Affinage

MAP4K4

Mitogen-activated protein kinase kinase kinase kinase 4 · UniProt O95819

Length
1239 aa
Mass
142.1 kDa
Annotated
2026-04-28
100 papers in source corpus 27 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP4K4 is a Ste20-family serine/threonine kinase that functions as a central regulator of cell migration, inflammatory signaling, and metabolic homeostasis by directly phosphorylating diverse substrates including moesin (to inactivate β1-integrin and promote focal adhesion disassembly), the Arp2 subunit of the Arp2/3 complex (to drive branched actin assembly and membrane protrusion), TRAF2 (targeting it for lysosomal degradation to suppress IL-6 in T cells), and MLK3 (to activate JNK/MAPK signaling in cancer) (PMID:25799996, PMID:25601402, PMID:25098764, PMID:34511598). MAP4K4 is delivered to focal adhesions via microtubule plus-end protein EB2 and activates Arf6 through IQSEC1 to drive integrin internalization, while upstream it is phosphorylated by FGFR1/FRS2 signaling and dephosphorylated by STRIPAK-directed PP2A to regulate YAP1 and the Hippo pathway (PMID:25490267, PMID:28771231, PMID:31913126). In immune cells, MAP4K4 mediates LPS-induced TNF-α/IL-1β production in macrophages and restrains LFA-1 activation on CD8 T cells via ERM proteins, while in cardiomyocytes its inhibition protects against ischemia-reperfusion injury by preserving mitochondrial function (PMID:19407801, PMID:32220977, PMID:30853557). MAP4K4 additionally suppresses adipocyte lipogenesis through AMPK/mTORC1/SREBP-1 independently of JNK, inhibits skeletal muscle differentiation via Myf5, and promotes NF-κB–dependent atherosclerotic inflammation in endothelial cells (PMID:23924694, PMID:23207904, PMID:26688060).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2009 High

    Establishing MAP4K4 as a key mediator of innate inflammatory cytokine production resolved the question of whether this kinase participates in TLR-driven macrophage responses in vivo.

    Evidence Oral siRNA delivery (GeRP) silencing Map4k4 in macrophages in vivo with LPS lethality model in mice

    PMID:19407801

    Open questions at the time
    • Direct substrates in the TLR-TNFα pathway not identified
    • Whether MAP4K4 acts through NF-κB, JNK, or another pathway in macrophages not resolved
  2. 2012 High

    Demonstration that MAP4K4 kinase activity suppresses myogenic differentiation through Myf5 established MAP4K4 as a negative regulator of skeletal muscle cell fate.

    Evidence Kinase-inactive mutant, siRNA knockdown, and Myf5 epistasis in C2C12 myoblast differentiation

    PMID:23207904

    Open questions at the time
    • Whether MAP4K4 directly phosphorylates a myogenic target or acts indirectly through Myf5 transcription unknown
    • In vivo relevance to muscle regeneration not tested
  3. 2013 High

    Identifying MAP4K4 as a JNK-independent suppressor of adipocyte lipogenesis via AMPK/mTORC1/SREBP-1 uncoupled MAP4K4 from its canonical JNK pathway and revealed a metabolic regulatory axis.

    Evidence siRNA knockdown in adipocytes with radiolabeled lipogenesis assays, rapamycin treatment, and JNK1/2 epistasis

    PMID:23924694

    Open questions at the time
    • Direct phosphorylation target linking MAP4K4 to AMPK activation not identified
    • Contribution to whole-body metabolic regulation not established in vivo
  4. 2014 High

    Two studies in 2014 identified direct substrates and trafficking partners of MAP4K4 at focal adhesions: TRAF2 phosphorylation controls IL-6/Th17 responses in T cells, while EB2/IQSEC1 binding delivers MAP4K4 to focal adhesions to activate Arf6-dependent integrin internalization, establishing MAP4K4 as a multi-substrate kinase governing both immune regulation and cell migration.

