasis. In resting cells, NIK is continuously synthesized but rapidly degraded via a TRAF3–TRAF2–cIAP1/2 ubiquitin ligase complex that recognizes an N-terminal IAP-binding motif on NIK; receptor ligation (LTβR, CD40, BAFF-R, EDA2R) competitively displaces NIK from TRAF3 and redirects cIAP-mediated ubiquitination to degrade TRAF3, thereby stabilizing NIK to phosphorylate IKKα and drive p100-to-p52/RelB processing (PMID:18997792, PMID:20348096, PMID:25246529, PMID:16223731). Beyond NF-κB, stabilized NIK activates STING-dependent type I interferon production, phosphorylates RIP1 to promote TNFR1-mediated apoptosis, suppresses hepatocyte proliferation through JAK2/STAT3, promotes Th17 differentiation via STAT3, and drives IKK-independent mitochondrial fission by recruiting and phosphorylating Drp1 (PMID:30018345, PMID:26045047, PMID:30070632, PMID:19411637, PMID:27889261). Biallelic loss-of-function mutations in MAP3K14 cause a human primary immunodeficiency characterized by B-cell lymphopenia, impaired NF-κB activation, and defective NK-cell synapse formation (PMID:25406581).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2001 High

    Defining the physiological requirement for NIK: whereas overexpression studies had implicated NIK broadly in NF-κB signaling, knockout mice revealed a selective requirement for LTβR-dependent NF-κB activation and lymphoid organogenesis, narrowing NIK's role to specific receptor pathways.

    Evidence NIK knockout mice analyzed for NF-κB activation by multiple stimuli and lymphoid organ development

    PMID:11251123

    Open questions at the time
    • Molecular mechanism of selective LTβR dependence was unknown
    • Whether NIK had NF-κB-independent functions was not addressed
    • Downstream substrate identity unresolved
  2. 2005 High

    Establishing post-translational stabilization as the activation mechanism: pulse-chase experiments showed NIK protein is constitutively synthesized and rapidly degraded in resting B cells, and BAFF/CD40L signals stabilize NIK protein without increasing transcription, explaining how receptor signals activate NIK.

    Evidence Pulse-chase, protein synthesis inhibitor experiments in B cells stimulated with BAFF or CD40L

    PMID:16223731

    Open questions at the time
    • The E3 ligase responsible for constitutive degradation was not identified
    • Whether stabilization mechanism applied to non-B cell types was untested
  3. 2008 High

    Identification of the degradation machinery: the TRAF3–TRAF2–cIAP1/2 complex was shown to constitutively ubiquitinate NIK for proteasomal destruction, and receptor engagement redirected cIAP activity to degrade TRAF3, releasing NIK; this explained both constitutive silencing and signal-induced activation of the noncanonical pathway.

    Evidence Co-IP, ubiquitination assays, TRAF3/TRAF2-deficient cells, and mouse genetic models across multiple labs

    PMID:18292232 PMID:18997792

    Open questions at the time
    • How TRAF3 physically contacts NIK was not mapped
    • Whether TRAF3 loss activates canonical NF-κB through NIK needed further dissection
  4. 2010 High

    Resolving the competitive displacement mechanism: mutagenesis showed that LTβR and NIK bind the same TRAF3 interface, so receptor ligation physically displaces NIK while recruiting TRAF3/TRAF2 for degradation, providing the switch logic for NIK stabilization.

    Evidence Charge-repulsion mutagenesis of TRAF3 receptor-binding site, Co-IP, LTβR signaling reconstitution

    PMID:20348096

    Open questions at the time
    • Stoichiometric and kinetic parameters of the switch unknown
    • Whether all NIK-activating receptors use the same displacement mechanism was untested
  5. 2012 High

    Structural basis for constitutive kinase activity: the crystal structure of the NIK kinase domain revealed a constitutively active conformation stabilized by an N-terminal extension locking helix αC, explaining why NIK does not require activation-loop phosphorylation and why N-terminal truncations are gain-of-function.

    Evidence X-ray crystallography at 2.5 Å with ATPγS, kinase activity assays, and mutational analysis

    PMID:22718757

    Open questions at the time
    • Full-length NIK structure including regulatory domains unavailable
    • How the IBM and TRAF3-binding regions interact with the kinase domain structurally unknown
  6. 2014 High

    Mapping the cIAP1 recognition motif on NIK: an N-terminal IAP-binding motif (IBM) on NIK was shown to directly engage cIAP1's BIR2 domain, providing the substrate-recognition mechanism for constitutive ubiquitination; IBM mutation stabilized NIK and constitutively activated p100 processing.

    Evidence IBM mutagenesis, Co-IP with cIAP1 BIR2, ubiquitylation assays, NF-κB reporter assays

    PMID:25246529

    Open questions at the time
    • Whether receptor signals modify the IBM-BIR2 interface is unknown
    • Structural details of IBM-BIR2 interaction not resolved
  7. 2007 High

    Expanding NIK function beyond NF-κB: NIK-mediated phosphorylation of IKKα at Ser-176 versus Ser-180 was shown to differentially activate IRF3/7-dependent interferon production versus NF-κB, establishing NIK as a bifunctional signaling node.

    Evidence Phosphomimetic IKKα mutagenesis (S176E, S180E), IRF3/7 reporter assays, TLR stimulation

    PMID:18068231

    Open questions at the time
    • Structural basis for differential substrate presentation unknown
    • In vivo validation of the dual-phosphorylation model not provided
  8. 2009 High

    NIK links adaptive immunity to T-helper cell fate: NIK-deficient T cells were selectively impaired in Th17 differentiation through defective STAT3 activation downstream of synergistic TCR and IL-6R signals, and NIK-null mice were resistant to EAE.

