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    MAP3K4 mitogen-activated protein kinase kinase kinase 4 [ Homo sapiens (human) ]

    Gene ID: 4216, updated on 15-Apr-2019

    Summary

    Official Symbol
    MAP3K4provided by HGNC
    Official Full Name
    mitogen-activated protein kinase kinase kinase 4provided by HGNC
    Primary source
    HGNC:HGNC:6856
    See related
    Ensembl:ENSG00000085511 MIM:602425
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    MTK1; MEKK4; MEKK 4; MAPKKK4; PRO0412
    Summary
    The central core of each mitogen-activated protein kinase (MAPK) pathway is a conserved cascade of 3 protein kinases: an activated MAPK kinase kinase (MAPKKK) phosphorylates and activates a specific MAPK kinase (MAPKK), which then activates a specific MAPK. While the ERK MAPKs are activated by mitogenic stimulation, the CSBP2 and JNK MAPKs are activated by environmental stresses such as osmotic shock, UV irradiation, wound stress, and inflammatory factors. This gene encodes a MAPKKK, the MEKK4 protein, also called MTK1. This protein contains a protein kinase catalytic domain at the C terminus. The N-terminal nonkinase domain may contain a regulatory domain. Expression of MEKK4 in mammalian cells activated the CSBP2 and JNK MAPK pathways, but not the ERK pathway. In vitro kinase studies indicated that recombinant MEKK4 can specifically phosphorylate and activate PRKMK6 and SERK1, MAPKKs that activate CSBP2 and JNK, respectively but cannot phosphorylate PRKMK1, an MAPKK that activates ERKs. MEKK4 is a major mediator of environmental stresses that activate the CSBP2 MAPK pathway, and a minor mediator of the JNK pathway. Several alternatively spliced transcripts encoding distinct isoforms have been described. [provided by RefSeq, May 2014]
    Expression
    Ubiquitous expression in testis (RPKM 9.3), endometrium (RPKM 7.2) and 25 other tissues See more
    Orthologs

    Genomic context

    See MAP3K4 in Genome Data Viewer
    Location:
    6q26
    Exon count:
    30
    Annotation release Status Assembly Chr Location
    109 current GRCh38.p12 (GCF_000001405.38) 6 NC_000006.12 (160991521..161117385)
    105 previous assembly GRCh37.p13 (GCF_000001405.25) 6 NC_000006.11 (161412816..161538417)

    Chromosome 6 - NC_000006.12Genomic Context describing neighboring genes Neighboring gene plasminogen-like protein B Neighboring gene uncharacterized LOC112267969 Neighboring gene uncharacterized LOC105378093 Neighboring gene uncharacterized LOC102724087 Neighboring gene AGPAT4 intronic transcript 1 Neighboring gene 1-acylglycerol-3-phosphate O-acyltransferase 4 Neighboring gene uncharacterized LOC105378094