    Evidence Conditional T-cell KO with in vitro kinase assay for TRAF2 (PMID:25098764); quantitative proteomics, KO, and live-cell FA dynamics for EB2/IQSEC1/Arf6 (PMID:25490267)

    PMID:25098764 PMID:25490267

    Open questions at the time
    • TRAF2 phosphorylation site(s) not mapped
    • How MAP4K4 activates IQSEC1 GEF activity mechanistically not determined
  5. 2015 High

    Identification of moesin and Arp2 as direct MAP4K4 substrates provided a unified mechanism for focal adhesion disassembly (phospho-moesin competing with talin for integrin binding) and membrane protrusion (Arp2/3-dependent branched actin assembly), answering how MAP4K4 coordinates the two sides of directed cell migration.

    Evidence In vitro kinase assays, phospho-moesin/talin competition for β1-integrin binding, dominant-negative Arp2 mutant, EGF-stimulated actin polymerization

    PMID:25601402 PMID:25799996

    Open questions at the time
    • Whether moesin and Arp2 phosphorylation are coordinated spatiotemporally in the same cell not shown
    • Structural basis for MAP4K4 substrate recognition unknown
  6. 2015 High

    MAP4K4 was shown to promote NF-κB nuclear localization in endothelial cells, driving atherosclerotic inflammation, while crystal structures of MAP4K4 with selective inhibitors (GNE-495 and pyridone-based compounds) validated it as a druggable ATP-competitive kinase target.

    Evidence Endothelial-specific KO in Apoe−/− mice (PMID:26688060); X-ray crystallography of inhibitor–MAP4K4 complexes with in vivo retinal angiogenesis models (PMID:25908259, PMID:26288693)

    PMID:25908259 PMID:26288693 PMID:26688060

    Open questions at the time
    • Direct NF-κB pathway target of MAP4K4 kinase activity in endothelial cells not identified
    • Long-term therapeutic safety of MAP4K4 inhibition not assessed
  7. 2017 High

    MAP4K4 was placed upstream of DLK/JNK in neuronal stress signaling and downstream of FGFR1/FRS2 in endothelial cells, defining both an upstream activator and a critical downstream cascade regulated by MAP4K4.

    Evidence DRG neuron trophic withdrawal with MAP4K4/MINK1/TNIK redundancy analysis (PMID:28993483); proximity ligation assay and Co-IP for FGFR1-MAP4K4 interaction (PMID:28771231)

    PMID:28771231 PMID:28993483

    Open questions at the time
    • Whether FGFR1 directly phosphorylates MAP4K4 or acts through an intermediate kinase not resolved
    • Redundancy with MINK1/TNIK complicates genetic dissection of MAP4K4-specific contributions
  8. 2019 High

    MAP4K4 inhibition with DMX-5804 protected cardiomyocytes from oxidative death and reduced infarct size by >50%, establishing MAP4K4 as a therapeutic target in cardiac ischemia-reperfusion injury.

    Evidence Gene silencing in hiPSC-CMs, DMX-5804 treatment, mouse ischemia-reperfusion model with mitochondrial function and calcium imaging

    PMID:30853557

    Open questions at the time
    • Direct cardiac substrate(s) of MAP4K4 mediating cell death not identified at this stage
    • Chronic cardiac effects of MAP4K4 inhibition not evaluated
  9. 2020 High

    Two studies resolved how MAP4K4 integrates into immune and growth-control signaling: STRIPAK/PP2A dephosphorylates MAP4K4 to activate YAP1 in oncogenic transformation, while MAP4K4 deletion enhances LFA-1/ERM-dependent CD8 T cell cytotoxicity, revealing MAP4K4 as both a Hippo pathway node and an immune checkpoint-like regulator.

    Evidence STRIPAK/STRN4 interactome with reciprocal Co-IP and Hippo reporter assays (PMID:31913126); genetic deletion and pharmacological inhibition with LFA-1 epistasis in antitumor/antiviral mouse models (PMID:32220977)

    PMID:31913126 PMID:32220977

    Open questions at the time
    • Phosphorylation sites on MAP4K4 targeted by PP2A not mapped
    • Whether MAP4K4 directly phosphorylates ERM proteins or acts through an intermediary kinase in CD8 T cells not definitively shown
  10. 2021 High

    Direct phosphorylation of MLK3 at Thr738 by MAP4K4 was identified as a mechanism driving pancreatic cancer proliferation, expanding the catalog of MAP4K4 substrates to include MAPK cascade kinases.

