Affinage

MAP3K4

Mitogen-activated protein kinase kinase kinase 4 · UniProt Q9Y6R4

Length
1608 aa
Mass
181.7 kDa
Annotated
2026-06-10
63 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP3K4 (MTK1/MEKK4) is a stress-responsive serine/threonine MAPKKK that channels environmental and developmental stress signals into the p38 and JNK MAPK pathways but not the ERK pathway, phosphorylating MKK6/SEK1 to activate p38 and JNK (PMID:9305639, PMID:16199873). Its activity is gated by an N-terminal autoinhibitory domain (residues 253–553) that holds the kinase domain away from its substrate MKK6; binding of GADD45 family proteins to this region relieves autoinhibition, drives dimerization via a coiled-coil motif, and triggers trans-autophosphorylation at Thr-1493 in the activation loop to switch on catalysis (PMID:9827804, PMID:12052864, PMID:17242196). This activation cycle is tuned by additional partners: TRAF4 promotes activity by inducing oligomerization, Axin and RACK1 likewise promote activation, whereas GSK3β binds the kinase domain and blocks the dimerization step to inhibit signaling (PMID:16157600, PMID:12878610, PMID:39805423, PMID:17726008). Beyond ligand-driven control, MAP3K4 acts as a direct redox sensor whose conserved cysteines undergo coupled oxidation–reduction to drive delayed, sustained SAPK activity that dictates cell fate, and it can be tyrosine-phosphorylated by Pyk2 and reversed by SHP2 (PMID:32637591, PMID:15601262). Genetically, MAP3K4 kinase activity is required for neural tube closure, neuronal migration via filamin-A, and gonadal sex determination, where MAP3K4→MKK4/p38 maintains Sry and Sox9 expression through GATA4 (PMID:15731347, PMID:17145501, PMID:19753101, PMID:23102580, PMID:33912929). In trophoblast stem cells it maintains epithelial identity by controlling CBP-mediated histone acetylation and by directing ubiquitin-dependent degradation of HDAC6, and it supports placental growth through IGF1R/IR–Akt signaling (PMID:21549327, PMID:28273454, PMID:35921893). MAP3K4 also phosphorylates non-MAPK substrates including HOXA10(Thr362) during embryo–endometrium adhesion and, via p38, Atg5(Thr75) to restrain autophagic flux (PMID:36216824, PMID:23059785). An ERK→EGR1→GADD45β→MTK1 circuit operates as a tumor-suppressive oncogenic stress response that is frequently silenced in ERK-hyperactive cancers (PMID:39526327).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1997 High

    Established MAP3K4 as a MAPKKK that selectively feeds the stress-activated p38 and JNK pathways rather than ERK, defining its place in the kinase cascade.

    Evidence In vitro kinase assays on MKK6/SEK1, dominant-negative expression in mammalian cells, and yeast complementation; parallel work tying it to Cdc42/Rac-driven JNK activation

    PMID:9079650 PMID:9305639

    Open questions at the time
    • Initial JNK-only selectivity was incomplete given later p38 activation data
    • Did not address how upstream stress is sensed
    • No structural basis for substrate selectivity
  2. 1998 High

    Identified GADD45 family proteins as direct N-terminal binding activators, providing the first defined input that switches the kinase on.

    Evidence Yeast two-hybrid, in vitro and in vivo kinase assays, dominant-negative coexpression

    PMID:9827804

    Open questions at the time
    • Did not resolve the conformational mechanism of activation
    • Physiological stimulus driving GADD45 production left open
  3. 2002 High

    Defined an autoinhibitory N-terminal domain that occludes substrate binding, explaining why the kinase is normally silent.

    Evidence Deletion mutagenesis in yeast and mammalian cells, functional complementation, Co-IP of MTK1 with MKK6

    PMID:12052864

    Open questions at the time
    • Structural details of the N-C interaction not resolved
    • How GADD45 binding geometrically relieves inhibition not yet shown
  4. 2007 High

    Resolved the full activation mechanism—N-C dissociation, coiled-coil dimerization, and Thr-1493 trans-autophosphorylation—giving a unified molecular switch model.

    Evidence Domain interaction and dimerization assays plus T1493A mutagenesis and kinase activity measurements

    PMID:17242196

    Open questions at the time
    • No crystal structure of the active dimer
    • Kinetics of the autophosphorylation step not quantified
  5. 2007 Medium

    Showed the activation switch is bidirectionally tunable, with GSK3β inhibiting by blocking dimerization while TRAF4/Axin/RACK1 activate by promoting oligomerization.

