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FLASH GENE
Symbol MAP3K1 contributors: mct/npt/pgu - updated : 15-10-2018
HGNC name mitogen-activated protein kinase kinase kinase 1
HGNC id 6848
Corresponding disease
XYDSDM 46,XY disorder of development, MAP3K1 related
Location 5q11.2      Physical location : 56.110.899 - 56.191.976
Synonym name
  • MEK kinase 1
  • MAP/ERK kinase kinase 1
    • Synonym symbol(s) MEKK1, MAP, ERK, MAPKKK1, MEKK
    EC.number 2.7.11.25
    DNA
    TYPE functioning gene
    STRUCTURE 81.08 kb     20 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
    20 - 7522 164.3 1512 - 2008 18984593
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Endocrinethyroid   highly
    Lymphoid/Immunelymph node   highly
    Reproductivefemale systemovary  highly
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal
    Text
  • highly expressed in the posterior of the developing eye and is required for retina development
  • highly expressed in the developing eyelid epithelium
    • PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a RING domain within its N-terminal regulatory region
  • a SWIM (SWI2/SNF2 and MuDR) domain, proximal to the RING domain, directly associating with the JUN DNA-binding domain, and required for MAP3K1-dependent JUN ubiquitylation
  • a kinase catalytic domain, hybrid between those of serine/threonine and tyrosine protein kinases
  • a PHD domain Ring-type zinc finger, required for JNK activation and efficient induction of apoptosis by drugs causing cytoskeletal disruption
  • a docking site, a stretch of about 20 amino acids immediately on the C-terminal side of the MAPKK catalytic domain
    • conjugated PhosphoP
    HOMOLOGY
    interspecies homolog to murine Map3k1
    homolog to C.elegans R13d11.7
    Homologene
    FAMILY
  • protein kinase superfamily
  • STE Ser/Thr protein kinase family
  • MAP kinase kinase kinase subfamily
    • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,cytoplasm,cytoskeleton
    text the cleaved 91kDa form is relocated from a particulate fraction to soluble cytoplasmic fraction
    basic FUNCTION
  • exercizing an antiapoptotic function as activator of C-Jun amino-terminal kinase (JNK) in response to changes in the microtubule cytoskeleton and extra signal-regulated protein kinase (ERK)
  • stimulating MADH2 mediated transcriptional activation in endothelial cells
  • acting as an E3 ubiquitin-ligase (by its PHD domain) and mediating ubiquitination and degradation of ERK1/2
  • involved in apoptosis as caspase-3 substrate and in the induction of apoptosis by genotoxins but not by microtubule altering drugs
  • important downstream component in the MAPK cascade that serves to integrate a variety of extracellular signals, and REG3A activity can be modulated through ERK signaling pathways by extracellular signals
  • required with TRAF6 by HSPPD2A to activate NF-kappaB and mitogen-activated protein kinases that are critical for the optimal induction of type I interferons
  • transmits wound signals, leading to the transcriptional activation of genes involved in extracellular matrix homeostasis, epithelial cell migration, and wound reepithelialization
  • involved in the canonical Wnt signalling pathway and positively regulates expression of Wnt target genes
  • activates the MAPK JNK and is required for microtubule inhibitor-induced apoptosis in B cells
  • novel role for MAP3K1 in which it crosstalks with the cell cycle regulatory pathways in the prevention of retina malformation and degeneration
  • integrates developmental signals for eyelid closure
  • potential roles of MAP3K1 in differentiation and lineage specification
  • both the MAP3K1 PHD and TAB1 are critical for ES-cell differentiation and tumourigenesis
  • potential crucial role of MAP3K1 in the development and function of inner ear and hearing
  • plays a major role in MAPK signaling, has been implicated in mechanical processes in cells, such as migration
    • CELLULAR PROCESS cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling signal transduction
  • importance of the MAP3K1-CNN3 signaling pathway to cell contractility
    • a component
    INTERACTION
    DNA
    RNA
    small molecule nucleotide,
  • ATP
    • protein
  • with CEBPB (activation for regulating gene expression)
  • binding ceramide
  • regulatory kinase for REG3A
  • physically interacted with CRTC1 and stimulated its nuclear translocation
  • interacting with STK10 (MAP3K1 and STK10 may have opposing roles in regulating the CD28RE/AP1 element of IL2)
  • AXIN1 inter-actor in JUN NH(2)-terminal kinase pathway
  • DCAF7 required to allow coupling of MAP3K1 to DYRK1 and HIPK2 (DCAF7 is a novel scaffold protein regulating kinase signalling by HIPK2 and MAP3K1)
  • forms with JUN, a regulatory axis that orchestrates morphogenesis by integrating two different networks of eyelid closure signals
  • MAP3K1 mediates TP53 protein stability in the presence of MDM2 and reduces TP53 ubiquitination, suggesting an interference with MDM2-mediated degradation of TP53 by the ubiquitin-proteasome pathway (26018553)
  • BAALC induced cell-cycle progression of leukemia cells by sustaining extracellular signal-regulated kinase (ERK) activity through an interaction with a scaffold protein MAP3K1, which inhibits the interaction between ERK and MAP kinase phosphatase 3 (MKP3/DUSP6)
  • COPS6 associates with MAP3K1 and reduces MAP3K1 expression level by facilitating the ubiquitin-mediated degradation of MAP3K1
  • MAP3K1 colocalizes with CNN3 at the actin cytoskeleton and phosphorylates it, leading to an increase in the cell-generated traction stress
    • cell & other
    REGULATION
    activated by autophosphorylation
    stress activated
    ASSOCIATED DISORDERS
    corresponding disease(s) XYDSDM
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional germinal mutation      
    mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination
    tumoral     --low  
    led to a potent inhibition on the invasion and migration of human pancreatic adenocarcinoma
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerdigestivepancreas
    may be a potential target for development of anti-invasion and metastasis drugs in pancreatic cancer
    ANIMAL & CELL MODELS
  • Mekk1 knockout mice; Map3k1 within the syntenic region was expressed in the embryonic mouse gonad prior to, and after, sex determination
  • mice lacking Map3k1 are fertile and exhibit no overt abnormalities of testis development
  • Map3K1-deficient mice exhibit increased proliferation and apoptosis, and Muller glial cell overproduction in the developing retinas