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FLASH GENE
Symbol MAP3K3 contributors: mct - updated : 26-05-2021
HGNC name mitogen-activated protein kinase kinase kinase 3
HGNC id 6855
Corresponding disease
CCM4 cerebral cavernous malformations 4
Location 17q23.3      Physical location : 61.699.800 - 61.773.669
Synonym name
  • MAP/ERK kinase kinase 3
  • MAPK/ERK kinase kinase 3
  • MEK kinase 3
    • Synonym symbol(s) MEKK3, MAPKKK3
    EC.number 2.7.11.25
    DNA
    TYPE functioning gene
    STRUCTURE 74.10 kb     17 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    16 - 4750 - 626 - 2018 29662197
  • isoform 2
    • 17 - 4843 - 657 - 2018 29662197
  • isoform 1
    • 17 - 4833 - 653 - 2018 29662197
    16 - 4740 - 622 - 2018 29662197
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Lymphoid/Immunelymph node    
    Respiratoryrespiratory tractlarynx   
    Skin/Tegumentskin   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectivebone  highly
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Lymphoid/ImmuneT cell Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • one OPR domain
  • one protein kinase domain
  • a PB1 domain in the N-terminus
  • a PPGY motif (AA 178-181), which may interact with YAP1
    • conjugated PhosphoP
    HOMOLOGY
    interspecies homolog to murine Map3k3 (96.6pc)
    homolog to C.elegans F59a3.8
    homolog to rattus Map3k3 (96.3pc)
    Homologene
    FAMILY
  • protein kinase superfamily
  • STE ser/thr protein kinase family
  • MAP (mitogen-activated protein) kinase kinase kinase subfamily
    • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus
    basic FUNCTION
  • serine/threonine protein kinase activating SEK and MEK
  • RIPK1-dependent recruitment of MAP3K3 plays a specific role in TNF-alpha signaling
  • may enhance transcription
  • mediates activation of the NFKappaB, AP1 and DDIT3 transcriptional regulators
  • is required for T cell immunity
  • specific role of MAP3K3 in mediating the TCR signals for IFNG production
  • CCM2/MAP3K3-mediated regulation of RHO signalling is required for maintenance of neurovascular integrity
  • plays an intrinsic role in embryonic vascular development
  • CCM2L and CCM2 cooperate to regulate the activity of MAP3K3
  • role of MAP3K3 in mediating NFKB1 signalling to promote the proliferation, invasion, migration, and chemotherapeutic resistance of ovarian carcinoma cells
  • is known to accelerate the RAS pathway of cellular proliferation
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling signal transduction
    ERK and SAPK pathway
    a component
  • ternary complex CCM1/CCM2/MAP3K3
  • associating with SQSTM1 in a complex and regulating NF-kappaB activation (Nakamura 2010)
    • INTERACTION
    DNA
    RNA
    small molecule cofactor, nucleotide,
  • ATP binding
  • cofactor Mg2+
    • protein
  • cooperates with MAP3K7, leading to NF-kappaB activation
  • interacting with MAP2K5 and SPAG9
  • activate the MAPK7 signal pathway by phosphorylating and activating MEK2K5 (Hu 2007)
  • MAP3K2 and MAP3K3 negatively regulated transforming growth factor-beta (TGFB1)-mediated Th cell differentiation
  • XIAP directly interacts with MAP3K3 and competes with PB1 domain-mediated binding to MAP2K5
  • harmonin homology domain (HHD)of CCM2 mediating interaction with the N terminus of MAP3K3
  • both CCM2L and CCM2 interfere with MAP3K3 activation and its ability to phosphorylate MAP2K5, a downstream target
  • specific interactions between YAP1 and proteins in the ERK5 pathway, such as MEK kinase 3 (MAP3K3) and MAPK7
    • cell & other
    REGULATION
    activated by phosphorylation
    the TLR and cellular stress pathways
    ASSOCIATED DISORDERS
    corresponding disease(s) CCM4
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in breast and ovarian cancer(leading to increased NFkappaB activity and increased expression of cell survival factors and ultimately contributing to their resistance to apoptosis)
    tumoral somatic mutation      
    in verrucous venous malformation (VVM), also called “verrucous hemangioma,”
    tumoral     --over  
    significantly increased in esophageal dysplasia and esophageal squamous cell carcinoma (ESCC) in comparison with normal mucosa
    tumoral     --over  
    in high-grade serous ovarian carcinoma
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerreproductivebreast
    may be a valuable therapeutic target in patients with MAP3K3-amplified breast cancers, and blocking MAP3K3 kinase activity with a small molecule inhibitor may sensitize MAP3K3-amplified breast cancer cells to chemotherapy
    cancer  
    therapeutic target to control cancer cell resistance to cytokine- or drug-induced apoptosis
    cancerdigestivepancreas
    silencing of MAP3K3 represents a valid approach to revert the aggressiveness of pancreatic cancer by modulating YAP1/TAZ transcriptional activities
    ANIMAL & CELL MODELS