    Evidence Co-IP, kinase and dimerization assays, GSK3β inhibitor treatment; earlier TRAF4 and Axin oligomerization studies; later RACK1 work

    PMID:12878610 PMID:16157600 PMID:17726008 PMID:39805423

    Open questions at the time
    • Most interactions rest on single-lab Co-IP without reciprocal structural validation
    • How competing regulators are integrated in vivo is unresolved
  6. 2005 High

    Kinase-dead knock-in and knockout mice mapped which downstream branch MAP3K4 controls in vivo, pinning antiapoptotic neural-tube and T-cell IFNγ functions to specific MKK readouts.

    Evidence MEKK4-/- and K1361R knock-in mice with MKK3/6 and MKK4 activity assays, MAPKAPK2 phosphorylation, TUNEL, and cytokine assays

    PMID:15044949 PMID:15731347 PMID:16199873

    Open questions at the time
    • Tissue-specific selection between p38 and JNK branches not fully explained
    • Substrate determinants of branch choice unknown
  7. 2005 Medium

    Revealed input layers beyond GADD45, including IFNγ-driven Pyk2 tyrosine phosphorylation reversed by SHP2.

    Evidence Co-IP, immunofluorescence, in vitro MKK6 phosphorylation, calcium chelation in keratinocytes

    PMID:15601262

    Open questions at the time
    • Tyrosine phosphosites not mapped
    • Integration with the GADD45/dimerization switch unclear
  8. 2009 High

    Defined MAP3K4 as essential for gonadal sex determination, linking its catalytic output through MKK4/p38/GATA4 to Sry/Sox9 maintenance.

    Evidence Forward-genetic byg mutant and knockout mice with phospho-MKK4/p38 immunostaining; later epistasis with Gadd45γ and rescue, and kinase-dead knock-in

    PMID:19753101 PMID:23102580 PMID:33912929

    Open questions at the time
    • Direct kinase-to-GATA4 phosphorylation not demonstrated
    • Cell-type specificity within somatic gonad partially defined
  9. 2011 Medium

    Established a chromatin-level role in trophoblast epithelial identity via CBP-dependent histone acetylation and HDAC6 turnover, broadening MAP3K4 beyond MAPK signaling.

    Evidence Kinase-inactive TS cells with CBP activity assays, histone acetylation ChIP, HDAC6 ubiquitination and shRNA rescue, TRAF4 coexpression analysis

    PMID:21549327 PMID:28273454 PMID:29710325

    Open questions at the time
    • Direct kinase substrate connecting MAP3K4 to CBP/HDAC6 not identified
    • Single-lab findings on a tissue-restricted program
  10. 2012 High

    Showed MAP3K4 phosphorylates non-MAPK substrates and spatially directs p38 output, exemplified by Atg5(Thr75) control of autophagic flux and later HOXA10(Thr362) in embryo adhesion.

    Evidence Gadd45β-/- and p38-/- cells with Atg5 T75 mutagenesis and autophagy assays; Co-IP and T362A mutagenesis for HOXA10 with conditional deletion and adhesion assays

    PMID:23059785 PMID:36216824

    Open questions at the time
    • Full substrate repertoire unknown
    • How substrate spatial targeting is achieved is only partly resolved
  11. 2020 High

    Demonstrated MAP3K4 acts as a direct redox sensor, with cysteine oxidation–reduction driving delayed sustained SAPK signaling that determines cell fate.

    Evidence Gene knockout, cysteine redox-state analysis, time-course SAPK assays, cell death and IL-6 readouts

    PMID:32637591

    Open questions at the time
    • Precise cysteine residues' contributions to the structural switch not fully mapped
    • How redox sensing intersects the GADD45 dimerization mechanism unclear
  12. 2024 Medium

    Placed MAP3K4 in a tumor-suppressive ERK→EGR1→GADD45β→MTK1 circuit that drives apoptotic/immune programs and is silenced in ERK-hyperactive cancers.

    Evidence Gene knockout, transcriptomics, GADD45β re-expression, p38/JNK and tumorigenesis assays

    PMID:39526327

    Open questions at the time
    • Causality of MTK1 silencing in tumorigenesis from a single lab
    • Clinical relevance across cancer types not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple, sometimes competing inputs—GADD45 binding, redox state, tyrosine phosphorylation, and oligomerization regulators—are integrated to set MAP3K4 output amplitude, duration, and p38-versus-JNK branch choice in a given cell remains unresolved.
  • No structural model of the active dimer or integrated input states
  • Branch-selection determinants between p38 and JNK unknown
  • Comprehensive non-MAPK substrate map lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016740 transferase activity 3 GO:0098772 molecular function regulator activity 2 GO:0140299 molecular sensor activity 1
Localization
GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1474165 Reproduction 2 R-HSA-4839726 Chromatin organization 2 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-9612973 Autophagy 1
Partners
AXIN1GADD45AGADD45BGSK3BHOXA10MKK6RACK1TRAF4