    Evidence In vitro kinase assay with phospho-site mutagenesis, Co-IP, KPC mouse model with GNE-495

    PMID:34511598

    Open questions at the time
    • Whether MLK3 phosphorylation is relevant in non-pancreatic cancer contexts unknown
    • Relative contribution of MLK3 versus other MAP4K4 substrates to JNK activation not quantified
  11. 2024 Medium

    MAP4K4 was shown to promote Drp1 S-nitrosylation by suppressing GPX4 expression, linking MAP4K4 to mitochondrial fission, ferroptosis, and diabetic cardiomyopathy, and providing a mechanistic basis for its cardiac-protective effects upon inhibition.

    Evidence Drp1 C650A knock-in mice, DMX-5804 treatment, GPX4 expression analysis, ferroptosis assays in db/db mice

    PMID:38724987

    Open questions at the time
    • How MAP4K4 kinase activity suppresses GPX4 expression mechanistically is unclear
    • Whether the GPX4/SNO-Drp1 pathway operates in non-diabetic cardiac injury not tested
    • Single-lab finding awaiting independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full repertoire of MAP4K4 phosphorylation sites on its known substrates (TRAF2, moesin, ERM proteins), the structural basis for its broad substrate selectivity, the relative contributions of MAP4K4 versus MINK1/TNIK in physiological contexts, and whether MAP4K4 inhibition can be safely pursued as therapy across inflammatory, cardiac, and oncologic indications.
  • No comprehensive phosphoproteomics of MAP4K4 substrates published
  • No full-length MAP4K4 structure available
  • Therapeutic window for MAP4K4 inhibition not defined given its roles in both immune activation and suppression

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0098772 molecular function regulator activity 3 GO:0140657 ATP-dependent activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-168256 Immune System 4 R-HSA-1500931 Cell-Cell communication 3 R-HSA-1430728 Metabolism 2 R-HSA-5357801 Programmed Cell Death 2
Partners
ACTR2IQSEC1MAPJD (EB2/MAPRE2)MLK3MSNPYK2STRN4TRAF2
Complex memberships
STRIPAK complex (as substrate/interactor)