    Genomic regions, transcripts, and products

    Expression

    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

    GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

    Pathways from BioSystems

    • Angiopoietin Like Protein 8 Regulatory Pathway, organism-specific biosystem (from WikiPathways)
      Angiopoietin Like Protein 8 Regulatory Pathway, organism-specific biosystemThe hepatic ANGPTL8 (Angiopoietin Like Protein 8) regulatory pathway represents an up-to-date curated interactive pathway for all of the interactions from the known regulators of ANGPTL8 and updated ...
    • DNA Damage Response (only ATM dependent), organism-specific biosystem (from WikiPathways)
      DNA Damage Response (only ATM dependent), organism-specific biosystemThis is the second pathway out of two pathways which deals with DNA damage response. It has two central gene products (ATM and TP53) which are connected with the first DNA damage response pathway. In...
    • EGF/EGFR Signaling Pathway, organism-specific biosystem (from WikiPathways)
      EGF/EGFR Signaling Pathway, organism-specific biosystemEpidermal growth factor receptor (EGFR) also known as ErbB1/HER1 is a member of the ErbB family of receptor tyrosine kinases which also includes ErbB2 (Neu, HER2), ErbB3 (HER3) and ErbB4 (HER4). Sev...
    • G13 Signaling Pathway, organism-specific biosystem (from WikiPathways)
      G13 Signaling Pathway, organism-specific biosystemThe G13 subunit is an alpha unit of heterotrimeric G proteins that regulates cell processes through the use of guanine nucleotide exchange factors. G13 regulates actin cytoskeletal remodeling in cell...
    • GnRH signaling pathway, organism-specific biosystem (from KEGG)
      GnRH signaling pathway, organism-specific biosystemGonadotropin-releasing hormone (GnRH) secretion from the hypothalamus acts upon its receptor in the anterior pituitary to regulate the production and release of the gonadotropins, LH and FSH. The GnR...
    • GnRH signaling pathway, conserved biosystem (from KEGG)
      GnRH signaling pathway, conserved biosystemGonadotropin-releasing hormone (GnRH) secretion from the hypothalamus acts upon its receptor in the anterior pituitary to regulate the production and release of the gonadotropins, LH and FSH. The GnR...
    • Insulin Signaling, organism-specific biosystem (from WikiPathways)
      Insulin Signaling, organism-specific biosystemInsulin signaling influences energy metabolism as well as growth. The presence of insulin signals the fed state, and this signal is passed via the AKT branch, which leads to the uptake of glucose fro...
    • Integrated Pancreatic Cancer Pathway, organism-specific biosystem (from WikiPathways)
      Integrated Pancreatic Cancer Pathway, organism-specific biosystemAn integrated pathway model which displays the protein-protein interactions (PPIs) among the relevant proteins for pancreatic cancer. This pathway is a collection of different mechanistic protein pat...
    • MAPK (JNK) signaling, organism-specific biosystem (from KEGG)
      MAPK (JNK) signaling, organism-specific biosystemFunctional set; Cellular processes; Cell signaling
    • MAPK (JNK) signaling, conserved biosystem (from KEGG)
      MAPK (JNK) signaling, conserved biosystemFunctional set; Cellular processes; Cell signaling
    • MAPK (p38) signaling, organism-specific biosystem (from KEGG)
      MAPK (p38) signaling, organism-specific biosystemFunctional set; Cellular processes; Cell signaling
    • MAPK (p38) signaling, conserved biosystem (from KEGG)
      MAPK (p38) signaling, conserved biosystemFunctional set; Cellular processes; Cell signaling
    • MAPK Signaling Pathway, organism-specific biosystem (from WikiPathways)
      MAPK Signaling Pathway, organism-specific biosystemThe mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals e...
    • MAPK signaling pathway, organism-specific biosystem (from KEGG)
      MAPK signaling pathway, organism-specific biosystemThe mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals e...
    • MAPK signaling pathway, conserved biosystem (from KEGG)
      MAPK signaling pathway, conserved biosystemThe mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals e...
    • p38 MAPK signaling pathway, organism-specific biosystem (from Pathway Interaction Database)
      p38 MAPK signaling pathway, organism-specific biosystem
      p38 MAPK signaling pathway

    Interactions

    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

    Markers

    Homology

    Clone Names

    • FLJ42439, KIAA0213

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    ATP binding IEA
    Inferred from Electronic Annotation
    more info
     
    MAP kinase kinase kinase activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    metal ion binding IEA
    Inferred from Electronic Annotation
    more info
     
    protein binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    protein serine/threonine kinase activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    Process Evidence Code Pubs
    MAPK cascade IEA
    Inferred from Electronic Annotation
    more info
     
    activation of MAPKK activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    activation of protein kinase activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    chorionic trophoblast cell differentiation IEA
    Inferred from Electronic Annotation
    more info
     
    intracellular signal transduction ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    male germ-line sex determination IEA
    Inferred from Electronic Annotation
    more info
     
    placenta development IEA
    Inferred from Electronic Annotation
    more info
     
    positive regulation of JUN kinase activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    positive regulation of p38MAPK cascade IDA
    Inferred from Direct Assay
    more info
    PubMed 
    positive regulation of telomerase activity IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    positive regulation of telomere capping IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    positive regulation of telomere maintenance via telomerase IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    regulation of gene expression IEA
    Inferred from Electronic Annotation
    more info
     
    response to UV-C IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    signal transduction by protein phosphorylation IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    stress-activated protein kinase signaling cascade IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    Component Evidence Code Pubs
    cytoplasm IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    cytoplasm IDA
    Inferred from Direct Assay
    more info
    PubMed 
    perinuclear region of cytoplasm IEA
    Inferred from Electronic Annotation
    more info
     

    General protein information

    Preferred Names
    mitogen-activated protein kinase kinase kinase 4
    Names
    MAP three kinase 1
    MAP/ERK kinase kinase 4
    MAPK/ERK kinase kinase 4
    MEK kinase 4
    SSK2/SSK22 MAP kinase kinase kinase, yeast, homolog of
    dJ473J16.1 (mitogen-activated protein kinase kinase kinase 4)
    predicted protein of HQ0412
    NP_001278887.1
    NP_001288001.1
    NP_006715.2
    XP_005267046.1
    XP_016866358.1

    NCBI Reference Sequences (RefSeq)