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 MTK1/MAP3K4 is a MAPKKK that phosphorylates and activates MKK6 and SEK1 in vitro, leading to activation of p38 and JNK MAPK pathways but not the ERK pathway; a dominant-negative MTK1 mutant strongly inhibits p38 activation by environmental stresses (osmotic shock, UV, anisomycin) but not by TNF-alpha. In vitro kinase assay (MKK6/SEK1 phosphorylation), dominant-negative overexpression in COS-7/HeLa cells, functional complementation of yeast ssk2Δ ssk22Δ sho1Δ triple mutant The EMBO journal High 9305639
1997 MEKK4 specifically activates the JNK pathway but not ERK or p38; MEKK4 binds Cdc42 and Rac, and kinase-inactive MEKK4 mutants block Cdc42/Rac stimulation of JNK; MEKK4 is localized to a perinuclear, vesicular compartment similar to the Golgi. Overexpression/dominant-negative in mammalian cells, co-immunoprecipitation with Cdc42/Rac, subcellular localization by immunofluorescence The Journal of biological chemistry Medium 9079650
1998 GADD45α, GADD45β, and GADD45γ bind an N-terminal domain of MTK1/MAP3K4 via yeast two-hybrid and activate MTK1 kinase activity both in vivo and in vitro; GADD45-induced p38/JNK activation and apoptosis can be suppressed by dominant-negative MTK1. Yeast two-hybrid, in vitro and in vivo kinase assays, dominant-negative coexpression Cell High 9827804
2002 MTK1/MAP3K4 contains an autoinhibitory domain (residues 253–553) in its N-terminal noncatalytic region; in the autoinhibited state, the kinase domain cannot interact with its substrate MKK6; GADD45 proteins bind near this inhibitory domain to relieve autoinhibition; constitutively active MTK1 mutants that bypass autoinhibition can interact with MKK6 in the absence of GADD45. Deletion mutagenesis in yeast and mammalian cells, functional complementation screen, co-immunoprecipitation of MTK1 with MKK6 Molecular and cellular biology High 12052864
2003 MEKK4 binds Axin at a site distinct from the MEKK1-binding region on Axin; dominant-negative MEKK4 attenuates JNK activation by Axin; siRNA against MEKK4 inhibits Axin-induced JNK activation independently of MEKK1, establishing MEKK4 as a second MAPKKK mediating Axin-induced JNK activation. Co-immunoprecipitation in vivo, dominant-negative overexpression, siRNA knockdown, MEKK1-/- MEFs The Journal of biological chemistry Medium 12878610
2004 In MEKK4-deficient mice, CD4 T cells show reduced p38 activity and defective IFNγ synthesis; GADD45β/GADD45γ promotion of IFNγ production requires MEKK4 and p38, establishing GADD45β/GADD45γ→MEKK4→p38 as the pathway for STAT4-independent IFNγ production in T cells. MEKK4-/- mouse generation, p38 activity assay, cytokine production assay, GADD45 overexpression in MEKK4+/+ vs MEKK4-/- T cells, p38 inhibitor treatment The EMBO journal High 15044949
2005 MEKK4-deficient mice develop neural tube defects with massively elevated apoptosis in the neuroepithelium; MEKK4 loss causes significant reduction in MKK4 activity in the neuroepithelium at sites of neural tube closure, establishing an antiapoptotic role for MEKK4 via MKK4 during neural tube development. MEKK4-/- mouse model, MKK4 activity assay in neuroepithelium, TUNEL assay, proliferation analysis Proceedings of the National Academy of Sciences of the United States of America High 15731347
2005 TRAF4 associates endogenously with MEKK4, binding the kinase domain of MEKK4 independently of MEKK4 kinase activity; TRAF4 and MEKK4 colocalize in cells; coexpression of TRAF4 and MEKK4 synergistically activates JNK; TRAF4 stimulates MEKK4 kinase activity by promoting MEKK4 oligomerization. Co-immunoprecipitation (endogenous in K562 cells and E10.5 embryos), immunofluorescence co-localization, JNK reporter assay, kinase-inactive MEKK4 dominant-negative The Journal of biological chemistry Medium 16157600