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 MAP4K4 (Map4k4) in macrophages mediates TNF-α and IL-1β cytokine production in response to LPS; siRNA-mediated silencing of Map4k4 in macrophages in vivo protected mice from LPS-induced lethality by inhibiting these cytokines, establishing Map4k4 as a mediator of inflammatory cytokine expression. siRNA knockdown in vivo (oral GeRP delivery), cytokine measurement, mouse LPS lethality model Nature High 19407801
2015 MAP4K4 phosphorylates moesin in retracting membranes of migrating endothelial cells, and phospho-moesin competes with talin for binding to the β1-integrin intracellular domain, thereby inactivating integrin and promoting focal adhesion disassembly and membrane retraction during cell migration. In vitro angiogenesis siRNA screen, epistasis analysis, phosphorylation assays, integrin-FERM binding competition assays, in vitro and in vivo angiogenesis models Nature High 25799996
2014 MAP4K4 associates with microtubule plus-end binding protein EB2 and the Arf6-specific guanine nucleotide exchange factor IQSEC1; microtubules deliver MAP4K4 to focal adhesions via EB2, where MAP4K4 activates Arf6 through IQSEC1 to promote integrin internalization and focal adhesion disassembly, thereby regulating cell migration. Quantitative proteomics, co-immunoprecipitation, MAP4K4 knockout, live-cell imaging of focal adhesion dynamics Developmental cell High 25490267
2014 In T cells, HGK (MAP4K4) directly phosphorylates TRAF2, leading to its lysosomal degradation and subsequent inhibition of IL-6 production; T-cell-specific conditional knockout of HGK causes TRAF2 stabilization, IL-6 overproduction, Th17 differentiation, and systemic insulin resistance. Conditional T-cell-specific KO mouse, in vitro kinase assay (direct phosphorylation of TRAF2), neutralization antibodies, genetic epistasis (CCR6 KO, leptin receptor KO) Nature communications High 25098764
2017 MAP4K4, together with MINK1 and TNIK, acts redundantly as upstream kinases that activate DLK (dual leucine zipper kinase) and downstream JNK signaling in neurons in response to trophic factor withdrawal; MAP4K4 inhibition blocks DLK stabilization/phosphorylation within axons and prevents retrograde translocation of the JNK signaling complex to the nucleus, protecting neurons from degeneration. Trophic factor withdrawal model in dorsal root ganglion neurons, pharmacological MAP4K inhibition, genetic KD, phosphorylation assays, live-cell axonal signaling imaging The Journal of neuroscience High 28993483
2015 MAP4K4 silencing in endothelial cells reduces NF-κB nuclear localization and activity, attenuating adhesion molecule expression and macrophage recruitment, thereby suppressing atherosclerotic plaque development in Apoe-/- mice. Endothelial-specific MAP4K4 gene silencing and gene ablation in Apoe-/- mice, small-molecule MAP4K4 inhibitor treatment, NF-κB nuclear localization assays Nature communications High 26688060
2013 MAP4K4 suppresses adipocyte lipogenesis by promoting AMPK signaling and phosphorylation of raptor (Ser792), thereby inhibiting mTORC1 and reducing Srebp-1 protein expression and cleavage; this mechanism is independent of JNK signaling. siRNA knockdown in adipocytes, radiolabeled lipogenesis assays (14C-glucose and 14C-acetate), microarray, rapamycin treatment, JNK1/2 siRNA epistasis Journal of lipid research High 23924694
2012 Map4k4 kinase activity is required to suppress skeletal muscle differentiation; Map4k4 silencing enhances Myf5 expression, myoblast fusion, and myotube diameter, while expression of a kinase-inactive mutant enhances myotube formation, and Myf5 knockdown blocks the pro-differentiation effects of Map4k4 depletion. siRNA knockdown, adenovirus-mediated overexpression, kinase-inactive mutant, C2C12 myoblast differentiation assays, gene expression analysis Molecular and cellular biology High 23207904
2019 MAP4K4 is activated in failing human hearts and relevant rodent models; MAP4K4 gene silencing or pharmacological inhibition with DMX-5804 protects human iPSC-derived cardiomyocytes from oxidative stress-induced death, preserves mitochondrial function and calcium cycling, and reduces ischemia-reperfusion infarct size in mice by >50%. Gene silencing in hiPSC-CMs, small-molecule inhibitor (DMX-5804), mouse ischemia-reperfusion model, mitochondrial function assays, calcium imaging Cell stem cell High 30853557
