Affinage

MAP3K14

Mitogen-activated protein kinase kinase kinase 14 · UniProt Q99558

Length
947 aa
Mass
104.0 kDa
Annotated
2026-06-14
12 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP3K14 (NIK) is a serine/threonine kinase that functions as the upstream activator of the noncanonical NF-κB pathway (PMID:15994789). Upon activation by stimuli such as RSV infection, NIK forms complexes with IKKα and NF-κB2 (p100), drives proteolytic processing of the 100-kDa p100 precursor into the 52-kDa p52 DNA-binding isoform, and transiently translocates into the nucleus complexed with p52, thereby driving a subset of NF-κB-dependent genes (PMID:15994789). This kinase-driven noncanonical signaling axis is obligate for RANKL-induced intestinal M cell differentiation, where loss of MAP3K14 abolishes induction of M cell genes including Spib, Ccl9, and Gp2 (PMID:27413168). In the kidney, tubular-cell MAP3K14 promotes acute kidney injury by driving inflammation and apoptosis through noncanonical NF-κB–dependent production of the chemokines MCP-1, RANTES, and CXCL10 (PMID:27620989). Across endometrial epithelial and macrophage systems, MAP3K14 acts as a positive upstream regulator of NF-κB activation and proinflammatory cytokine output and is post-transcriptionally repressed by specific microRNAs (PMID:31242957, PMID:36634655).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2005 High

    Established MAP3K14/NIK as an upstream activator of the noncanonical NF-κB pathway by showing it physically assembles with IKKα and p100 and drives p100-to-p52 processing during RSV infection.

    Evidence IP kinase assay, reciprocal Co-IP, DNA pull-down, and siRNA knockdown in RSV-infected cells

    PMID:15994789

    Open questions at the time
    • Direct phosphorylation site(s) on IKKα or p100 by NIK not mapped in this study
    • Mechanism of NIK nuclear translocation with p52 not defined
    • Activating signal upstream of NIK in RSV infection not resolved
  2. 2016 High

    Demonstrated that MAP3K14 is an obligate node downstream of the RANKL receptor for a differentiation program, extending its role beyond inflammation to cell-fate specification.

    Evidence Genetic loss-of-function in Map3k14-null mouse enteroids with M cell gene-expression readouts

    PMID:27413168

    Open questions at the time
    • Direct transcriptional targets bridging NIK and M cell genes not identified
    • Whether p52/RelB directly binds M cell gene promoters not shown
  3. 2016 High

    Localized MAP3K14's pathogenic role in acute kidney injury to tubular cells and identified specific chemokine effectors, distinguishing tissue-intrinsic from immune-cell contributions.

    Evidence aly/aly kinase-deficient mice, bone marrow transplantation epistasis, and tubular-cell siRNA across two AKI models

    PMID:27620989

    Open questions at the time
    • Direct kinase substrates linking NIK to chemokine induction not defined
    • Whether MCP-1/RANTES/CXCL10 are direct p52/RelB transcriptional targets not established
  4. 2019 Medium

    Positioned MAP3K14 under post-transcriptional control, showing miRNA-mediated repression tunes NF-κB activation and cytokine output.

    Evidence Dual-luciferase reporter validation of direct miR-106-5p targeting plus mimic/inhibitor functional assays in porcine endometrial epithelial cells

    PMID:31242957

    Open questions at the time
    • Single-lab finding in a non-human system
    • Canonical vs noncanonical NF-κB branch not distinguished in the cytokine readout
  5. 2023 Low

    Reinforced miRNA control of MAP3K14 in a second species and cell type, with exosomal delivery repressing the kinase and downstream cytokines.

    Evidence Luciferase reporter and exosome-mediated miR-20a-5p delivery in chicken macrophages with qRT-PCR cytokine readouts

    PMID:36634655

    Open questions at the time
    • Mechanistic link to MAP3K14 pathway is indirect
    • Single lab, single method per readout
  6. 2019 Low

    Characterized the determinants of small-molecule inhibitor selectivity at the MAP3K14 active site, informing kinase-targeted design.

    Evidence Computational docking, QM/MM, molecular dynamics, and DFT comparison of NIK versus PAK4 binding pockets

    PMID:31657381

    Open questions at the time
    • No experimental mutagenesis or biochemical validation of the predicted binding mode
    • No co-crystal structure reported in the timeline

Open questions

Synthesis pass · forward-looking unresolved questions
  • The direct phosphorylation substrates of NIK and the structural basis of its assembly with IKKα and p100 remain undefined in the available corpus.
  • No mapped NIK phosphosites on IKKα or p100
  • No experimental structure of the NIK–IKKα–p100 complex
  • Regulation of NIK protein stability/turnover not characterized here

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2 R-HSA-1266738 Developmental Biology 1
Partners
IKKANFKB2