    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    mRNA and Protein(s)

    1. NM_001291958.1NP_001278887.1  mitogen-activated protein kinase kinase kinase 4 isoform c

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) contains an alternate exon compared to variant 1. The resulting isoform (c) has a shorter and distinct N-terminus compared to isoform a.
      Source sequence(s)
      AL591045, BC143750, BC146770
      UniProtKB/Swiss-Prot
      Q9Y6R4
      Conserved Domains (2) summary
      smart00220
      Location:7961054
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      cd06626
      Location:7951054
      STKc_MEKK4; Catalytic domain of the Protein Serine/Threonine Kinase, Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 4
    2. NM_001301072.1NP_001288001.1  mitogen-activated protein kinase kinase kinase 4 isoform d

      Status: REVIEWED

      Description
      Transcript Variant: This variant (5) lacks an in-frame segment of a coding exon, compared to variant 1, resulting in a shorter protein (isoform d) compared to isoform a.
      Source sequence(s)
      AF002715, AK307866, BC143743, BC146770, BE278366, BQ009477
      Consensus CDS
      CCDS75544.1
      UniProtKB/Swiss-Prot
      Q9Y6R4
      Related
      ENSP00000355887.2, ENST00000366920.6
      Conserved Domains (2) summary
      smart00220
      Location:13391597
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      cd06626
      Location:13381597
      STKc_MEKK4; Catalytic domain of the Protein Serine/Threonine Kinase, Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 4
    3. NM_001363582.1NP_001350511.1  mitogen-activated protein kinase kinase kinase 4 isoform e

      Status: REVIEWED

      Description
      Transcript Variant: This variant (6) uses an alternate in-frame splice junction and lacks an alternate in-frame exon compared to variant 1. The resulting isoform (e) has the same N- and C-termini but is shorter compared to isoform a.
      Source sequence(s)
      AL109942, AL139393, AL591045, AL596452, D86968
      Consensus CDS
      CCDS87464.1
      Conserved Domains (1) summary
      cd06626
      Location:12881547
      STKc_MEKK4; Catalytic domain of the Protein Serine/Threonine Kinase, Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 4
    4. NM_005922.4NP_005913.3  mitogen-activated protein kinase kinase kinase 4 isoform a

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) encodes the longest isoform (a).
      Source sequence(s)
      AL109942, AL139393, AL591045, AL596452
      Consensus CDS
      CCDS34565.1
      Related
      ENSP00000375986.4, ENST00000392142.9
      Conserved Domains (1) summary
      cd06626
      Location:13421601
      STKc_MEKK4; Catalytic domain of the Protein Serine/Threonine Kinase, Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 4
    5. NM_006724.3NP_006715.2  mitogen-activated protein kinase kinase kinase 4 isoform b

      See identical proteins and their annotated locations for NP_006715.2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) lacks an alternate in-frame exon compared to variant 1, resulting in a shorter protein (isoform b) compared to isoform a.
      Source sequence(s)
      AF002715, AF116604, AL591045, AL596452, BC146770, BQ009477
      Consensus CDS
      CCDS34566.1
      UniProtKB/Swiss-Prot
      Q9Y6R4
      UniProtKB/TrEMBL
      Q9P1M2
      Related
      ENSP00000355886.2, ENST00000366919.6
      Conserved Domains (2) summary
      smart00220
      Location:12931551
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      cd06626
      Location:12921551
      STKc_MEKK4; Catalytic domain of the Protein Serine/Threonine Kinase, Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 4

    RNA

    1. NR_120425.1 RNA Sequence

      Status: REVIEWED

      Description
      Transcript Variant: This variant (4) contains an alternate exon compared to variant 1. This variant is represented as non-coding because the use of the 5'-most expected translational start codon renders the transcript a candidate for nonsense-mediated mRNA decay (NMD).
      Source sequence(s)
      AL591045, BC143743, BC146770
      Related
      ENST00000544041.5

    RefSeqs of Annotated Genomes: Homo sapiens Annotation Release 109

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p12 Primary Assembly

    Genomic

    1. NC_000006.12 Reference GRCh38.p12 Primary Assembly

      Range
      160991521..161117385
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_017010869.1XP_016866358.1  mitogen-activated protein kinase kinase kinase 4 isoform X2

    2. XM_005266989.3XP_005267046.1  mitogen-activated protein kinase kinase kinase 4 isoform X1

      UniProtKB/TrEMBL
      J3KNB8
      Related
      ENSP00000297332.10, ENST00000348824.11

    RNA

    1. XR_001743422.2 RNA Sequence

    2. XR_002956284.1 RNA Sequence

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