2020 STRIPAK complex (via STRN4) recruits PP2A to dephosphorylate MAP4K4, activating the Hippo pathway effector YAP1 and promoting oncogenic cell transformation; ST antigen promotes A-C subunit interactions with STRIPAK and facilitates PP2A-mediated MAP4K4 dephosphorylation. Co-immunoprecipitation, mass spectrometry interactome, siRNA knockdown, cell transformation assays, Hippo pathway reporter assays eLife High 31913126
2015 MAP4K4 (NIK, Nck-interacting kinase) binds and directly phosphorylates the Arp2 subunit of the Arp2/3 complex, increasing its nucleating activity and promoting branched actin filament assembly, plasma membrane protrusion, and cell migration in response to EGF. In vitro kinase assay with recombinant MAP4K4 and Arp2/3 subunits, dominant-negative Arp2 mutant, EGF stimulation assays, actin polymerization assays The Journal of cell biology High 25601402
2015 Crystal structure of a militarinone-inspired 4-hydroxy-2-pyridone inhibitor in complex with MAP4K4 identifies MAP4K4 as an ATP-competitive kinase target; the inhibitor is selective for MAP4K4 over other stress pathway kinases. X-ray crystallography of inhibitor-MAP4K4 complex, biochemical kinase selectivity assays Angewandte Chemie (International ed. in English) High 25908259
2021 MAP4K4 directly phosphorylates MLK3 (mixed lineage kinase 3) on Thr738, increasing MLK3 kinase activity and downstream signaling to promote pancreatic cancer cell proliferation and migration; MAP4K4 and MLK3 form a physical complex. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, cell proliferation/migration assays, KPC mouse tumor model with MAP4K4 inhibitor GNE-495 Oncogene High 34511598
2017 MAP4K4 activates ERK signaling in lung adenocarcinoma by inhibiting protein phosphatase 2A (PP2A) activity; MAP4K4 knockdown prevents ERK reactivation in EGFR inhibitor erlotinib-treated cells. siRNA knockdown, xenograft models, PP2A activity assays, ERK phosphorylation assays Molecular oncology Medium 28306189
2017 Alternative splicing of MAP4K4 pre-mRNA is regulated by the RBM4-SRSF3 cascade; SRSF3 modulates MAP4K4 exon 16 inclusion in a sequence-dependent manner, and alternatively spliced MAP4K4 variants differentially phosphorylate JNK1, modulating E-cadherin, N-cadherin, and vimentin expression and affecting CRC cell migration and invasion. Transcriptome analysis, splicing reporter assays, siRNA, Western blot for JNK1 phosphorylation and EMT markers, migration/invasion assays Biochimica et biophysica acta. Molecular cell research Medium 29138007
2013 MAP4K4 promotes KSHV reactivation from latency in endothelial cells and enhances invasiveness by regulating COX-2, MMP-7, and MMP-13 expression; identified through siRNA and small molecule library screening. siRNA library screen, small molecule inhibitor screen, KSHV reactivation assay, MMP/COX-2 expression analysis PLoS pathogens Medium 24244164
2013 MAP4K4 interacts with Pyk2 via the Pyk2 FERM domain, is a substrate for Pyk2, and cooperates with Pyk2 to regulate glioma cell migration; MAP4K4 knockdown inhibits Pyk2-stimulated glioma migration, and MAP4K4 overexpression-induced migration is blocked by Pyk2 knockdown. Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, cell migration assays Journal of signal transduction Medium 24163766
2020 MAP4K4 deletion or inhibition enhances LFA-1 activation on CD8 T cells via ERM (ezrin, radixin, moesin) proteins as intermediaries; loss of Map4k4 increases CD8 T cell priming, proliferation, cytokine production, and cytotoxic activity, improving antitumor and antiviral immunity, and these phenotypes are reversed by LFA-1 inhibition. Genetic deletion, pharmacological inhibition, LFA-1 activation assays, ERM protein analysis, antitumor and antiviral mouse models Science immunology High 32220977
2019 MAP4K4 is essential for glioblastoma invasion; CRISPR-Cas9 loss-of-function screen identified MAP4K4 as the strongest regulator of invasion, with MAP4K4 loss or inhibition reducing migration, invasion, and shifting EMT markers toward a non-invasive state. CRISPR-Cas9 loss-of-function screen, transwell invasion assay, wound healing assay, EMT marker analysis, MAP4K4 inhibitor treatment, human glioma organotypic slice cultures Scientific reports Medium 31570734