    Evidence NIK-/- T-cell differentiation, Rag2-/- reconstitution, STAT3 phosphorylation assays, EAE model

    PMID:19411637

    Open questions at the time
    • Direct substrate linking NIK to STAT3 phosphorylation not identified
    • Whether NIK acts through IKKα or independently in this context was unresolved
  9. 2011 High

    Oncogenic hijacking of NIK: the API2-MALT1 fusion oncoprotein was shown to proteolytically cleave NIK at Arg325, generating a degradation-resistant C-terminal kinase fragment that drives constitutive noncanonical NF-κB, linking NIK stabilization to MALT lymphoma pathogenesis.

    Evidence Biochemical cleavage assays, Arg325 mutagenesis, NF-κB reporter and adhesion/apoptosis assays

    PMID:21273489

    Open questions at the time
    • Whether therapeutic targeting of the cleavage product is feasible unknown
    • Frequency and contribution of this mechanism across MALT lymphoma subtypes unclear
  10. 2011 High

    NIK in bone biology: NIK stabilization in osteoclast precursors accelerated osteoclastogenesis and bone resorption via constitutive alternative NF-κB, while NIK deficiency blocked osteoclast differentiation through cytoplasmic p100 retention, establishing NIK as a critical regulator of bone homeostasis.

    Evidence Transgenic gain-of-function (TRAF3-binding-deficient NIK), NIK-/- osteoclast cultures, bone resorption assays, arthritis models

    PMID:18322009 PMID:21151480

    Open questions at the time
    • NIK's role in osteoblasts not examined
    • Whether therapeutic NIK inhibition could treat osteoporosis without immunosuppression unknown
  11. 2012 High

    Metabolic function of NIK: hepatic NIK was shown to promote glucagon-stimulated glucose production by stabilizing CREB; NIK was abnormally activated in obese mouse livers, linking NIK to metabolic disease.

    Evidence Liver-specific NIK KO, hepatocyte-specific transgene, primary hepatocyte glucose production, CREB stability assays

    PMID:22581287

    Open questions at the time
    • How NIK stabilizes CREB mechanistically (direct phosphorylation vs indirect) not resolved
    • Human relevance of hepatic NIK elevation in obesity not established
  12. 2014 High

    Human disease causation: biallelic loss-of-function MAP3K14 mutations were identified as a cause of primary immunodeficiency, with abolished kinase activity leading to defective NF-κB activation, B-cell lymphopenia, and impaired NK-cell function, confirming the mouse knockout phenotype in humans.

    Evidence Patient genetics, in vitro kinase assays, lymphocyte subset flow cytometry, NK synapse imaging

    PMID:25406581

    Open questions at the time
    • Genotype-phenotype spectrum in additional patients not established
    • Whether partial loss-of-function alleles cause milder phenotypes unknown
  13. 2015 High

    NF-κB-independent apoptotic function: NIK was shown to directly phosphorylate RIP1 and promote RIP1/FADD/caspase-8 complex assembly for TNFR1-mediated apoptosis, a function independent of p100 processing, revealing that NIK integrates cell death and survival signals.

    Evidence In vitro kinase assay (NIK phosphorylating RIP1), NIK-/- and p100-/- mice, in vivo thymus/liver damage models

    PMID:26045047

    Open questions at the time
    • RIP1 phosphorylation site(s) not identified
    • How cells balance NIK's pro-survival NF-κB and pro-death RIP1 functions unclear
  14. 2016 High

    NF-κB-independent mitochondrial function: NIK was found to localize to mitochondria and promote fission by recruiting and regulating Drp1 phosphorylation (Ser-616/Ser-637), independently of IKKα/β, linking NIK to organelle dynamics and cell migration.

    Evidence Subcellular fractionation, live-cell imaging, Co-IP of NIK-Drp1, IKK-null MEFs, invasion assays

    PMID:27889261

    Open questions at the time
    • How NIK is targeted to mitochondria unknown
    • Whether mitochondrial NIK pool is regulated by the TRAF3 degradation machinery unclear
  15. 2018 High

    Innate DNA sensing: NIK was shown to interact with STING independently of alternative NF-κB components; NIK autophosphorylation and oligomerization activate STING-dependent IFN, and NIK-deficient mice are more susceptible to DNA viruses, establishing NIK as a node linking innate DNA sensing to interferon production.

    Evidence Reciprocal Co-IP of NIK-STING, autophosphorylation/oligomerization assays, IFN reporters, in vivo DNA virus infection

    PMID:30018345

    Open questions at the time
    • Whether NIK directly phosphorylates STING or another intermediate unknown
    • Relationship between NIK-STING and NIK-IKKα-IRF3 pathways not clarified
  16. 2018 High

    Hepatocyte proliferation control: conditional deletion of NIK or IKKα in hepatocytes accelerated liver regeneration after partial hepatectomy by derepressing JAK2/STAT3, positioning NIK-IKKα as a brake on hepatocyte proliferation.

    Evidence Hepatocyte-specific Map3k14 and Chuk KO mice, partial hepatectomy, JAK2/STAT3 phosphorylation, disease models

    PMID:30070632

    Open questions at the time
    • Mechanism by which NIK-IKKα suppresses JAK2/STAT3 not identified
    • Whether this pathway operates in non-hepatocyte epithelial cells untested
  17. 2018 High

    Cell-type-specific immune roles: DC-specific NIK was shown to drive IL-23 production for intestinal Th17/ILC3 maintenance and IgA homeostasis, while LEC-specific NIK controlled CXCL13-dependent B-cell homing to lymph nodes, demonstrating that NIK acts through distinct effector programs in different stromal and immune cell types.

    Evidence DC-specific and LEC-specific NIK conditional KO mice, infection/colitis models, B-cell adoptive transfer, chemokine assays

    PMID:29503445 PMID:30250187

    Open questions at the time
    • Whether NIK-dependent transcriptional programs differ across DC subsets not fully resolved
    • Upstream receptor activating NIK in LECs not identified
  18. 2022 High

    IKKα-independent biliary function: cholangiocyte-specific NIK deletion (but not IKKα deletion) blunted ductular reaction, fibrosis, and inflammation during cholestasis, demonstrating an IKKα-independent NIK effector pathway in biliary epithelial cells.

