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Symbol MAP3K5 contributors: mct - updated : 19-09-2019
HGNC name mitogen-activated protein kinase kinase kinase 5
HGNC id 6857
Location 6q23.3      Physical location : 136.878.187 - 137.113.656
Synonym name
  • apoptosis signal-regulating kinase 1
  • MAPK/ERK kinase kinase 5
  • extracellular signal-regulated kinase
  • MEK kinase 5
  • Synonym symbol(s) MAPKK1, MEK1, MEKK5, MAPKKK5, ASK1
    TYPE functioning gene
    STRUCTURE 235.47 kb     30 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    text structure a non-consensus E2F-binding site located 12 bp upstream of the transcription start site, the -95/+11 region critical for E2F-mediated up-regulation
    MAPPING cloned Y linked N status confirmed
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    30 - 5215 154 1374 - 2009 19004820
    Type ubiquitous
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Endocrineadrenal gland   highly
     pancreas   highly
     thyroid   highly
    Lymphoid/Immunelymph node   highly
    Reproductivemale systemprostate  highly
    Respiratoryrespiratory tracttrachea  highly
    Urinarybladder   moderately
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectiveadipose  predominantly
    cell lineage
    cell lines
    fluid/secretion highly in blood
    at STAGE
  • an N-terminal auto-inhibitory domain
  • a kinase catalytic domain with eleven kinases subdomains (hybrid between those of serine/threonine and tyrosine protein kinases)
  • a thioredoxin-binding domain
  • two distinct motifs, C-terminal and kinase domain, additively contribute to its repressive activity on 26 S proteasome (
  • conjugated PhosphoP
    mono polymer homomer , dimer , polymer
    interspecies homolog to murine Map3k5 (94.6 pc)
  • protein kinase superfamily
  • STE Ser/Thr protein kinase family
  • MAP kinase kinase kinase subfamily
  • CATEGORY enzyme , receptor membrane serine/threonine kinase
    SUBCELLULAR LOCALIZATION     intracellular
    basic FUNCTION
  • acting as a serine/threonine protein kinase and as an activator of p38 MAPK signaling cascades
  • involved in the caspase-independent pathway
  • phosphorylating and activating MAP2K4 and MAP2K6
  • activating c-jun terminal kinase (JNK)/stress activated protein kinase (SAPK), in response to TNF-alpha and FasL
  • phosphorylates cardiac troponin T to regulate cardiac contractile function
  • playing an essential role in cell death induced by ER stress
  • plays an essential role in stress and immune response and linked to the development of several diseases
  • with MAP3K6, are critically involved in tumorigenesis by differentially regulating apoptosis and inflammation
  • role in the regulation of 26 S proteasome
  • potentially acting as a novel binding partner of SMN and controls the steady-state level of SMN through complex formation with SMN in neurite outgrowth
  • contributes to apoptosis of plasma cells because MAP3K5 activity was induced during differentiation of short-lived plasma cells
  • promotes apoptosis of normal and malignant plasma cells
  • is regulated in response to the early inflammation phase and regulates the differentiation of Neural stem cells (NSCs) after inflammatory-inducing events, such as ischemic stroke
  • degradation of MAP3K5 mediated by RC3H2 is an evolutionarily conserved mechanism required for the appropriate regulation of stress responses, including pathogen resistance and cell death
  • role for MAP3K5 in regulating endochondral bone formation
  • may mediate the teratogenicity of diabetes through activating the JNK1/2-ER stress pathway and inhibiting cell cycle progression, thereby impeding the cardiogenesis pathways essential for ventricular septation and outflow tract development
  • regulates brown and beige adipocytes function
  • activity of MAP3K5 is triggered by various stress stimuli and is involved in the pathogenesis of cancer, neurodegeneration, inflammation, and diabetes
  • is an oxidative stress-responsive kinase that is regulated by various interacting molecules and post-translational modifications
  • CELLULAR PROCESS cell life, cell death/apoptosis
    text embryonic development
    signaling signal transduction
  • component of a protein kinase signal transduction cascade
  • MAP3K5 signalling axis is a regulator of brown and beige adipocyte gene expression and function
  • a component
  • homo-oligomerization
  • inactive homodimer
  • components of the two MAPK cascades, MAP3K5-MAP2K4-MAPK10 and c-Raf-1-MEK1-ERK2
    small molecule metal binding, nucleotide,
  • Mg2+
  • ATP
  • protein
  • TRAF family
  • PPP5C
  • ARBB2
  • DAXX
  • DUSP19