2005 Kinase-inactive MEKK4(K1361R) knock-in embryos show loss of phosphorylation of MKK3/6 and reduced p38 pathway activity (as measured by reduced MAPKAPK2 phosphorylation), while MKK4-JNK and MEK1/2-ERK1/2 pathways are unaffected; MEKK4(K1361R) fibroblasts show reduced p38 and HSP27 phosphorylation with actin cytoskeletal instability upon heat shock. Kinase-dead knock-in mouse model, in vivo phosphorylation assays for MKK3/6 and MAPKAPK2, heat shock/actin cytoskeleton assay in fibroblasts Molecular and cellular biology High 16199873
2005 IFNγ induces tyrosine phosphorylation of MEKK4 in keratinocytes via Pyk2 in a calcium-dependent manner; annexin II co-immunoprecipitates with MEKK4 after IFNγ treatment, and SHP2 co-immunoprecipitates with MEKK4 to dephosphorylate it; Pyk2-dependent phosphorylation correlates with MEKK4 ability to phosphorylate MKK6 in vitro and subsequent p38 activation. Co-immunoprecipitation, immunofluorescence co-localization, in vitro kinase assay (MEKK4 phosphorylation of MKK6), calcium chelation The Biochemical journal Medium 15601262
2006 MEKK4-/- mice develop periventricular heterotopia (PVH) with failed neuronal migration; Filamin-A (FLN-A) expression is elevated in MEKK4-/- forebrains; MKK4 precipitates a complex containing MEKK4 and FLN-A, suggesting MKK4 bridges MEKK4 and FLN-A; wild-type FLN-A overexpression inhibits neuronal migration. MEKK4-/- mouse model, co-immunoprecipitation of MEKK4-MKK4-FLN-A complex using recombinant MKK4, RNAi knockdown, FLN-A overexpression Neuron Medium 17145501
2007 GADD45 binding to MTK1/MAP3K4 induces N-C domain dissociation (releasing autoinhibition), MTK1 dimerization via a coiled-coil dimerization domain, and trans-autophosphorylation at Thr-1493 in the kinase activation loop; an alanine substitution at Thr-1493 severely reduces kinase activity. Domain interaction assays, dimerization assays, site-directed mutagenesis (T1493A), in vitro and in vivo kinase activity measurements Molecular and cellular biology High 17242196
2007 GSK3β binds the kinase domain of MEKK4 and inhibits MEKK4 dimerization required for activation, thereby suppressing JNK and p38 signaling; inhibition of GSK3β kinase activity enhances MEKK4 activity; GSK3β phosphorylates specific serines/threonines in the MEKK4 N-terminus; unlike TRAF4 and Axin (which activate MEKK4 by promoting dimerization), GSK3β is an inhibitor. Co-immunoprecipitation, kinase activity assays, GSK3β inhibitor (SB216763) treatment, dimerization assays The Journal of biological chemistry Medium 17726008
2008 MEKK4 binds RIP2 to sequester it from the NOD2 signaling pathway; upon NOD2 agonist MDP exposure, the MEKK4:RIP2 complex dissociates, allowing NOD2 to bind RIP2 and activate NFκB; knockdown of MEKK4 in macrophages results in increased NFκB activity and absent p38 activity following MDP; Crohn's disease-associated NOD2 polymorphisms cannot compete with MEKK4 for RIP2 binding. Co-immunoprecipitation, MEKK4 knockdown in macrophages, NFκB and p38 activity assays Current biology : CB Medium 18775659
2009 MAP3K4 loss-of-function (byg mutation causing premature stop codon) in XY mice results in gonadal sex reversal with reduced Sry and Sox9 expression; activated MKK4 (direct MAP3K4 target) and activated p38 are detected in the coelomic region of XY gonads at E11.5, linking MAP3K4→MKK4/p38 signaling in gonadal somatic cells to Sry expression regulation. Forward genetic screen, mouse knockout, RT-PCR/protein expression analysis, immunostaining for phospho-MKK4 and phospho-p38 in gonad PLoS biology High 19753101
2009 FGF4-stimulated JNK and p38 activity is markedly reduced in MEKK4 kinase-inactive trophoblast stem (TS) cells; chemical inhibition of JNK (not p38) in wild-type TS cells induces EMT hallmarks similar to MEKK4 kinase inactivation; chromatin immunoprecipitation shows altered AP-1 composition (increased Fra-2, decreased Fra-1/JunB) at Gcm1 and MMP2 gene regulatory regions in MEKK4 kinase-inactive TS cells. Kinase-inactive knock-in TS cells, JNK/p38 activity assays, JNK inhibitor treatment, chromatin immunoprecipitation Molecular and cellular biology High 19289495