    Evidence Cholangiocyte-specific NIK KO vs IKKα KO, BDL/DDC/ANIT cholestasis models, proliferation/apoptosis/cholangiokine assays

    PMID:36042192

    Open questions at the time
    • The IKKα-independent substrate mediating ductular reaction not identified
    • Whether this pathway contributes to cholangiocarcinoma unknown
  19. 2023 High

    Muscle atrophy via EDA2R-NIK axis: EDA-A2/EDA2R signaling was shown to activate NIK-dependent noncanonical NF-κB in skeletal muscle, upregulating atrophy genes; muscle-specific NIK deletion protected against cancer cachexia, identifying a new receptor-kinase axis in muscle wasting.

    Evidence Primary myotube assays, muscle-specific NIK KO, EDA2R KO, tumor-bearing cachexia models, NIK inhibitor treatment

    PMID:37165186

    Open questions at the time
    • Whether NIK inhibitors can treat cachexia without immunosuppression unknown
    • Direct NIK substrates in skeletal muscle not characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the full-length structure of NIK with its regulatory domains, the mechanism by which NIK is targeted to mitochondria, the identity of IKKα-independent substrates in cholangiocytes, and how cells integrate NIK's pro-survival (NF-κB), pro-death (RIP1), and metabolic (CREB, JAK2/STAT3) outputs.
  • Full-length NIK structure unavailable
  • Mitochondrial targeting mechanism unknown
  • IKKα-independent downstream effectors in non-immune cells unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0140657 ATP-dependent activity 1
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0005739 mitochondrion 1
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-168256 Immune System 7 R-HSA-1266738 Developmental Biology 3 R-HSA-1430728 Metabolism 1 R-HSA-1852241 Organelle biogenesis and maintenance 1 R-HSA-5357801 Programmed Cell Death 1
Partners
BIRC2CHUKDNM1LNEK2RIPK1STING1TRAF2TRAF3
Complex memberships
TRAF3-TRAF2-cIAP1/2 degradation complex (substrate)

