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

    Gene ID: 4216, updated on 14-Nov-2024

    Summary

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    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; AllianceGenome:HGNC:6856
    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
    mouse all
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    Genomic context

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    See MAP3K4 in Genome Data Viewer
    Location:
    6q26
    Exon count:
    29
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 6 NC_000006.12 (160991769..161117380)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 6 NC_060930.1 (162350255..162475786)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 6 NC_000006.11 (161412801..161538412)

    Chromosome 6 - NC_000006.12Genomic Context describing neighboring genes Neighboring gene plasminogen-like protein B Neighboring gene uncharacterized LOC112267969 Neighboring gene OCT4-NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr6:161298543-161299475 Neighboring gene OCT4-NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr6:161303800-161304432 Neighboring gene MPRA-validated peak6293 silencer Neighboring gene MPRA-validated peak6294 silencer Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chr6:161309865-161310670 Neighboring gene MPRA-validated peak6295 silencer Neighboring gene uncharacterized LOC105378093 Neighboring gene uncharacterized LOC102724087 Neighboring gene Sharpr-MPRA regulatory region 6130 Neighboring gene NANOG-H3K27ac hESC enhancer GRCh37_chr6:161396855-161397569 Neighboring gene MPRA-validated peak6299 silencer Neighboring gene ATAC-STARR-seq lymphoblastoid active region 25407 Neighboring gene H3K27ac hESC enhancer GRCh37_chr6:161412339-161413208 Neighboring gene Sharpr-MPRA regulatory region 85 Neighboring gene NANOG hESC enhancer GRCh37_chr6:161422459-161422960 Neighboring gene MAP3K4 antisense RNA 1 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 25409 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 25410 Neighboring gene MPRA-validated peak6300 silencer Neighboring gene MED14-independent group 3 enhancer GRCh37_chr6:161500530-161501729 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 25411 Neighboring gene BRD4-independent group 4 enhancer GRCh37_chr6:161549261-161550460 Neighboring gene Sharpr-MPRA regulatory region 15502 Neighboring gene uncharacterized LOC124901455 Neighboring gene H3K27ac hESC enhancer GRCh37_chr6:161579309-161579810 Neighboring gene H3K27ac hESC enhancer GRCh37_chr6:161579811-161580310 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr6:161581716-161582274 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr6:161582962-161583462 Neighboring gene 1-acylglycerol-3-phosphate O-acyltransferase 4 Neighboring gene AGPAT4 intronic transcript 1

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: HPA RNA-seq normal tissues 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

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    Related articles in PubMed

    1. Role of mitogen-activated protein kinase kinase 4 in cancer. Whitmarsh AJ, et al. Oncogene, 2007 May 14. PMID 17496914
    2. Identification of MAP3K4 as a novel regulation factor of hepatic lipid metabolism in non-alcoholic fatty liver disease. He Z, et al. J Transl Med, 2022 Nov 14. PMID 36376950, Free PMC Article
    3. Association between MAP3K4 gene polymorphisms and the risk of schizophrenia susceptibility in a Northeast Chinese Han population. Sun Y, et al. Metab Brain Dis, 2022 Jun. PMID 35445959
    4. Incorporating age at onset of smoking into genetic models for nicotine dependence: evidence for interaction with multiple genes. Grucza RA, et al. Addict Biol, 2010 Jul. PMID 20624154, Free PMC Article
    5. Defective IL-1A expression in patients with Crohn's disease is related to attenuated MAP3K4 signaling. van der Pouw Kraan CT, et al. Hum Immunol, 2012 Sep. PMID 22732089

    See all (71) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. CircMAP3K4 Suppresses H2O2-Induced Human Lens Epithelial Cell Injury by miR-630/ERCC6 Axis in Age-Related Cataract.
      Title: CircMAP3K4 Suppresses H2O2-Induced Human Lens Epithelial Cell Injury by miR-630/ERCC6 Axis in Age-Related Cataract.
    2. CircMAP3K4 protects human lens epithelial cells from H2O2-induced dysfunction by targeting miR-193a-3p/PLCD3 axis in age-related cataract.
      Title: CircMAP3K4 protects human lens epithelial cells from H(2)O(2)-induced dysfunction by targeting miR-193a-3p/PLCD3 axis in age-related cataract.
    3. Identification of MAP3K4 as a novel regulation factor of hepatic lipid metabolism in non-alcoholic fatty liver disease.
      Title: Identification of MAP3K4 as a novel regulation factor of hepatic lipid metabolism in non-alcoholic fatty liver disease.
    4. Association between MAP3K4 gene polymorphisms and the risk of schizophrenia susceptibility in a Northeast Chinese Han population.
      Title: Association between MAP3K4 gene polymorphisms and the risk of schizophrenia susceptibility in a Northeast Chinese Han population.
    5. Coordinated regulation of Rel expression by MAP3K4, CBP, and HDAC6 controls phenotypic switching.
      Title: Coordinated regulation of Rel expression by MAP3K4, CBP, and HDAC6 controls phenotypic switching.
    6. A genome-wide analysis of targets of macrolide antibiotics in mammalian cells.
      Title: A genome-wide analysis of targets of macrolide antibiotics in mammalian cells.
    7. These mutations increase the binding of the RHOA, MAP3K4 and FRAT1 proteins and generally decrease the binding of RAC1. Thus, pathologies in MAP3K1 disrupt the balance between the pro-kinase activities of the RHOA and MAP3K4 binding partners and the inhibitory activity of RAC1.
      Title: Mutations in MAP3K1 that cause 46,XY disorders of sex development disrupt distinct structural domains in the protein.
    8. MAP3K4 was up-regulated and its expression was inversely correlated with collagen expression in the osteoblasts from older donors.
      Title: Activation of JNK signaling in osteoblasts is inversely correlated with collagen synthesis in age-related osteoporosis.
    9. IL-21 expression is promoted by MEKK4 in malignant T cells and is associated with progression risk in cutaneous T-cell lymphoma
      Title: The Expression of IL-21 Is Promoted by MEKK4 in Malignant T Cells and Associated with Increased Progression Risk in Cutaneous T-Cell Lymphoma.
    10. Mutations in genes such as AKT2, CCNA1, MAP3K4, and TGFBR1, were associated significantly with Epstein-Barr-positive gastric tumors, compared with EBV-negative tumors.
      Title: Integrative identification of Epstein-Barr virus-associated mutations and epigenetic alterations in gastric cancer.
    Submit: New GeneRIF Correction See all GeneRIFs (22)