2024 MAP4K4 promotes S-nitrosylation of Drp1 at C644 (human)/C650 (mouse) by inhibiting GPX4 expression, thereby inducing mitochondrial dysfunction and endothelial ferroptosis in diabetic cardiomyopathy; MAP4K4 inhibition with DMX-5804 reduces SNO-Drp1, alleviates cardiac microvascular dysfunction and cardiac dysfunction in db/db mice. Western blot, MAP4K4 inhibitor (DMX-5804), Drp1 C650A knock-in mice, GPX4 expression analysis, ferroptosis assays, cardiac function measurements Cardiovascular diabetology Medium 38724987
2018 MAP4K4 controls integrin β1 activation and promotes c-Met endocytic recycling in medulloblastoma cells, leading to accumulation of activated c-Met in cytosolic vesicles required for sustained HGF/c-Met signaling and downstream pathway activation that drives invasion. MAP4K4 siRNA knockdown, HGF-driven matrix invasion assay, brain slice ex vivo invasion, integrin β1 activation assays, c-Met endocytosis and recycling assays Oncotarget Medium 29796184
2017 FGFR1 signaling through FRS2 induces MAP4K4 phosphorylation in endothelial cells; phospho-MAP4K4 physically interacts with FGFR1 (confirmed by proximity ligation and immunoprecipitation), and MAP4K4 knockdown induces Smad3 phosphorylation and endothelial-to-mesenchymal transition (EndMT), which is not suppressed by AcSDKP treatment. Proximity ligation assay, co-immunoprecipitation, siRNA knockdown, phosphorylation assays, EndMT markers, in vivo diabetic mouse model Cell death & disease Medium 28771231
2021 SOX6 transcriptionally upregulates MAP4K4 by binding to double binding sites in the MAP4K4 promoter via its HMG domain; MAP4K4 then mediates SOX6-induced autophagy by inhibiting the PI3K-Akt-mTOR pathway and activating the MAPK/ERK pathway, reducing cisplatin sensitivity in cervical cancer cells. ChIP assay, promoter luciferase assay, siRNA knockdown, MAP4K4 inhibitor, PI3K/Akt/mTOR pathway analysis, autophagy assays Cell death & disease Medium 34930918
2015 MAP4K4 (NIK/Nck-interacting kinase) binds and phosphorylates the Arp2 subunit of the Arp2/3 complex in mammary carcinoma cells, and this kinase activity is necessary for increased Arp2 phosphorylation and plasma membrane protrusion in response to EGF; a phosphorylation-deficient Arp2 mutant dominantly suppresses actin filament assembly. In vitro kinase assay, dominant-negative Arp2 mutant, EGF stimulation, actin polymerization assays, co-immunoprecipitation The Journal of cell biology High 25601402
2014 Fragment-based lead discovery yielded selective MAP4K4 inhibitors (pyridopyrimidine series, compound 29) with nanomolar potency that demonstrate in vivo pharmacodynamic effects in a human tumor xenograft model, validating MAP4K4 as a druggable kinase target. Fragment-based drug discovery, biochemical kinase assay, X-ray crystallography (implied by structure-based optimization), xenograft pharmacodynamic study Journal of medicinal chemistry Medium 24673130
2015 Structure-based design of GNE-495, a potent and selective MAP4K4 inhibitor, demonstrated in vivo efficacy in a retinal angiogenesis model, recapitulating effects observed in inducible Map4k4 knockout mice. Structure-based drug design, X-ray crystallography, inducible Map4k4 KO mice, in vivo retinal angiogenesis model ACS medicinal chemistry letters High 26288693
2015 MAP4K4 knockdown in hepatocellular carcinoma cells represses JNK, NF-κB, and toll-like receptor signaling pathways; MAP4K4 promotes EMT by activating JNK and NF-κB signaling, upregulating vimentin and downregulating E-cadherin, to enhance HCC invasiveness and lung metastasis in vivo. ShRNA knockdown, MAP4K4 overexpression, JNK/NF-κB chemical inhibitors, EMT marker analysis, in vivo lung metastasis assay, qRT-PCR arrays Tumour biology Medium 27010469
2013 Map4k4 silencing in adipocytes negatively regulates insulin-responsive glucose transport and mediates some actions of TNF-α; Map4k4 depletion upregulates lipogenic gene expression and increases adipogenesis. siRNA-based RNAi screen in adipocytes, glucose transport assays, gene expression profiling Acta physiologica (Oxford, England) Medium 18171433