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 TRAF2 and TRAF3 form a ubiquitin ligase complex with cIAP1/cIAP2 that constitutively targets NIK (MAP3K14) for proteasomal degradation; receptor activation (CD40 or BAFF-R) triggers TRAF2-mediated K63-linked ubiquitination and activation of cIAP1/cIAP2, redirecting their E3 ligase activity to degrade TRAF3, thereby releasing NIK from the complex, stabilizing it, and enabling NF-κB2/p100 processing to p52. Co-immunoprecipitation, ubiquitination assays, TRAF3-deficient and TRAF2-deficient cell lines, mouse genetic models Nature immunology High 18997792
2001 NIK is selectively required for NF-κB transcriptional activation downstream of the lymphotoxin-β receptor (LTβR) but not downstream of TNF receptor or IL-1 receptor; NIK knockout mice show defects in lymphoid tissue development and antibody responses. Gene targeting/knockout mouse, NF-κB DNA binding assays, cytokine stimulation of NIK-/- cells, reporter gene assays Science High 11251123
2012 Crystal structure of the truncated human NIK kinase domain (with N-terminal extension) in complex with ATPγS at 2.5 Å reveals a constitutively active conformation that does not require phosphorylation; the N-terminal extension stabilizes helix αC in the active orientation, explaining NIK's intrinsic constitutive kinase activity and the gain-of-function of N-terminal deletion mutants. X-ray crystallography, kinase activity assays, mutational analysis The Journal of biological chemistry High 22718757
2011 The API2-MALT1 fusion oncoprotein proteolytically cleaves NIK at arginine 325; both API2 and MALT1 partners are required, and the resulting C-terminal NIK fragment retains kinase activity, is resistant to proteasomal degradation, and drives constitutive noncanonical NF-κB signaling, enhanced B-cell adhesion, and apoptosis resistance. Biochemical cleavage assays, mutagenesis (Arg325 site), co-expression experiments, NF-κB reporter assays, apoptosis/adhesion assays Science High 21273489
2010 Recruitment of TRAF3 and TRAF2 to the ligated LTβR competitively displaces NIK from the TRAF3-binding site (shown by charge-repulsion mutation ablating both LTβR and NIK binding to TRAF3); ligated LTβR also allosterically redirects the ubiquitin:NIK E3 ligase to polyubiquitinate and degrade TRAF3/TRAF2 via the RING domain of TRAF2, thereby halting NIK turnover and promoting NIK association with IKKα. Mutagenesis of TRAF3/TRAF2 receptor-binding domains, co-immunoprecipitation, ubiquitination assays, LTβR signaling reconstitution The Journal of biological chemistry High 20348096
2014 NIK contains an IAP-binding motif (IBM) at its amino terminus that interacts with the BIR2 domain of c-IAP1, providing substrate recognition for c-IAP1-mediated ubiquitylation and proteasomal degradation of NIK; IBM mutation stabilizes NIK and constitutively elevates p100-to-p52 processing and NF-κB target gene expression. Mutagenesis of the NIK IBM, co-immunoprecipitation with c-IAP1 BIR2 domain, ubiquitylation assays, NF-κB reporter assays The Journal of biological chemistry High 25246529
2005 NIK protein undergoes constitutive synthesis but rapid proteasomal degradation in resting B cells; BAFF and CD40L stabilize basally translated NIK post-translationally (without increasing mRNA or translation rate), and stabilized NIK is sufficient to trigger p100-to-p52 processing even in the presence of a protein synthesis inhibitor. Pulse-chase experiments, protein synthesis inhibitor treatment, immunoblot for NIK and p100/p52, stimulation with BAFF/CD40L vs. TNFα/PMA The Journal of biological chemistry High 16223731
2008 NIK (MAP3K14) is localized to mitochondria in cancer cells and MEFs; NIK promotes mitochondrial fission and directional migration by recruiting Drp1 to mitochondria, forming a complex with Drp1, and regulating Drp1 phosphorylation (Ser-616) and dephosphorylation (Ser-637); this function is independent of IKKα/β and NF-κB. Subcellular fractionation, live-cell imaging, co-immunoprecipitation (NIK-Drp1 complex), Drp1 phosphorylation assays, IKK/NF-κB-null MEFs, invasion assays Current biology High 27889261
2015 NIK (MAP4K4) binds and directly phosphorylates the Arp2 subunit of the Arp2/3 complex, increasing its nucleating activity; NIK kinase activity is necessary for EGF-stimulated Arp2 phosphorylation and plasma membrane protrusion in mammary carcinoma cells. In vitro kinase assay (recombinant NIK phosphorylating Arp2), co-immunoprecipitation, phospho-mimetic/phospho-dead Arp2 mutants, actin assembly assays, EGF stimulation of cells The Journal of cell biology High 25601402
2001 MAP4K4/NIK (the Ste20-related kinase, not the NF-κB-inducing kinase) is essential for mesodermal and endodermal cell migration during gastrulation; NIK-null mouse embryos die at E9.5-10.5 with failure of presomitic mesodermal cells to migrate from the primitive streak; chimeric analysis reveals both cell-nonautonomous (migration stimulation) and cell-autonomous (dermomyotome differentiation) functions. Homologous recombination knockout, embryo phenotype analysis, chimeric mouse analysis Development High 11290295
2008 TRAF3 depletion leads to accumulation of NIK, which then activates both canonical (p50-dependent) and noncanonical (p52-dependent) NF-κB pathways; deregulated canonical NF-κB activation in TRAF3-deficient cells is dependent on NIK accumulation. TRAF3-deficient cell lines, NIK knockdown/overexpression, NF-κB reporter assays, EMSA, immunoblot for p100/p52 processing Proceedings of the National Academy of Sciences of the United States of America High 18292232
