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Symbol MAP3K4 contributors: mct/npt - updated : 17-04-2019
HGNC name mitogen-activated protein kinase kinase kinase 4
HGNC id 6856
Location 6q26      Physical location : 161.412.821 - 161.538.416
Synonym name
  • SSK2/SSK22 MAP kinase kinase kinase, yeast, homolog of
  • MAPK/ERK kinase kinase 4
  • dJ473J16.1 (mitogen-activated protein kinase kinase kinase
  • 4)
  • MAP three kinase 1
  • Synonym symbol(s) MTK1, MEKK4, KIAA0213, RP3-473J16.1, FLJ42439, MAPKKK4, PRO0412
    TYPE functioning gene
    STRUCTURE 125.86 kb     27 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    Physical map
    RSHL2 6q25.3 radial spokehead-like 2 TAGAP 6q25.3 T-cell activation GTPase activating protein LOC389441 6 LOC389441 LOC389442 6 LOC389442 LOC389443 6 LOC389443 LOC389444 6 similar to frazzled CG8581-PA FNDC1 6q25 fibronectin type III domain containing 1 LOC389445 6 similar to 60S ribosomal protein L21 SOD2 6q25.2 superoxide dismutase 2, mitochondrial WTAP 6q25-q27 Wilms tumor 1 associated protein ACAT2 6q25.3-q26 acetyl-Coenzyme A acetyltransferase 2 (acetoacetyl Coenzyme A thiolase) TCP1 6q25.1-q25.2 t-complex 1 MRPL18 6q25.3 mitochondrial ribosomal protein L18 PNLDC1 6q25.3 poly(A)-specific ribonuclease (PARN)-like domain containing 1 MAS1 6q25.3-q26 MAS1 oncogene IGF2R 6q26-q27 insulin-like growth factor 2 receptor SLC22A1 6q27 solute carrier family 22 (organic cation transporter), member 1 SLC22A2 6q26-q27 solute carrier family 22 (organic cation transporter), member 2 SLC22A3 6q26-q27 solute carrier family 22 (extraneuronal monoamine transporter), member 3 APOAL 6q26-q27 apolipoprotein A-like LPA 6q26-q27 lipoprotein, Lp(a) PLG 6q26 plasminogen LOC389446 6 similar to apolipoprotein(a) (EC 3.4.21.-) - rhesus macaque (fragment) LOC389447 6 LOC389447 MAP3K4 6q25.3 mitogen-activated protein kinase kinase kinase 4 AGPAT4 6q25.3 1-acylglycerol-3-phosphate O-acyltransferase 4 (lysophosphatidic acid acyltransferase, delta) C6orf59 6q25.3 chromosome 6 open reading frame 59 PARK2 6q25.2-q27 Parkinson disease (autosomal recessive, juvenile) 2, parkin PACRG 6q26 PARK2 co-regulated
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    27 splicing 5501 181 1608 - 2016 26802931
    26 splicing 5351 - 1558 missing 49 codons 2016 26802931
    28 - 5662 - 1061 - 2016 26802931
    27 - 5552 - 1604 - 2016 26802931
    26 - 5382 - 1554 - 2016 26802931
    Type ubiquitous
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivepharynx   highly
    Endocrineparathyroid   highly
    Respiratoryrespiratory tractlarynx  highly
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    SystemCellPubmedSpeciesStageRna symbol
    Hearing / Equilibriumhair cell receptor Homo sapiens
    cell lineage
    cell lines
    at STAGE
    physiological period embryo, fetal, pregnancy
    Text expressed strongly in the developing embryo, TS (trophoblast stem) cells, and cells derived from TS cells (Abell 2009)
  • a N-terminal kinase catalytic domain, and a nonkinase domain that may contain a regulatory domain
  • a docking site, a stretch of about 20 amino acids immediately on the C-terminal side of the MAPKK catalytic domain (Takekawa 2005)
  • hybrid between those of serine/threonine and tyrosine protein kinases at the C-terminus
    interspecies homolog to C.elegans B0414.7
    homolog to yeast S.cerevisiae SSK2
  • protein kinase superfamily
  • STE Ser/Thr protein kinase family
  • MAP kinase kinase kinase subfamily
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     intracellular
    basic FUNCTION
  • activating the MAPK and JNK signal transduction pathway (see MAP4K4)
  • major mediator of environmental stresses that activate the CSBP2 MAPK pathway, and a minor mediator of the JNK pathway
  • signaling hub for FGF4 activation of JNK that is required for maintenance of trophoblast stem cells in an undifferentiated state (Abell 2009)
  • coordinates the activity of the JNK and MAPK14 modules in trophoblast stem cells required for stem cell maintenance (Abell 2009)
  • MAP3K4-dependent signalling events are required for normal expression of SRY during testis development, and implicated in disorders of sexual development (Bogani 2009)
  • is a mitogen-activated protein kinase kinase kinase that regulates the activity of its downstream mitogen-activated kinases, MAPK14, and JUN N-terminal kinase (JNK)
  • plays an important role in the regulation of cell death and is also involved in the pathogenesis of heart failure
  • MAP3K4 expression is highly regulated during inner ear development and is critical to normal cytoarchitecture and function
    signaling signal transduction
    MAP3K4 pathway is involved in FLNA regulation and periventricular heterotopia formation
    a component
    small molecule
  • SH3KBP1-interacting partner (enhances the activation of MKK6 and of the downstream MAPK14 following oxidative stress and growth factor stimulation)
  • FLNA, impacts neuronal migration initiation and provides insight into the pathogenesis of periventricular heterotopia
  • link between MAPK signalling in proliferating gonadal somatic cells and regulation of SRY expression (Bogani 2009)
  • interacts with TRAF4 (MAP3K4 is the MAPK kinase kinase for TRAF4 regulation of the JNK pathway) (Abell 2005)
  • MAP3K4 controls the activity of the histone acetyltransferase CREBBP, and acetylation of histones H2A and H2B by CREBBP is required to maintain the epithelial phenotype
  • spatial regulation of MAPK14 by GADD45B/MAP3K4 negatively regulates the autophagic process
  • interaction of SH3KBP1 with MAP3K4 was increased during the late phase of TNFSF10 incubation, suggesting that sustained MAPK14 and HSPB1 phosphorylation protects cells by preventing further cell death
  • MAP3K4 acts as a critical node to integrate FGF20-FGFR1 signaling responses to specifically influence hair cells (HCs) development
  • GADD45A interacts with multiple proteins in skeletal muscle fibers, including, most prominently, MAP3K4, a mitogen-activated protein kinase kinase kinase that was not previously known to play a role in skeletal muscle atrophy
  • MAP3K4 activity controls epithelial-to-mesenchymal transition (EMT) through the ubiquitination and degradation of HDAC6
  • cell & other
    activated by phosphorylation
    corresponding disease(s)
    Variant & Polymorphism
    Candidate gene
    Therapy target
  • mice homozygous for a kinase-inactive Mekk4 mutation exhibit significant hearing loss