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 RSV infection induces NIK (MAP3K14) kinase activity within 6 h of adsorption, leading to NIK complex formation with IKKα and NF-κB2 (p100/p52). NIK mediates processing of the 100-kDa NF-κB2 precursor into its 52-kDa DNA-binding isoform. Notably, NIK transiently translocates into the nucleus complexed with 52-kDa NF-κB2. siRNA-mediated NIK knockdown blocked RSV-inducible NF-κB2 p52 processing and interfered with early activation of a subset of NF-κB-dependent genes, establishing NIK as an upstream activator of the noncanonical NF-κB pathway in RSV infection. Immunoprecipitation kinase assay, coimmunoprecipitation, Western immunoblot, microaffinity DNA pull-down, siRNA knockdown Journal of virology High 15994789
2016 MAP3K14 (NIK) is required for RANKL-induced M cell differentiation in intestinal enteroids. Enteroids from Map3k14 null-mutant mice failed to induce M cell-associated genes (Spib, Ccl9, Tnfaip2, Anxa5, Marcksl1, Gp2) upon RANKL stimulation, placing MAP3K14-dependent noncanonical NF-κB signaling as an obligate pathway downstream of RANKL receptor activation for M cell differentiation. Genetic loss-of-function (Map3k14 null mice), 3D enteroid culture, gene expression analysis American journal of physiology. Cell physiology High 27413168
2016 MAP3K14 promotes acute kidney injury (AKI) through tubular cell inflammation and apoptosis via the noncanonical NF-κB pathway. MAP3K14 activity-deficient (aly/aly) mice showed less kidney dysfunction, inflammation, and apoptosis in folic acid- and cisplatin-induced AKI models. Bone marrow exchange experiments showed the protective effect was independent of immune cell MAP3K14, implicating tubular cell MAP3K14. In cultured tubular cells, MAP3K14 siRNA decreased inflammation and cell death, and the chemokines MCP-1, RANTES, and CXCL10 were identified as MAP3K14 targets. MAP3K14 activity-deficient (aly/aly) mouse model, bone marrow transplantation, siRNA knockdown in tubular cell culture, DNA binding assay (RelB/NF-κB2 nuclear fractions), immunohistochemistry Journal of the American Society of Nephrology : JASN High 27620989
2019 MAP3K14 (NIK) is a direct target of ssc-novel-miR-106-5p in porcine endometrial epithelial cells. miR-106-5p mimic downregulated MAP3K14 mRNA and protein, inhibited NF-κB phosphorylation, and decreased IL-1 and TNF-α secretion, while miR-106-5p inhibitor had the opposite effect, placing MAP3K14 as a positive upstream regulator of NF-κB activation and proinflammatory cytokine production in endometrial cells. Dual-luciferase reporter assay (direct miRNA target validation), miRNA mimic/inhibitor transfection, Western blot, cytokine measurement Reproduction, fertility, and development Medium 31242957
2023 MAP3K14 is a direct target of gga-miR-20a-5p in chicken macrophages. Luciferase reporter assay confirmed direct binding; exosome-mediated delivery of gga-miR-20a-5p repressed MAP3K14 expression and downstream proinflammatory cytokine (IFNG, IL1B, TNFA) production, consistent with MAP3K14's role upstream of NF-κB/MAPK-driven inflammatory signaling. Luciferase reporter assay, exosome-mediated miRNA delivery, qRT-PCR Animal bioscience Low 36634655
2019 Computational structural analysis revealed that selectivity of type I 1/2 kinase inhibitors between MAP3K14 (NIK) and PAK4 is determined by differences in protein-ligand interactions, positions and conformations of key active-site residues, and ligand flexibilities, reflecting the distinct binding pocket architecture of MAP3K14. Molecular docking, QM/MM simulation, molecular dynamics simulation, DFT calculation Physical chemistry chemical physics : PCCP Low 31657381

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Respiratory syncytial virus influences NF-kappaB-dependent gene expression through a novel pathway involving MAP3K14/NIK expression and nuclear complex formation with NF-kappaB2. Journal of virology 61 15994789
2016 TNF-α augments RANKL-dependent intestinal M cell differentiation in enteroid cultures. American journal of physiology. Cell physiology 59 27413168
2014 Autophagy-dependent PELI3 degradation inhibits proinflammatory IL1B expression. Autophagy 59 25483963
2011 Differential gene expression signatures between colorectal cancers with and without KRAS mutations: crosstalk between the KRAS pathway and other signalling pathways. European journal of cancer (Oxford, England : 1990) 53 21531130
2016 Mitogen-Activated Protein Kinase 14 Promotes AKI. Journal of the American Society of Nephrology : JASN 37 27620989
2023 Comprehensive Analyses Revealed Eight Immune Related Signatures Correlated With Aberrant Methylations as Prognosis and Diagnosis Biomarkers for Kidney Renal Papillary Cell Carcinoma. Clinical genitourinary cancer 25 37455213
2019 Molecular dynamics simulation and QM/MM calculation reveal the selectivity mechanism of type I 1/2 kinase inhibitors: the effect of intramolecular H-bonds and conformational restriction for improved selectivity. Physical chemistry chemical physics : PCCP 23 31657381
2020 Silencing CDC25A inhibits the proliferation of liver cancer cells by downregulating IL‑6 in vitro and in vivo. International journal of molecular medicine 20 31922225
2023 Exosome-mediated delivery of gga-miR-20a-5p regulates immune response of chicken macrophages by targeting IFNGR2, MAPK1, MAP3K5, and MAP3K14. Animal bioscience 5 36634655
2019 Ssc-novel-miR-106-5p reduces lipopolysaccharide-induced inflammatory response in porcine endometrial epithelial cells by inhibiting the expression of the target gene mitogen-activated protein kinase kinase kinase 14 (MAP3K14). Reproduction, fertility, and development 4 31242957
2026 Influenza a virus NS2 suppresses NFKB/NF-κB signaling to facilitate viral replication by mediating the autophagic-degradation of IKBKG/NEMO. Autophagy 0 42152489
2025 The Role of microRNAs in Lidocaine-Induced Spinal Cord Neurotoxicity: An Exploration Based on Bioinformatics Analysis. DNA and cell biology 0 40014404

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