2008 NIK is required for osteoclast differentiation; NIK deficiency blocks both alternative and classical NF-κB due to cytoplasmic p100 retention; p100 deletion or RelB overexpression (but not p65) rescues osteoclastogenesis in NIK-/- precursors; RelB-/- mice show impaired osteoclast formation and reduced tumor-induced osteolysis. NIK-/- and RelB-/- mouse osteoclast cultures, retroviral overexpression of RelB/p65, in vivo serum transfer/tumor models, bone histomorphometry Proceedings of the National Academy of Sciences of the United States of America High 18322009
2012 NIK promotes glucagon-stimulated hepatic glucose production in obesity by increasing cAMP response element-binding protein (CREB) stability; hepatic NIK is abnormally activated in obese mice; liver-specific inhibition of NIK reduces glucagon responses and HGP, while hepatocyte-specific NIK overexpression increases them. Map3k14 systemic knockout, liver-specific NIK deletion, hepatocyte-specific NIK transgene, primary hepatocyte glucose production assays, CREB stability assays Nature medicine High 22581287
2009 NIK is required for Th17 cell differentiation; NIK-deficient naive CD4+ T cells are defective in Th17 commitment but not other lineages; NIK mediates synergistic STAT3 activation by TCR and IL-6 receptor signals, and its loss attenuates STAT3 phosphorylation and STAT3 target gene induction needed for Th17 commitment; NIK-/- mice are resistant to EAE. NIK-/- mouse T-cell differentiation assays, Rag2-/- reconstitution with NIK-/- T cells, STAT3 phosphorylation assays, EAE model Blood High 19411637
2014 Biallelic loss-of-function mutations in MAP3K14 (NIK) cause primary immunodeficiency in humans; mutant NIK loses kinase activity (confirmed by functional assays), leading to defective canonical and noncanonical NF-κB activation, B-cell lymphopenia, impaired ICOSL expression, perturbed follicular helper and memory T cells, and defective NK-cell immunological synapse formation. Patient genetics, NIK kinase activity assays, NF-κB signaling assays, flow cytometry of lymphocyte subsets, NK-cell immunological synapse imaging Nature communications High 25406581
2018 NIK interacts with the innate DNA-sensing adaptor STING independently of alternative NF-κB signaling components; NIK autophosphorylation and oligomerization are required to activate STING-dependent IFN induction; NIK-deficient mice are more susceptible to DNA virus infection; TRAF3, a positive regulator of RNA-pathway IFN, inhibits the DNA pathway by limiting NIK availability. NIK-/- mouse infection models, co-immunoprecipitation of NIK-STING, autophosphorylation assays, NIK oligomerization assays, IFN reporter assays, epistasis with alternative NF-κB components Nature communications High 30018345
2007 NIK confers IKKα the ability to activate IRF3/7 for IFN production; NIK phosphorylates IKKα at Ser-176 and Ser-180, but these two phosphorylations have differential effects: IKKα(S176E) constitutively activates IRF3/7 while IKKα(S180E) loses this ability, revealing that NIK differentially regulates NF-κB versus IRF3/7 activation through IKKα. Phosphomimetic IKKα mutagenesis (S176E, S180E), IRF3/7 reporter assays, TLR7/9 stimulation, kinase assays Molecular immunology High 18068231
2005 NIK physically interacts with IKKβ (but not IKKα or IKKγ) and with a novel brain-enriched protein NIBP (identified by yeast two-hybrid screen); NIBP overexpression potentiates TNFα-induced NF-κB activation through increased IKK complex phosphorylation and downstream IκBα/p65 phosphorylation, while NIBP knockdown reduces NF-κB activation. Yeast two-hybrid screen, co-immunoprecipitation, overexpression/siRNA knockdown in PC12 cells, NF-κB reporter assays, phosphorylation assays The Journal of biological chemistry Medium 15951441
2003 NIK is a component of EGF/heregulin receptor signaling complexes; NIK interacts with Grb7 (via Grb7's GM domain), Grb10, and Grb14, and can be simultaneously recruited with Grb7 into EGFR, ErbB2, ErbB3, and ErbB4 complexes; NIK potentiates EGF/heregulin-induced NF-κB activation, and EGF activates NF-κB in wild-type but not NIK-/- fibroblasts. Antibody array screen for NIK-associated proteins, co-immunoprecipitation, domain mapping (Grb7 GM domain), NF-κB reporter assays in NIK-/- MEFs Oncogene Medium 12853971
2003 Cytokine (IL-1/TNFα)-induced suppression of PPAR-γ adipogenic function is mediated through the TAK1/TAB1/NIK cascade activating NF-κB; NF-κB blocks PPAR-γ DNA binding by forming a complex with PPAR-γ and its AF-1-specific co-activator PGC-2. Dominant-negative kinase constructs, NF-κB reporter assays, co-immunoprecipitation of NF-κB/PPAR-γ/PGC-2 complex, PPAR-γ DNA binding assays, adipogenesis assays Nature cell biology Medium 12598905
2015 NIK promotes TNFR1-mediated RIP1-dependent apoptosis independently of alternative NF-κB (p100-to-p52 processing); NIK stabilization (via Fn14 or LTβR) is required for TNFα-induced cIAP1/2 depletion to trigger RIP1 phosphorylation and RIP1/FADD/caspase-8 complex assembly; in vitro kinase assays show RIP1 is a direct NIK substrate. In vitro kinase assay (NIK phosphorylating RIP1), genetic models (NIK-/- and p100-/- mice), thymus involution and liver damage in vivo models, immunoprecipitation of RIP1/FADD/caspase-8 complex Cell death and differentiation High 26045047