  • interacting with AKT2 and DAB2IP
  • binding to PKR
  • forming a complex with IGF1R
  • direct E2F1 target gene
  • interacts with PRDX1 via its thioredoxin-binding domain (interaction highly inducible by H2O2)(Kim 2008)
  • interacting with PGAM5 (associates with the MAP kinase kinase kinase MAP3K5 and acts as a specific protein Ser/Thr phosphatase that activates MAP3K5 by dephosphorylation of inhibitory sites)
  • association between MAP3K5 and STRAP is mediated through the C-terminal domain of MAP3K5 and the fourth and sixth WD40 repeats of STRAP
  • stabilizes SMN protein by inhibiting SMN poly-ubiquitination, and the kinase activity of MAP3K5 is less important than its ability to bind to SMN
  • ZNF622 physically interact with MAP3K5
  • NOTCH1-intracellular domain may act as a negative regulator in MAP3K5 signaling cascades
  • ARR3 binds MAPK10, MAP2K4, and MAP3K5
  • MAP3K5 a representative stress kinase, interacts with both GAPDH and SIAH1 and is likely able to phosphorylate Siah1 at specific amino acid residues
  • PPIA negatively regulates MAP3K5 functions by its physical interaction with MAP3K5
  • YWHAE interacts with the kinase domain of MAP3K5 in close proximity to its active site, thus indicating this interaction might block its accessibility and/or affect its conformation
  • TXN dissociates in response to oxidative stress allowing the MAP3K5 activation
  • the catalytic site of TXN interacts with MAP3K5-TXN-binding domain(TBD) region containing cysteine C200 and the oxidative stress induces intramolecular disulfide bond formation within MAP3K5-TBD
  • LRRK2 played an important role in neuronal cell death by directly phosphorylating and activating apoptosis signal-regulating kinase 1 (MAP3K5)
  • TRIM48 orchestrates the regulation of oxidative stress-induced MAP3K5 activation
  • TRIM48 facilitates MAP3K5 activation by promoting K48-linked polyubiquitination and degradation of PRMT1
  • TNFAIP3 is a key endogenous suppressor of MAP3K5 activation, and TNFAIP3 directly interacts with and deubiquitinates MAP3K5 in hepatocytes
  • MAP3K5, MAP3K6 was required for NLRP3 up-regulation after lipopolysaccharide treatment in primary bone marrow-derived macrophages and lung fibroblasts as well as during infection with Burkholderia thailandensis and influenza virus
  • BTRC and FBXW11 is capable of suppressing oxidative stress-induced CASP3-dependent apoptosis through suppression of MAP3K5, assisting in the organism's ability to maintain homeostasis in an unstable environment
  • cell & other
    activated by TRAF2, TRAF5, TRAF6 overexpression
    PPP3R1 through direct dephosphorylation
    phosphorylation at Thr-842
    various stress stimuli, including cytokines (TNF), serum deprivation, genotoxic chemicals, reactive oxygen species and agents that trigger ER stress
    induced by DAXX
    inhibited by IGF1R via its phosphorylation on a tyrosine residue, resulting in a decreased JNK1 stimulation
    HIV-1 Nef
    phosphorylation at Ser-966 and Ser-1033
    phosphorylation of serine 967 (promoting MAP3K5 binding to 14-3-3, an event associated with suppression of MAP3K5 function)
    Other regulated by reactive oxygen species through dephosphorylation
    phosphorylated by PIM1
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       gain of function
    activated in response to diverse stresses and apoptotic stimuli that participate in the pathogenesis and exacerbation of various diseases (
    tumoral somatic mutation      
    in metastatic melanoma
    Variant & Polymorphism
    Candidate gene
    Therapy target
    could be a new target for mechanistic approaches aimed at stabilizing proteasomal activity under various stresses
    could be a new target for mechanistic approaches aimed at stabilizing proteasomal activity under various
    therapeutic potential of MAP3K5 inhibition to reduce kidney injury and fibrosis
    respiratorylungchr.Bronchopathy obstructive
    MAP3K5 inhibition attenuates airway smooth muscle growth and migration in chronic obstructive pulmonary disease
    selective MAP3K5 inhibition confers anti-hypertrophic and anti-fibrotic effects in cardiac cells, and anti-inflammation in monocytic cells
    potential new molecular target for nonalcoholic steatohepatitis (NASH) therapy
    inhibition of MAP3K5 has clinical potential to treat fractures or to slow osteoarthritic progression by enhancing chondrocyte survival and slowing hypertrophy
  • activation of apoptosis signal regulating kinase 1 (MAP3K5) and translocation of death-associated protein, Daxx, in substantia nigra pars compacta in a mouse model of Parkinson's disease: protection by alpha-lipoic acid