2010 GADD45β activates C/EBPβ transcriptional function via MTK1/MKK3/MKK6/p38 to drive Col10a1 transcription in chondrocytes; dominant-negative p38α (but not JNK) disrupts GADD45β/C/EBPβ-mediated Col10a1 promoter activity; GADD45β knockdown prevents p38 phosphorylation and decreases Col10a1 mRNA levels without affecting C/EBPβ binding to the promoter, demonstrating that GADD45β/MTK1/p38 controls C/EBPβ transactivation function specifically. Dominant-negative p38 and JNK constructs, siRNA knockdown, promoter reporter assays, ChIP, in vivo phosphorylation assays The Journal of biological chemistry Medium 20048163
2011 MAP3K4 controls the activity of the histone acetyltransferase CBP; loss of MAP3K4/CBP activity represses acetylation of histones H2A and H2B, which is required to maintain the epithelial phenotype in trophoblast stem cells; loss of MAP3K4/CBP-mediated H2B acetylation causes EMT while maintaining stemness. MAP3K4 loss-of-function in TS cells, CBP activity assays, histone acetylation ChIP, transcriptomic profiling Cell stem cell Medium 21549327
2012 GADD45γ and Map3k4 genetically interact during mouse sex determination; transgenic overexpression of Map3k4 rescues gonadal defects in Gadd45γ-deficient embryos; sex reversal in both Gadd45γ and Map3k4 mutants is associated with reduced phosphorylation of p38 MAPK and GATA4; embryos lacking both p38α and p38β also exhibit XY gonadal sex reversal. Mouse knockouts (Gadd45γ-/-, Map3k4-/-), transgenic overexpression rescue, phospho-p38 and phospho-GATA4 immunostaining, double p38α/β knockout Developmental cell High 23102580
2012 The GADD45β–MEKK4 pathway specifically directs p38 to autophagosomes; this spatial regulation results in p38-mediated phosphorylation of Atg5 at Thr75, which inhibits lysosome–autophagosome fusion and blocks autophagic flux; Gadd45β-deficient and p38-deficient cells show increased autophagic flux. Gadd45β-/- and p38-/- fibroblasts, autophagosome tracking, Atg5 phosphorylation mapping (T75 site-directed mutagenesis), lysosome fusion assays Cell death and differentiation High 23059785
2013 RNAi depletion of MAP3K4 inhibits TGFβ-induced p38 MAPK phosphorylation; depletion of MAP3K10 from cells homozygously expressing catalytically inactive MAP3K4 completely abolishes TGFβ-induced p38 phosphorylation, indicating MAP3K4 and MAP3K10 together (not TAK1) are sufficient to mediate TGFβ-induced p38 activation. RNAi depletion, catalytically inactive MAP3K4 knock-in cells, p38 phosphorylation immunoblotting in MEFs and HaCaT keratinocytes Open biology Medium 23760366
2013 MTK1/MAP3K4 is required for HER2/HER3-heregulin-β1-induced cell migration and extracellular acidification in breast cancer cells; activated HER3 associates with MTK1 in a HER2-dependent manner; the actin-interacting region (AIR) of MTK1 is identified, and disruption of actin polymerization inhibits HRG-induced MTK1/HER3 association. Co-immunoprecipitation of MTK1 with HER3, MTK1 knockdown (scratch assay, acidification assay), cytochalasin D treatment, HER2 inhibitor lapatinib Cellular signalling Medium 24036211
2016 Gadd45a forms a complex with MEKK4 in skeletal muscle fibers in vivo; this interaction increases MEKK4 kinase activity; MEKK4 kinase activity is both sufficient to induce skeletal muscle fiber atrophy and required for Gadd45a-mediated skeletal muscle fiber atrophy. Biochemical isolation and co-immunoprecipitation of Gadd45a-associated proteins from mouse muscle in vivo, MEKK4 kinase activity assay, in vivo gain- and loss-of-function in muscle fibers The Journal of biological chemistry Medium 27358404
2017 MAP3K4 controls EMT in trophoblast stem cells through ubiquitination and degradation of HDAC6; loss of MAP3K4 activity results in elevated HDAC6 expression; in the nucleus, HDAC6 deacetylates promoters of tight junction genes; HDAC6 knockdown in MAP3K4 kinase-inactive TS cells restores epithelial features including cell-cell adhesion and barrier formation. MAP3K4 kinase-inactive TS cells, HDAC6 expression/ubiquitination assays, HDAC6 knockdown (shRNA), immunofluorescence, gene expression analysis Cell reports Medium 28273454