2003 NIK mediates NF-κB activation downstream of caspase-8 and caspase-10 prodomain isoforms (PDCasp8/10); GST pulldown shows NIK (and RIP) directly bind PDCasp8/10; dominant-negative IKKα or kinase-dead RIP blocks PDCasp8/10-mediated NF-κB activation; siRNA knockdown shows IKKα (not IKKβ) is the relevant downstream kinase. GST pulldown, dominant-negative mutants, siRNA knockdown, NF-κB reporter assays European journal of immunology Medium 12884866
2018 NIK promotes liver inflammation and fibrosis through a hepatocyte NIK-liver immune cell (macrophage) axis; hepatocyte NIK overexpression stimulates release of chemokines/cytokines that activate macrophages, which in turn secrete proapoptotic factors inducing hepatocyte apoptosis; depletion of Kupffer cells/macrophages reverses NIK-induced liver destruction. Hepatocyte-specific NIK transgene, primary hepatocyte conditioned medium experiments, macrophage activation assays, Kupffer cell depletion, liver histology/fibrosis assays Hepatology High 25088600
2018 NIK (MAP3K14) and its substrate IKKα suppress the mitogenic JAK2/STAT3 pathway to restrain hepatocyte proliferation and liver regeneration; hepatocyte-specific deletion of Map3k14 or Chuk (IKKα) substantially accelerates hepatocyte proliferation after partial hepatectomy, even under liver disease conditions (hepatotoxin or high-fat diet). Hepatocyte-specific Map3k14 and Chuk knockout mice, partial hepatectomy, STAT3/JAK2 phosphorylation assays, cell cycle analysis, liver disease models eLife High 30070632
2011 NIK stabilization in osteoclast precursors (via deletion of TRAF3-binding domain) constitutively activates alternative NF-κB and enhances both osteoclast differentiation speed and resorptive function, causing high-turnover osteoporosis and exaggerated inflammatory osteolysis in vivo. OC-lineage transgenic mice expressing TRAF3-binding-deficient NIK (NT3), in vitro osteoclastogenesis assays, bone resorption/actin ring measurements, serum transfer arthritis model PloS one High 21151480
2023 EDA-A2 ligand activates EDA2R receptor signaling that requires NIK activity to promote skeletal muscle atrophy; EDA-A2 stimulation induces noncanonical NF-κB pathway activation and upregulates Atrogin1/MuRF1; muscle-specific NIK deletion protects tumour-bearing mice from cancer cachexia-associated muscle wasting; oncostatin M (OSM) upregulates muscle EDA2R expression upstream of NIK. Primary myotube EDA-A2 stimulation assays, muscle-specific NIK knockout mice, EDA2R knockout mice, tumour-bearing mouse cachexia model, NIK kinase inhibitor treatment, OSMR muscle-specific KO Nature High 37165186
2022 Biliary NIK promotes ductular reaction independently of its canonical substrate IKKα; cholangiocyte-specific NIK deletion (but not IKKα deletion) blunts cholestasis-induced ductular reaction, liver injury, inflammation and fibrosis; NIK directly increases cholangiocyte proliferation, suppresses their death, and stimulates secretion of cholangiokines that activate macrophages and hepatic stellate cells. Cholangiocyte-specific NIK KO, cholangiocyte-specific IKKα KO, BDL/DDC/ANIT cholestasis models, NIK inhibitor treatment, cholangiocyte proliferation/apoptosis assays, cholangiokine secretion assays Nature communications High 36042192
2015 NIK is required in dendritic cells for CD40-dependent cross-priming of CD8+ T cells; DC-specific NIK deletion impairs antigen cross-presentation to CD8+ T cells and IL-12p40 secretion by splenic CD8+ DCs, without affecting antigen presentation to CD4+ T cells. CD11c-Cre NIK conditional knockout mice, vaccination/cross-priming assays, in vitro cross-presentation assays, cytokine ELISA Proceedings of the National Academy of Sciences of the United States of America High 26561586
2018 DC-specific NIK activates noncanonical NF-κB to induce IL-23 expression in intestinal DCs, which maintains TH17 cells and type 3 ILCs; these produce IL-17 that drives pIgR expression on intestinal epithelial cells, enabling IgA secretion and microbiota homeostasis; DC-specific NIK deletion renders mice sensitive to Citrobacter rodentium and ameliorates colitis. DC-specific NIK knockout mice, intestinal IgA measurements, TH17/ILC3 quantification, IL-23/IL-17/pIgR expression assays, infection and colitis models Nature immunology High 30250187
2018 NIK in lymphatic endothelial cells (LECs) regulates B-cell homing to lymph nodes by mediating expression of CXCL13 (exclusively in LECs, not blood endothelial cells) and CCL19; LEC-conditional NIK deletion severely reduces B-cell frequency in LNs without affecting LN integrity or splenic B cells. LEC-specific NIK conditional KO mice, B-cell adoptive transfer assays, chemokine ELISA/qPCR, flow cytometry of LN/spleen B-cell subsets Cellular & molecular immunology High 29503445
2011 NIK (MAP3K14) mediates cigarette smoke (CS)- and TNFα-induced histone H3K9 acetylation at pro-inflammatory gene promoters via phosphorylation of IKKα; NIK accumulates in the nuclear compartment and is recruited to promoters of pro-inflammatory genes; NIK knockdown attenuates CS/TNFα-induced histone acetylation; the canonical IKKβ/NF-κB pathway does not mediate CS-induced histone acetylation. NIK siRNA knockdown, chromatin immunoprecipitation (ChIP) for NIK and acetylated H3K9, in vivo CS exposure mouse model, immunoblot for nuclear NIK, IKKα/β phosphorylation PloS one Medium 21887257
2022 NEK2 phosphorylates NIK (MAP3K14), increasing NIK activity and stability, thereby activating noncanonical NF-κB signaling to promote GBM malignancy; NEK2 knockdown reduces NIK-dependent NF-κB activity and tumor progression. Co-immunoprecipitation, kinase assays showing NEK2 phosphorylates NIK, siRNA knockdown, NF-κB reporter assays, in vivo xenograft transplantation Cell death & disease Medium 35031599

