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FLASH GENE
Symbol MAP3K7 contributors: mct/shn - updated : 08-12-2019
HGNC name mitogen-activated protein kinase kinase kinase 7
HGNC id 6859
Corresponding disease
CSCF cardiospondylocarpofacial syndrome
FMTD2 frontometaphyseal dysplasia 2
Location 6q15      Physical location : 91.225.352 - 91.296.907
Synonym name
  • transforming growth factor beta-activated kinase 1
  • transforming growth factor-beta-activated kinase 1
  • TGF-beta activated kinase 1
  • TGF-beta-activated kinase 1
    • Synonym symbol(s) TAK1, MEKK7, TGF1a
    EC.number 2.7.11.25
    DNA
    TYPE functioning gene
    STRUCTURE 71.56 kb     17 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence cytosine-phosphate-guanine/HTF
    MAPPING cloned Y linked N status provisional
    Map cen - D6S462 - D6S1570 - MAP3K7 - D6S450 - D6S1631 - qter
    RNA
    TRANSCRIPTS type messenger
    text two alternative exons 12 and 16
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    16 - 5091 64 579 - 2009 19410630
    also called TAK1a
    17 splicing 5172 67 606 brain, kidney, lung and small intestine 2009 19410630
    also called TAK1b
    16 splicing 5056 - 518 ubiquitously but predominantly in prostate 2009 19410630
    also called TAK1c
    15 splicing 4975 - 491 in most tissues as a minor variant 2009 19410630
    also called TAK1d
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart     Homo sapiensFetal
    Digestiveintestinelarge intestinecolon   Homo sapiensFetal
     intestinelarge intestinecolon lowly Homo sapiensAdult
     liver     Homo sapiensFetal
     liver   highly Homo sapiensAdult
     stomach   highly Homo sapiensAdult
     stomach     Homo sapiensFetal
    Lymphoid/Immunespleen   lowly Homo sapiensAdult
    Nervousbrain     Homo sapiensFetal
     brain   highly Homo sapiensAdult
    Respiratorylung     Homo sapiensFetal
     lung   moderately Homo sapiensAdult
    Urinarykidney   highly Homo sapiensAdult
     kidney     Homo sapiensFetal
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticneutrophil Homo sapiensAdult
    cell lineage
    cell lines human lung cancer cell lines (
    fluid/secretion
    at STAGE
    Text fetal brain, lung, heart, stomach, liver, kidney and colon (
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N terminal catalytic domain, hybrid between those of serine/threonine and tyrosine protein kinases,
  • a double leucine zipper domain
    • HOMOLOGY
    interspecies ortholog to MAP3K7, Pan troglodytes
    ortholog to Map3k7, Mus musculus
    ortholog to Map3k7, Rattus norvegicus
    ortholog to map3k7, Danio rerio
    Homologene
    FAMILY
  • mitogen-activated protein kinase kinase kinase family
    • CATEGORY enzyme , immunity/defense , signaling
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus
    text
  • neutrophils express MAP3K7, as well as its associated partners, TAB1, TAB2, in both the cytoplasm and nucleus
    • basic FUNCTION
  • may function as a mediator of ceramide signaling to SAPK/JNK activation (
  • links TRAF6 to the NIK-IKK cascade in the IL-1 signalling pathway (
  • phosphorylating MAPKs mediator of TGF beta signal transduction
  • activator of NFKBs, involved in IL18 mediated signaling
  • mediating the activation of NF-kappaB in response to stimulation by proinflammatory cytokines and microbial pathogens in the innate immunity pathways (
  • required for the activation of NF-kappaB in thymocytes and plays a central role in both innate and adaptive immunity (
  • mitogen-activated kinase kinase kinase, repressing the TERT core promoter activity in an E-box-independent manner
  • induces cellular senescence programs in normal human diploid cells