2020 MTK1/MAP3K4 functions as a redox sensor: following oxidative stress, MTK1 is rapidly oxidized and then gradually reduced at evolutionarily conserved cysteine residues; these coupled oxidation-reduction modifications elicit catalytic activity; oxidative-stress-induced SAPK signaling is mediated by coordinated activation of MTK1 and ASK1 with different kinetics; MTK1-mediated redox sensing is crucial for delayed and sustained SAPK activity that dictates cell fate (cell death and IL-6 production). MTK1 gene knockout, redox state analysis at cysteine residues, time-course SAPK activity assays, cell death and IL-6 production assays Science advances High 32637591
2021 MAP3K4 kinase activity (not just protein presence) is required for male gonadal sex determination; homozygous kinase-inactive MAP3K4 (Map3k4KI/KI) embryos lose Sry expression in XY gonads at E11.5, causing embryonic male gonadal sex reversal; adult XY Map3k4KI/KI mice exhibit female phenotype with diverse ovarian abnormalities. Kinase-inactive knock-in from endogenous locus, Sry expression analysis at E11.5, adult phenotyping Biology of reproduction High 33912929
2022 MAP3K4 directly phosphorylates HOXA10 at Thr362; this phosphorylation enhances HOXA10-mediated transcriptional activity and promotes embryo adhesion to the endometrial epithelium; deletion or kinase inactivation of MEKK4 in endometrial epithelial cells attenuates embryo-epithelium adhesion; T362A mutation of HOXA10 reduces protein stability and transcriptional activity. Co-immunoprecipitation of MEKK4 with HOXA10, in vitro/in vivo phosphorylation at Thr362, site-directed mutagenesis (T362A), conditional MEKK4 deletion/kinase-inactivation, adhesion assays Cell death discovery Medium 36216824
2022 MAP3K4 kinase inactivation in trophoblast stem cells reduces IGF1R and IR expression and decreases Akt activation; MAP3K4 promotes Igf1r transcript expression through activation of CBP; in kinase-inactive cells, Igf1r is repressed due to reduced CBP activity and increased HDAC6 expression/activity; MAP3K4 kinase inactivation causes fetal growth restriction due to placental insufficiency. MAP3K4 kinase-inactive TS cells and placenta, IGF1R/IR protein/mRNA analysis, Akt phosphorylation assays, CBP activity assays, HDAC6 activity assays, in vivo fetal/placental growth measurements The Journal of biological chemistry Medium 35921893
2024 Aberrant ERK signaling induces sustained EGR1 expression, which promotes GADD45β production; GADD45β then activates MTK1/MAP3K4, leading to persistent p38/JNK activation; this GADD45β/MTK1 cross-talk preferentially upregulates genes involved in apoptosis and immune response; EGR1, GADD45β, and MTK1 are frequently downregulated in cancers with high ERK activity, disrupting this tumor-suppressive pathway. Gene knockout, transcriptome analysis, GADD45β re-expression in cancer cells, p38/JNK activity assays, tumorigenesis assays Cancer science Medium 39526327
2024 HDAC6 forms a protein complex with TRAF4 in trophoblast stem cells; HDAC6 promotes TRAF4 protein expression independently of its deacetylase activity; HDAC6 knockdown in MAP3K4 kinase-inactive TS cells reduces TRAF4 protein expression; during placental labyrinth differentiation, there is a switch from Traf4 coexpression with Map3k4 to Traf4 coexpression with Hdac6. Co-immunoprecipitation (HDAC6-TRAF4 complex), HDAC6 shRNA knockdown, single-cell RNA-seq data analysis, immunoblotting The Journal of biological chemistry Medium 39710325
2025 Under hypoxia, cytoplasmic FTO binds RACK1, which impairs the interaction between RACK1 and MTK1/MAP3K4, thereby blocking JNK1/2 activation and preventing apoptosis; RACK1 functions as an activating binding partner of MTK1 that promotes JNK1/2-mediated apoptosis under hypoxic stress. Immunoprecipitation (FTO-RACK1 and RACK1-MTK1 interactions), knockdown experiments (atg7, nedd4), subcellular fractionation, flow cytometry (apoptosis), FTO m6A-demethylase-dead mutant (H228A/D230A) Journal of advanced research Medium 39805423