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling. Nature immunology 524 18997792
2001 Defective lymphotoxin-beta receptor-induced NF-kappaB transcriptional activity in NIK-deficient mice. Science (New York, N.Y.) 325 11251123
2003 Cytokines suppress adipogenesis and PPAR-gamma function through the TAK1/TAB1/NIK cascade. Nature cell biology 243 12598905
2008 Control of canonical NF-kappaB activation through the NIK-IKK complex pathway. Proceedings of the National Academy of Sciences of the United States of America 165 18292232
2001 Micrococci and peptidoglycan activate TLR2-->MyD88-->IRAK-->TRAF-->NIK-->IKK-->NF-kappaB signal transduction pathway that induces transcription of interleukin-8. Infection and immunity 140 11254583
1998 Fetuin (alpha2-HS-glycoprotein) opsonizes cationic macrophagedeactivating molecules. Proceedings of the National Academy of Sciences of the United States of America 138 9826717
2020 Targeting NF-κB-Inducing Kinase (NIK) in Immunity, Inflammation, and Cancer. International journal of molecular sciences 136 33187137
2006 An RNA interference-based screen identifies MAP4K4/NIK as a negative regulator of PPARgamma, adipogenesis, and insulin-responsive hexose transport. Proceedings of the National Academy of Sciences of the United States of America 135 16461467
2011 Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation. Science (New York, N.Y.) 127 21273489
2003 The involvement of heparan sulfate (HS) in FGF1/HS/FGFR1 signaling complex. The Journal of biological chemistry 125 12604602
2008 RelB is the NF-kappaB subunit downstream of NIK responsible for osteoclast differentiation. Proceedings of the National Academy of Sciences of the United States of America 121 18322009
2014 Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity. Nature communications 111 25406581
2011 MicroRNA-520e suppresses growth of hepatoma cells by targeting the NF-κB-inducing kinase (NIK). Oncogene 105 22105365
2005 NIBP, a novel NIK and IKK(beta)-binding protein that enhances NF-(kappa)B activation. The Journal of biological chemistry 104 15951441
2012 NF-κB–inducing kinase (NIK) promotes hyperglycemia and glucose intolerance in obesity by augmenting glucagon action. Nature medicine 90 22581287
2004 NF-kappaB activation mechanism of 4-hydroxyhexenal via NIK/IKK and p38 MAPK pathway. FEBS letters 85 15147892
2014 Mouse hepatocyte overexpression of NF-κB-inducing kinase (NIK) triggers fatal macrophage-dependent liver injury and fibrosis. Hepatology (Baltimore, Md.) 84 25088600
2005 Stabilization of basally translated NF-kappaB-inducing kinase (NIK) protein functions as a molecular switch of processing of NF-kappaB2 p100. The Journal of biological chemistry 80 16223731
2023 Characterization and metabolism pathway of volatile compounds in walnut oil obtained from various ripening stages via HS-GC-IMS and HS-SPME-GC-MS. Food chemistry 79 37769558
2016 NIK/MAP3K14 Regulates Mitochondrial Dynamics and Trafficking to Promote Cell Invasion. Current biology : CB 77 27889261
2001 Mesodermal patterning defect in mice lacking the Ste20 NCK interacting kinase (NIK). Development (Cambridge, England) 76 11290295
2023 EDA2R-NIK signalling promotes muscle atrophy linked to cancer cachexia. Nature 74 37165186
2014 Post-Synthetic Regulation of HS Structure: The Yin and Yang of the Sulfs in Cancer. Frontiers in oncology 74 24459635
2012 Genetic lesions of the TRAF3 and MAP3K14 genes in classical Hodgkin lymphoma. British journal of haematology 73 22469134
2009 Regulation of Th17 cell differentiation and EAE induction by MAP3K NIK. Blood 73 19411637
2016 A small-molecule inhibitor of NF-κB-inducing kinase (NIK) protects liver from toxin-induced inflammation, oxidative stress, and injury. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 67 27871061
2012 Hodgkin lymphoma requires stabilized NIK and constitutive RelB expression for survival. Blood 66 22968463
2010 Allosteric regulation of the ubiquitin:NIK and ubiquitin:TRAF3 E3 ligases by the lymphotoxin-beta receptor. The Journal of biological chemistry 65 20348096
2008 The ribosomal protein L10/QM-like protein is a component of the NIK-mediated antiviral signaling. Virology 64 18789471
2017 Suppression of Th17 cell differentiation by misshapen/NIK-related kinase MINK1. The Journal of experimental medicine 60 28400474
2010 NSP-interacting kinase, NIK: a transducer of plant defence signalling. Journal of experimental botany 60 20624762
2018 Melatonin improves insulin resistance and hepatic steatosis through attenuation of alpha-2-HS-glycoprotein. Journal of pineal research 57 29607540
2010 NIK stabilization in osteoclasts results in osteoporosis and enhanced inflammatory osteolysis. PloS one 57 21151480
2018 HS-1371, a novel kinase inhibitor of RIP3-mediated necroptosis. Experimental & molecular medicine 54 30237400
2009 High glucose induces transactivation of the alpha2-HS glycoprotein gene through the ERK1/2 signaling pathway. Journal of atherosclerosis and thrombosis 52 19672022
2003 Caspase-8 and caspase-10 activate NF-kappaB through RIP, NIK and IKKalpha kinases. European journal of immunology 50 12884866
2001 Identification of the nik gene cluster of Brucella suis: regulation and contribution to urease activity. Journal of bacteriology 47 11133934
2017 Tumor vessel normalization by the PI3K inhibitor HS-173 enhances drug delivery. Cancer letters 46 28688971
2012 Structure of the nuclear factor κB-inducing kinase (NIK) kinase domain reveals a constitutively active conformation. The Journal of biological chemistry 46 22718757
2015 Dendritic cells require NIK for CD40-dependent cross-priming of CD8+ T cells. Proceedings of the National Academy of Sciences of the United States of America 45 26561586
2011 NF-kappaB-inducing kinase (NIK) mediates skeletal muscle insulin resistance: blockade by adiponectin. Endocrinology 45 21846802
2010 NF-kappaB inducing kinase (NIK) inhibitors: identification of new scaffolds using virtual screening. Bioorganic & medicinal chemistry letters 44 20580552
2011 NF-κB inducing kinase, NIK mediates cigarette smoke/TNFα-induced histone acetylation and inflammation through differential activation of IKKs. PloS one 43 21887257
2015 NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis. Cell death and differentiation 40 26045047
2013 Downregulation of TRAF2 mediates NIK-induced pancreatic cancer cell proliferation and tumorigenicity. PloS one 40 23301098
2018 NIK signaling axis regulates dendritic cell function in intestinal immunity and homeostasis. Nature immunology 39 30250187
2015 Misshapen/NIK-related kinase (MINK1) is involved in platelet function, hemostasis, and thrombus formation. Blood 39 26598717
2022 Biliary NIK promotes ductular reaction and liver injury and fibrosis in mice. Nature communications 37 36042192
2010 Lipopolysaccharide-induced activation of NF-κB non-canonical pathway requires BCL10 serine 138 and NIK phosphorylations. Experimental cell research 37 20466000
2018 A TRAF3-NIK module differentially regulates DNA vs RNA pathways in innate immune signaling. Nature communications 36 30018345
2009 NIK is involved in constitutive activation of the alternative NF-kappaB pathway and proliferation of pancreatic cancer cells. Biochemical and biophysical research communications 36 19646419