  • thought to play a causative role in the determination of a finite replicative lifespan of normal and cancer cells
  • playing an essential role for thymocyte development and activation
  • plays a critical role in T cell activation by controlling production of IL-2
  • cooperates with MAP3K3 leading to NF-kappaB activation
  • plays an essential role in activation of JNK/MAPK14
  • work as a common mediator for NF-kappaB and MAPK pathways and with TNF, may be involved in the pathogenesis of endometriosis
  • a novel player uniting inflammation and ROS regulation in skin redox biology (
  • is a central target for short-term inhibition of key signaling pathways and neuroprotection in cerebral ischemia
  • is an essential regulator of dendritic cell survival and immune system homeostasis and function
  • orchestrates a prosurvival program in DCs by regulating expression of apoptotic molecules and further links them with expression of immune response genes
  • required for tumor cell viability
  • is potentially an important modulator of both apoptosis and necroptosis
  • is a key regulator of receptor crosstalk between BCR and TLR9, thus playing a critical role in B cell development and activation
  • regulates hepatic lipid metabolism and tumorigenesis via the AMPK/MTOR axis, affecting both autophagy and PPARA activity
  • novel role for the MAP3K7-JNK pathway as a critical regulator of NLRP3 inflammasome activation
  • is a key regulator of several cell signaling pathways that coordinately regulate osteogenesis
  • is required to insure the normal organization of chondrocytes in the growth plate, and also plays a major role in articular cartilage development
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS inflammation
    text inflammatory mediator
    PATHWAY
    metabolism
    signaling signal transduction
  • IL1, TNF, JNK, BMP, KGF, NF-kappa B signaling pathways
  • transforming growth factor-beta-activated kinase (MAP3K7)-Nemo-like kinase (NLK) pathway negatively regulates FOXO1
    • a component
  • complex MAP3K7-MAP3K7IP1, MAP3K7IP2 (TAB1, TAB2) (protein kinase complex)and complex TAB1-TAB3
  • forming a complex with TAB2 and NLK, which may constitutive a negative feedback mechanism for canonical Wnt signaling
  • part of ECSIT complex, including MAP3K7 and TRAF6, playing a pivotal role in TLR4-mediated signals to activate NFKB1
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • repeat-1 response elements (RE) and RIP-140 (
  • TNF receptor-associated factor 6, E3 ubiquitin protein ligase, TRAF6 (
  • IKKalpha and IKKbeta (
  • Smad6 (
  • NIK and IKK2 (
  • PP2Cbeta-1 (
  • hepatocyte growth factor-regulated tyrosine kinase substrate, HGS (
  • Raf kinase inhibitor protein, RKIP (
  • XIAP, NAIP, and JNK1 (
  • ILPIP and XIAP (
  • TRAF6,TAB1, TAB2 (
  • PP2Cepsilon (
  • Smad7 (
  • TLR3-TRAF6-TAK1-TAB2-PKR complex (
  • TAK1-binding protein-3, TAB3 (
  • Sef (
  • Signal transducer and activator of transcription 3, STAT3 (
  • TNF-alpha receptor complex and MEKK3 (
  • CARMA1 (
  • Suppressor of cytokine signaling (SOCS)-3, SOCS-3 (
  • TAB1 is constitutively associated with MAP3K7 through its C-terminal region
  • ubiquitin-conjugating enzyme complex consisting of UBE2N and UBE2V1 catalyses Lys 63-linked polyubiquitination, which activates the MAP3K7 kinase complex
  • USP4 is a deubiquitinase for MAP3K7
  • TRIM8 interacted with MAP3K7, a serine/threonine kinase essential for TNF- and IL1B–induced NFKB activation
  • FYB regulating T cell receptor-mediated activation of integrins via association with the SKAP1 adapter and the NFKB1 pathway through interactions with both the CARD11 adapter and MAP3K7
  • KRAS stimulates BMP7 secretion and BMP signaling, leading to MAP3K7 activation and enhancement of Wnt-dependent transcription