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
2009 Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation. Nature 452 19407801
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
2020 Targeting NF-κB-Inducing Kinase (NIK) in Immunity, Inflammation, and Cancer. International journal of molecular sciences 136 33187137
2013 miRNA-141, downregulated in pancreatic cancer, inhibits cell proliferation and invasion by directly targeting MAP4K4. Molecular cancer therapeutics 127 24013097
2011 Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation. Science (New York, N.Y.) 127 21273489
2015 MAP4K4 regulates integrin-FERM binding to control endothelial cell motility. Nature 116 25799996
2014 Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity. Nature communications 111 25406581
2005 NIBP, a novel NIK and IKK(beta)-binding protein that enhances NF-(kappa)B activation. The Journal of biological chemistry 104 15951441
2013 Galactosylated trimethyl chitosan-cysteine nanoparticles loaded with Map4k4 siRNA for targeting activated macrophages. Biomaterials 102 23419643
2014 Microtubules regulate focal adhesion dynamics through MAP4K4. Developmental cell 100 25490267
2015 Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis. Nature communications 93 26688060
2012 NF-κB–inducing kinase (NIK) promotes hyperglycemia and glucose intolerance in obesity by augmenting glucagon action. Nature medicine 90 22581287
2010 ShRNA-targeted MAP4K4 inhibits hepatocellular carcinoma growth. Clinical cancer research : an official journal of the American Association for Cancer Research 90 21196414
2017 The Ste20 Family Kinases MAP4K4, MINK1, and TNIK Converge to Regulate Stress-Induced JNK Signaling in Neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 86 28993483
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
2013 SOX2 regulates apoptosis through MAP4K4-survivin signaling pathway in human lung cancer cells. Carcinogenesis 84 24233838
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
2016 NIK/MAP3K14 Regulates Mitochondrial Dynamics and Trafficking to Promote Cell Invasion. Current biology : CB 77 27889261
2014 HGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance. Nature communications 77 25098764
1995 Isolation of prostatic kallikrein hK2, also known as hGK-1, in human seminal plasma. Biochimica et biophysica acta 77 8541306
1991 Identification and androgen-regulated expression of two major human glandular kallikrein-1 (hGK-1) mRNA species. Molecular and cellular endocrinology 75 1726490
2023 EDA2R-NIK signalling promotes muscle atrophy linked to cancer cachexia. Nature 74 37165186
2009 Regulation of Th17 cell differentiation and EAE induction by MAP3K NIK. Blood 73 19411637
2019 MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo. Cell stem cell 72 30853557
2016 MAP4K4: an emerging therapeutic target in cancer. Cell & bioscience 72 27800153
2015 MiR-194, commonly repressed in colorectal cancer, suppresses tumor growth by regulating the MAP4K4/c-Jun/MDM2 signaling pathway. Cell cycle (Georgetown, Tex.) 72 25602366
2023 Histone lactylation-derived LINC01127 promotes the self-renewal of glioblastoma stem cells via the cis-regulating the MAP4K4 to activate JNK pathway. Cancer letters 71 38084701
2018 Downregulated miR-98-5p promotes PDAC proliferation and metastasis by reversely regulating MAP4K4. Journal of experimental & clinical cancer research : CR 70 29970191
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
2017 FGFR1 is critical for the anti-endothelial mesenchymal transition effect of N-acetyl-seryl-aspartyl-lysyl-proline via induction of the MAP4K4 pathway. Cell death & disease 61 28771231
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
2010 NIK stabilization in osteoclasts results in osteoporosis and enhanced inflammatory osteolysis. PloS one 57 21151480
2021 MAP4K4 mediates the SOX6-induced autophagy and reduces the chemosensitivity of cervical cancer. Cell death & disease 56 34930918
2017 MAP4K4 is a novel MAPK/ERK pathway regulator required for lung adenocarcinoma maintenance. Molecular oncology 50 28306189
2017 RBM4-SRSF3-MAP4K4 splicing cascade modulates the metastatic signature of colorectal cancer cell. Biochimica et biophysica acta. Molecular cell research 50 29138007
2008 RNAi screens reveal novel metabolic regulators: RIP140, MAP4k4 and the lipid droplet associated fat specific protein (FSP) 27. Acta physiologica (Oxford, England) 50 18171433
2003 Caspase-8 and caspase-10 activate NF-kappaB through RIP, NIK and IKKalpha kinases. European journal of immunology 50 12884866
2021 The membrane-localized protein kinase MAP4K4/TOT3 regulates thermomorphogenesis. Nature communications 48 33990595
2001 Identification of the nik gene cluster of Brucella suis: regulation and contribution to urease activity. Journal of bacteriology 47 11133934
1989 hGK-1: a kallikrein gene expressed in human prostate. Clinical and experimental pharmacology & physiology 47 2472912
2020 STRIPAK directs PP2A activity toward MAP4K4 to promote oncogenic transformation of human cells. eLife 46 31913126