2007 Differential regulation of IKK alpha-mediated activation of IRF3/7 by NIK. Molecular immunology 35 18068231
2006 Improving solubility and refolding efficiency of human V(H)s by a novel mutational approach. Protein engineering, design & selection : PEDS 35 16971398
2015 The Nck-interacting kinase NIK increases Arp2/3 complex activity by phosphorylating the Arp2 subunit. The Journal of cell biology 34 25601402
2016 HS-173, a novel PI3K inhibitor suppresses EMT and metastasis in pancreatic cancer. Oncotarget 33 27793006
2016 Glucocorticoids increase skeletal muscle NF-κB inducing kinase (NIK): links to muscle atrophy. Physiological reports 33 27905294
1996 Antibodies to endometrial transferrin and alpha 2-Heremans Schmidt (HS) glycoprotein in patients with endometriosis. American journal of reproductive immunology (New York, N.Y. : 1989) 33 8738720
2024 NETs induce ferroptosis of endothelial cells in LPS-ALI through SDC-1/HS and downstream pathways. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 32 38677244
2013 Combined Cathepsin S and hs-CRP predicting inflammation of abdominal aortic aneurysm. Clinical biochemistry 32 23742758
2020 Nitric oxide and TNF-α are correlates of diabetic retinopathy independent of hs-CRP and HbA1c. Endocrine 31 32494901
2018 Hepatic NF-kB-inducing kinase (NIK) suppresses mouse liver regeneration in acute and chronic liver diseases. eLife 31 30070632
2013 Ceriponols A-K, tremulane sesquitepenes from Ceriporia lacerate HS-ZJUT-C13A, a fungal endophyte of Huperzia serrata. Phytochemistry 31 23954076
2003 NIK is a component of the EGF/heregulin receptor signaling complexes. Oncogene 30 12853971
1999 Levels of transferrin and alpha 2-HS glycoprotein in women with and without endometriosis. Autoimmunity 30 10433073
2002 Alpha2-HS glycoprotein: a protein in search of a function. Diabetes/metabolism research and reviews 29 12203946
2022 NEK2 enhances malignancies of glioblastoma via NIK/NF-κB pathway. Cell death & disease 28 35031599
2020 HS and Inflammation: A Potential Playground for the Sulfs? Frontiers in immunology 27 32318065
2011 SMG1 and NIK regulate apoptosis induced by Smac mimetic compounds. Cell death & disease 26 21490678
2018 Adipose tissue-derived stem cells inhibit hypertrophic scar (HS) fibrosis via p38/MAPK pathway. Journal of cellular biochemistry 25 30260015
2015 GAG-ID: Heparan Sulfate (HS) and Heparin Glycosaminoglycan High-Throughput Identification Software. Molecular & cellular proteomics : MCP 24 25887393
2014 Nuclear factor-κB-inducing kinase (NIK) contains an amino-terminal inhibitor of apoptosis (IAP)-binding motif (IBM) that potentiates NIK degradation by cellular IAP1 (c-IAP1). The Journal of biological chemistry 24 25246529
2012 The relationship between hs-CRP and asthma control test in asthmatic patients. Allergologia et immunopathologia 24 22284830
2011 Characterisation of the legume SERK-NIK gene superfamily including splice variants: implications for development and defence. BMC plant biology 24 21385462
2017 gga-miR-99a targets SMARCA5 to regulate Mycoplasma gallisepticum (HS strain) infection by depressing cell proliferation in chicken. Gene 23 28652181
2020 Identification of N-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine Derivatives as Novel, Potent, and Selective NF-κB Inducing Kinase (NIK) Inhibitors for the Treatment of Psoriasis. Journal of medicinal chemistry 22 32479083
2017 Anti-Restriction Protein, KlcAHS, Promotes Dissemination of Carbapenem Resistance. Frontiers in cellular and infection microbiology 22 28512626
2017 Noncanonical NF-κB signaling and the essential kinase NIK modulate crucial features associated with eosinophilic esophagitis pathogenesis. Disease models & mechanisms 22 29259025
2010 The RET/PTC3 oncogene activates classical NF-κB by stabilizing NIK. Oncogene 22 20818435
2021 Pharmacological inhibition of NF-κB-inducing kinase (NIK) with small molecules for the treatment of human diseases. RSC medicinal chemistry 21 34046627
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
2014 Apoptosis repressor with caspase recruitment domain modulates second mitochondrial-derived activator of caspases mimetic-induced cell death through BIRC2/MAP3K14 signalling in acute myeloid leukaemia. British journal of haematology 21 25079338
2022 Spatiotemporal tracking of small extracellular vesicle nanotopology in response to physicochemical stresses revealed by HS-AFM. Journal of extracellular vesicles 20 36317784
2015 Downregulation of miR-518a-3p activates the NIK-dependent NF-κB pathway in colorectal cancer. International journal of molecular medicine 20 25812680
2004 Deletion of the major GATA1 enhancer HS 1 does not affect eosinophil GATA1 expression and eosinophil differentiation. Blood 20 15016648
2025 Correlation between hs-CRP-triglyceride glucose index and NAFLD and liver fibrosis. BMC gastroenterology 19 40221654
2023 EGR1 knockdown confers protection against ferroptosis and ameliorates intervertebral disc cartilage degeneration by inactivating the MAP3K14/NF-κB axis. Genomics 19 37453477
2022 Quality and Metabolomics Analysis of Houttuynia cordata Based on HS-SPME/GC-MS. Molecules (Basel, Switzerland) 19 35745045
1978 Linkage and gene localization of hereditary spherocytosis (HS). Blood 19 100151
2019 gga-miR-146c Activates TLR6/MyD88/NF-κB Pathway through Targeting MMP16 to Prevent Mycoplasma Gallisepticum (HS Strain) Infection in Chickens. Cells 18 31137698
2018 Lymphatic endothelial cells regulate B-cell homing to lymph nodes via a NIK-dependent mechanism. Cellular & molecular immunology 18 29503445
2022 Potentially functional variants of MAP3K14 in the NF-κB signaling pathway genes predict survival of HBV-related hepatocellular carcinoma patients. Frontiers in oncology 17 36119471
2019 gga-miR-21 modulates Mycoplasma gallisepticum (HS strain)-Induced inflammation via targeting MAP3K1 and activating MAPKs and NF-κB pathways. Veterinary microbiology 17 31585644
2017 Exome Sequencing Identifies a Novel MAP3K14 Mutation in Recessive Atypical Combined Immunodeficiency. Frontiers in immunology 17 29230214
2014 HS-23, Lonicera japonica extract, attenuates septic injury by suppressing toll-like receptor 4 signaling. Journal of ethnopharmacology 17 24862492
2024 Gram-negative anaerobes elicit a robust keratinocytes immune response with potential insights into HS pathogenesis. Experimental dermatology 16 38685821
2021 MicroRNA-17-3p suppresses NF-κB-mediated endothelial inflammation by targeting NIK and IKKβ binding protein. Acta pharmacologica Sinica 16 33623121
2021 Exosomal miR-181a-5p reduce Mycoplasma gallisepticum (HS strain) infection in chicken by targeting PPM1B and activating the TLR2-mediated MyD88/NF-κB signaling pathway. Molecular immunology 16 34715577
2019 SMAC mimetics promote NIK-dependent inhibition of CD4+ TH17 cell differentiation. Science signaling 16 31455723
2015 Lowering the quantification limit of the QubitTM RNA HS assay using RNA spike-in. BMC molecular biology 16 25943882
2011 The kinase NIK as a therapeutic target in multiple myeloma. Expert opinion on therapeutic targets 16 21204728