    Phenotypes

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    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    EBI GWAS Catalog

    Description
    Linkage and association of successful aging to the 6q25 region in large Amish kindreds.
    EBI GWAS Catalog

    Variation

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    See Variation Viewer (GRCh37.p13)

    Pathways from PubChem

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    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Clone Names

    • FLJ42439, KIAA0213

    Gene Ontology Provided by GOA

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

    General protein information

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    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_001288001.2
    NP_001350511.2
    NP_005913.3
    NP_006715.3
    XP_047274739.1
    XP_054211427.1

    NCBI Reference Sequences (RefSeq)

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    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_001291958.2 → NP_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)
      AL109942, AL139393, AL591045, AL596452
      UniProtKB/Swiss-Prot
      Q9Y6R4
      Conserved Domains (2) summary
      smart00220
      Location:796 → 1054
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      cd06626
      Location:795 → 1054
      STKc_MEKK4; Catalytic domain of the Protein Serine/Threonine Kinase, Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 4

    2. NM_001301072.2 → NP_001288001.2  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)
      AL109942, AL139393, AL591045, AL596452
      Consensus CDS
      CCDS75544.1
      UniProtKB/TrEMBL
      F5H4R1, F5H538
      Related
      ENSP00000355887.2, ENST00000366920.6
      Conserved Domains (1) summary
      cd06626
      Location:1338 → 1597
      STKc_MEKK4; Catalytic domain of the Protein Serine/Threonine Kinase, Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 4

    3. NM_001363582.2 → NP_001350511.2  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
      Consensus CDS
      CCDS87464.1
      UniProtKB/TrEMBL
      F5H4R1, J3KNB8
      Related
      ENSP00000297332.10, ENST00000348824.11
      Conserved Domains (1) summary
      cd06626
      Location:1288 → 1547
      STKc_MEKK4; Catalytic domain of the Protein Serine/Threonine Kinase, Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 4

    4. NM_005922.4 → NP_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
      UniProtKB/Swiss-Prot
      A6H8W0, B7ZLD3, B9EG75, Q5VTT8, Q5VTT9, Q92612, Q9H408, Q9Y6R4
      UniProtKB/TrEMBL
      F5H4R1
      Related
      ENSP00000375986.4, ENST00000392142.9
      Conserved Domains (1) summary
      cd06626
      Location:1342 → 1601
      STKc_MEKK4; Catalytic domain of the Protein Serine/Threonine Kinase, Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 4

    5. NM_006724.4 → NP_006715.3  mitogen-activated protein kinase kinase kinase 4 isoform b

      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)
      AL109942, AL139393, AL591045, AL596452
      Consensus CDS
      CCDS34566.1
      UniProtKB/TrEMBL
      F5H4R1
      Related
      ENSP00000355886.2, ENST00000366919.6
      Conserved Domains (1) summary
      cd06626
      Location:1292 → 1551
      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_120425.2 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)
      AL109942, AL139393, AL591045, AL596452
      Related
      ENST00000544041.5

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

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

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000006.12 Reference GRCh38.p14 Primary Assembly

      Range
      160991769..161117380
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_047418783.1 → XP_047274739.1  mitogen-activated protein kinase kinase kinase 4 isoform X1

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060930.1 Alternate T2T-CHM13v2.0

      Range
      162350255..162475786
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054355452.1 → XP_054211427.1  mitogen-activated protein kinase kinase kinase 4 isoform X1

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q9Y6R4.2 GenPept UniProtKB/Swiss-Prot:Q9Y6R4

    Gene LinkOut

    The following LinkOut resources are supplied by external providers. These providers are responsible for maintaining the links.

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