2019 Targeted genomic CRISPR-Cas9 screen identifies MAP4K4 as essential for glioblastoma invasion. Scientific reports 46 31570734
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
2015 Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis. ACS medicinal chemistry letters 37 26288693
2014 Discovery of selective 4-Amino-pyridopyrimidine inhibitors of MAP4K4 using fragment-based lead identification and optimization. Journal of medicinal chemistry 37 24673130
2013 The inflammatory kinase MAP4K4 promotes reactivation of Kaposi's sarcoma herpesvirus and enhances the invasiveness of infected endothelial cells. PLoS pathogens 37 24244164
2010 Lipopolysaccharide-induced activation of NF-κB non-canonical pathway requires BCL10 serine 138 and NIK phosphorylations. Experimental cell research 37 20466000
2022 Transcriptome profiling of microRNAs reveals potential mechanisms of manual therapy alleviating neuropathic pain through microRNA-547-3p-mediated Map4k4/NF-κb signaling pathway. Journal of neuroinflammation 36 36045396
2018 A TRAF3-NIK module differentially regulates DNA vs RNA pathways in innate immune signaling. Nature communications 36 30018345
2016 Map4k4 Signaling Nodes in Metabolic and Cardiovascular Diseases. Trends in endocrinology and metabolism: TEM 36 27160798
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
2019 NIK as a Druggable Mediator of Tissue Injury. Trends in molecular medicine 34 30926358
2015 The Nck-interacting kinase NIK increases Arp2/3 complex activity by phosphorylating the Arp2 subunit. The Journal of cell biology 34 25601402
2016 Glucocorticoids increase skeletal muscle NF-κB inducing kinase (NIK): links to muscle atrophy. Physiological reports 33 27905294
2015 Neuritogenic militarinone-inspired 4-hydroxypyridones target the stress pathway kinase MAP4K4. Angewandte Chemie (International ed. in English) 33 25908259
2013 Map4k4 suppresses Srebp-1 and adipocyte lipogenesis independent of JNK signaling. Journal of lipid research 32 23924694
2024 MAP4K4 exacerbates cardiac microvascular injury in diabetes by facilitating S-nitrosylation modification of Drp1. Cardiovascular diabetology 31 38724987
2018 Hepatic NF-kB-inducing kinase (NIK) suppresses mouse liver regeneration in acute and chronic liver diseases. eLife 31 30070632
2021 MAP4K4 promotes pancreatic tumorigenesis via phosphorylation and activation of mixed lineage kinase 3. Oncogene 30 34511598
2003 NIK is a component of the EGF/heregulin receptor signaling complexes. Oncogene 30 12853971
2022 NEK2 enhances malignancies of glioblastoma via NIK/NF-κB pathway. Cell death & disease 28 35031599
2018 MAP4K4 controlled integrin β1 activation and c-Met endocytosis are associated with invasive behavior of medulloblastoma cells. Oncotarget 27 29796184
2012 Identification of Map4k4 as a novel suppressor of skeletal muscle differentiation. Molecular and cellular biology 27 23207904
2016 MAP4K4 promotes epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 26 27010469
2011 SMG1 and NIK regulate apoptosis induced by Smac mimetic compounds. Cell death & disease 26 21490678
2012 Association of common genetic variants in the MAP4K4 locus with prediabetic traits in humans. PloS one 25 23094072
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
2011 Characterisation of the legume SERK-NIK gene superfamily including splice variants: implications for development and defence. BMC plant biology 24 21385462
2020 MAP4K4 negatively regulates CD8 T cell-mediated antitumor and antiviral immunity. Science immunology 22 32220977
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 Noncanonical NF-κB signaling and the essential kinase NIK modulate crucial features associated with eosinophilic esophagitis pathogenesis. Disease models & mechanisms 22 29259025
2013 A Novel Interaction between Pyk2 and MAP4K4 Is Integrated with Glioma Cell Migration. Journal of signal transduction 22 24163766
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 Fragment-based identification and optimization of a class of potent pyrrolo[2,1-f][1,2,4]triazine MAP4K4 inhibitors. Bioorganic & medicinal chemistry letters 21 25139565
2023 Molecular Insights of MAP4K4 Signaling in Inflammatory and Malignant Diseases. Cancers 20 37190200
2022 MAP4K4 controlled transcription factor POUM1 regulates PxABCG1 expression influencing Cry1Ac resistance in Plutella xylostella (L.). Pesticide biochemistry and physiology 20 35249643
2018 MicroRNA-200c suppressed cervical cancer cell metastasis and growth via targeting MAP4K4. European review for medical and pharmacological sciences 20 29461619
2015 Downregulation of miR-518a-3p activates the NIK-dependent NF-κB pathway in colorectal cancer. International journal of molecular medicine 20 25812680
2015 Cellular MicroRNA Let-7a Suppresses KSHV Replication through Targeting MAP4K4 Signaling Pathways. PloS one 20 26197270
2020 Selective protection of human cardiomyocytes from anthracycline cardiotoxicity by small molecule inhibitors of MAP4K4. Scientific reports 19 32694738
2018 RBM4a-SRSF3-MAP4K4 Splicing Cascade Constitutes a Molecular Mechanism for Regulating Brown Adipogenesis. International journal of molecular sciences 19 30200638