Source papers

Stage 0 corpus · 63 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Cell 654 9827804
1997 Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway. The Journal of biological chemistry 212 9079650
1997 A human homolog of the yeast Ssk2/Ssk22 MAP kinase kinase kinases, MTK1, mediates stress-induced activation of the p38 and JNK pathways. The EMBO journal 159 9305639
2002 Regulation of MTK1/MEKK4 kinase activity by its N-terminal autoinhibitory domain and GADD45 binding. Molecular and cellular biology 139 12052864
2009 Loss of mitogen-activated protein kinase kinase kinase 4 (MAP3K4) reveals a requirement for MAPK signalling in mouse sex determination. PLoS biology 111 19753101
2012 Gadd45γ and Map3k4 interactions regulate mouse testis determination via p38 MAPK-mediated control of Sry expression. Developmental cell 110 23102580
2012 Phosphorylation of Atg5 by the Gadd45β-MEKK4-p38 pathway inhibits autophagy. Cell death and differentiation 104 23059785
2011 MAP3K4/CBP-regulated H2B acetylation controls epithelial-mesenchymal transition in trophoblast stem cells. Cell stem cell 104 21549327
2006 MEKK4 signaling regulates filamin expression and neuronal migration. Neuron 98 17145501
2007 Activation of MTK1/MEKK4 by GADD45 through induced N-C dissociation and dimerization-mediated trans autophosphorylation of the MTK1 kinase domain. Molecular and cellular biology 96 17242196
2004 GADD45beta/GADD45gamma and MEKK4 comprise a genetic pathway mediating STAT4-independent IFNgamma production in T cells. The EMBO journal 90 15044949
2005 Loss of mitogen-activated protein kinase kinase kinase 4 (MEKK4) results in enhanced apoptosis and defective neural tube development. Proceedings of the National Academy of Sciences of the United States of America 82 15731347
2009 Trophoblast stem cell maintenance by fibroblast growth factor 4 requires MEKK4 activation of Jun N-terminal kinase. Molecular and cellular biology 61 19289495
2005 Ablation of MEKK4 kinase activity causes neurulation and skeletal patterning defects in the mouse embryo. Molecular and cellular biology 60 16199873
2003 Axin utilizes distinct regions for competitive MEKK1 and MEKK4 binding and JNK activation. The Journal of biological chemistry 57 12878610
2017 MAP3K4 Controls the Chromatin Modifier HDAC6 during Trophoblast Stem Cell Epithelial-to-Mesenchymal Transition. Cell reports 50 28273454
2007 MEKK4 stimulation of p38 and JNK activity is negatively regulated by GSK3beta. The Journal of biological chemistry 50 17726008
2020 LncRNA-MAP3K4 regulates vascular inflammation through the p38 MAPK signaling pathway and cis-modulation of MAP3K4. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 46 33184917
2016 Gadd45a Protein Promotes Skeletal Muscle Atrophy by Forming a Complex with the Protein Kinase MEKK4. The Journal of biological chemistry 41 27358404
2005 MEKK4 is an effector of the embryonic TRAF4 for JNK activation. The Journal of biological chemistry 41 16157600
2010 GADD45beta enhances Col10a1 transcription via the MTK1/MKK3/6/p38 axis and activation of C/EBPbeta-TAD4 in terminally differentiating chondrocytes. The Journal of biological chemistry 40 20048163
2005 Interferon-gamma-dependent tyrosine phosphorylation of MEKK4 via Pyk2 is regulated by annexin II and SHP2 in keratinocytes. The Biochemical journal 34 15601262
2020 ALV-J inhibits autophagy through the GADD45β/MEKK4/P38MAPK signaling pathway and mediates apoptosis following autophagy. Cell death & disease 33 32826872
2020 Stress-responsive MTK1 SAPKKK serves as a redox sensor that mediates delayed and sustained activation of SAPKs by oxidative stress. Science advances 32 32637591
2000 MEKK4 mediates differentiation in response to retinoic acid via activation of c-Jun N-terminal kinase in rat embryonal carcinoma P19 cells. The Journal of biological chemistry 32 10807916
2006 D-MEKK1, the Drosophila orthologue of mammalian MEKK4/MTK1, and Hemipterous/D-MKK7 mediate the activation of D-JNK by cadmium and arsenite in Schneider cells. BMC cell biology 29 16451733
2010 MEKK1/MEKK4 are responsible for TRAIL-induced JNK/p38 phosphorylation. Oncology reports 27 21152872
2019 Upregulation of miR-183 represses neuropathic pain through inhibiton of MAP3K4 in CCI rat models. Journal of cellular physiology 25 31602666
2014 Transgenic expression of Map3k4 rescues T-associated sex reversal (Tas) in mice. Human molecular genetics 25 24452333
2012 TRAIL/MEKK4/p38/HSP27/Akt survival network is biphasically modulated by the Src/CIN85/c-Cbl complex. Cellular signalling 25 23085457
2005 Angiotensin II stimulated transcription of cyclooxygenase II is regulated by a novel kinase cascade involving Pyk2, MEKK4 and annexin II. Molecular and cellular biochemistry 25 15881658
2003 Actin recovery and bud emergence in osmotically stressed cells requires the conserved actin interacting mitogen-activated protein kinase kinase kinase Ssk2p/MTK1 and the scaffold protein Spa2p. Molecular biology of the cell 24 12857882