  • is indispensable to TNFSF11-induced osteoclastogenesis
  • DUSP14 interacted with MAP3K7 and this interaction was enhanced by TNF or IL1 stimulation
  • RPS6KB1 negatively regulates TLR-mediated signals by inhibiting MAP3K7 activity
  • TAB2 is a sensor of stress conditions in the liver and functions to protect the liver by activating the MAP3K7 pathway
  • NLK functions as a pivotal negative regulator in TNF-induced activation of NFKB1 via disrupting the interaction of MAP3K7 with IKBKB
  • ECSIT interacted with each protein and regulated MAP3K7 activity, leading to the activation of NFKB1
  • MAP3K7 regulates necroptotic signaling as well as CASP8-mediated apoptotic signaling through both NFKB1-dependent and -independent mechanisms
  • essential role for the adaptor protein TRADD in CASP8 activation and necrosome formation triggered by MAP3K7 inhibition
  • TNFAIP8L2 interacts with MAP3K7, a crucial regulatory molecule of inflammatory and immune signals, and consequently acts as a powerful negative regulator of MAP3K7
  • TRIM8 plays a deleterious role in pressure overload-induced cardiac hypertrophy by accelerating the activation of MAP3K7-dependent signaling pathways
  • IRAK4 activity regulates likely MAP3K7 and IKBKB activation, leading to the nuclear translocation of IRF5 and induction of inflammatory cytokines in human monocytes
  • mechanistically, USP19 interacted with MAP3K7 in a TNF or IL1B-dependent manner
  • GRAMD4 interacted with MAP3K7 to promote its protein degradation, thus, resulting in the inactivation of MAPK (Mitogen-activated protein kinase) and NFKB1 pathways
    • cell & other
    REGULATION
    activated by MAP4K4 (see symbol) in JNK signaling pathway
    IL1 or MAP3K7IP1 (TAK1 binding protein)
    TGFBeta (
    TAB1 (
    innate immune stimuli including bacterial components and proinflammatory cytokines such as interleukin-1 and TNF
    Bone morphogenetic protein 2, BMP2 (
    Receptor activator of NF-kappaB ligand, RANKL (
    ATM (
    Other phosphorylation of MAP2K6 (by ubiquitin activated MAP3K7)
    phosphorylated by IRAK at the plasma membrane and activated (TAK1) in the cytosol
    regulated by E3 ligase Itch and deubiquitinase Cyld (
    regulated through two unique, TAB1-dependent basal and TAB2-mediated stimuli-dependent mechanisms
    ASSOCIATED DISORDERS
    corresponding disease(s) FMTD2 , CSCF
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional   deletion    
    causes dysregulation of reactive oxygen species in keratinocytes, which is causally associated with skin inflammation
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerdigestivecolon
    MAP3K7 inhibition is a potential therapeutic strategy for a treatment-refractory subset of colon cancers exhibiting aberrant KRAS and Wnt pathway activation
    ANIMAL & CELL MODELS
  • TAK1-deficient mous embryonic fibroblasts demonstrated loss of responses to interleukin 1beta and tumor necrosis factor (
  • antigen-induced immune responses were considerably impaired in mice with B cell-specific TAK1 deficiency (
  • deletion of TAK1 in mouse T cells prevented the maturation of single-positive thymocytes displaying CD4 or CD8, leading to reduction of T cells in the peripheral tissues (
  • TAK1 deficiency in keratinocytes led to increased apoptosis in response to anoikis and TNF-&
    • 945; treatment and was associated with elevated ROS level (
  • epithelial-specific TAB1 and TAB2 double- but not TAB1 or TAB2 single-knockout mice phenocopied epithelial-specific TAK1 knockout mice
  • Ablation of both TAB1 and TAB2 diminished the activity of TAK1 in vivo and causes accumulation of ROS in the epithelial tissues
  • homozygous Tak1-deficient mice died early in embryonic development, at day 9.5