2013 The TGFβ-induced phosphorylation and activation of p38 mitogen-activated protein kinase is mediated by MAP3K4 and MAP3K10 but not TAK1. Open biology 23 23760366
2008 MEKK4 sequesters RIP2 to dictate NOD2 signal specificity. Current biology : CB 23 18775659
2013 HER2/HER3 regulates extracellular acidification and cell migration through MTK1 (MEKK4). Cellular signalling 21 24036211
2007 The MEK kinases MEKK4/Ssk2p facilitate complexity in the stress signaling responses of diverse systems. Journal of cellular biochemistry 21 17348032
2005 CIN85 regulates the ability of MEKK4 to activate the p38 MAP kinase pathway. Biochemical and biophysical research communications 20 16256071
2006 MEKK4 regulates developmental EMT in the embryonic heart. Developmental dynamics : an official publication of the American Association of Anatomists 16 16894626
2016 MEKK4 Signaling Regulates Sensory Cell Development and Function in the Mouse Inner Ear. The Journal of neuroscience : the official journal of the Society for Neuroscience 14 26818521
2019 Long non-coding RNA-OIS1 inhibits HPV-positive, but not HPV-negative cervical squamous cell carcinoma by upregulating MTK-1. Oncology letters 13 30854069
2024 Blockade of the ADAM8-Fra-1 complex attenuates neuroinflammation by suppressing the Map3k4/MAPKs axis after spinal cord injury. Cellular & molecular biology letters 12 38755530
2024 MAP3K4 kinase action and dual role in cancer. Discover oncology 9 38568424
2018 Downregulation of ERBB3 decreases the proliferation, migration and invasion of cervical cancer cells though the interaction with MTK-1. Oncology letters 9 30127948
2022 MAP3K4 promotes fetal and placental growth by controlling the receptor tyrosine kinases IGF1R/IR and Akt signaling pathway. The Journal of biological chemistry 8 35921893
2022 Identification of MAP3K4 as a novel regulation factor of hepatic lipid metabolism in non-alcoholic fatty liver disease. Journal of translational medicine 8 36376950
2019 Upregulation of lncRNA GATA6-AS suppresses the migration and invasion of cervical squamous cell carcinoma by downregulating MTK-1. Oncology letters 8 31404324
2017 Molecular cloning, characterization and functional analysis of a putative mitogen-activated protein kinase kinase kinase 4 (MEKK4) from blood clam Tegillarca granosa. Fish & shellfish immunology 8 28476674
2009 Activation of MTK1/MEKK4 induces cardiomyocyte death and heart failure. Journal of molecular and cellular cardiology 8 19850048
2024 Circ_0005615 enhances multiple myeloma progression through interaction with EIF4A3 to regulate MAP3K4 m6A modification mediated by ALKBH5. Leukemia research 7 38663164
2022 MEKK4-mediated Phosphorylation of HOXA10 at Threonine 362 facilitates embryo adhesion to the endometrial epithelium. Cell death discovery 7 36216824
2021 MAP3K4 kinase activity dependent control of mouse gonadal sex determination†. Biology of reproduction 7 33912929
2025 Hypoxia-induced degradation of FTO promotes apoptosis by unmasking RACK1-mediated activation of MTK1-JNK1/2 pathway. Journal of advanced research 6 39805423
2020 Transcriptomic Analysis of MAP3K1 and MAP3K4 in the Developing Marsupial Gonad. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 6 32008010
2020 Associations of novel variants in PIK3C3, INSR and MAP3K4 of the ATM pathway genes with pancreatic cancer risk. American journal of cancer research 6 32775006
2019 HER2/HER3 regulates lactate secretion and expression of lactate receptor mRNA through the MAP3K4 associated protein GIT1. Scientific reports 5 31346208
2024 Her2 promotes early dissemination of breast cancer by inhibiting the p38 pathway through the downregulation of MAP3K4. Cell communication and signaling : CCS 4 39702199
2020 Coordinated regulation of Rel expression by MAP3K4, CBP, and HDAC6 controls phenotypic switching. Communications biology 4 32859943
2012 Defective IL-1A expression in patients with Crohn's disease is related to attenuated MAP3K4 signaling. Human immunology 4 22732089
2024 GADD45β-MTK1 signaling axis mediates oncogenic stress-induced activation of the p38 and JNK pathways. Cancer science 2 39526327
2021 Grass carp MAP3K4 participates in the intestinal immune response to bacterial challenge. Fish & shellfish immunology 2 34780976
2022 Association between MAP3K4 gene polymorphisms and the risk of schizophrenia susceptibility in a Northeast Chinese Han population. Metabolic brain disease 1 35445959
2026 WGCNA-derived lncRNA MAP3K4-AS1 regulates apoptosis and cell cycle in TNBC MDA-MB-231 cells validated by siRNA knockdown. Discover oncology 0 41644793
2024 MAP3K4 signaling regulates HDAC6 and TRAF4 coexpression and stabilization in trophoblast stem cells. The Journal of biological chemistry 0 39710325

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