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

Gene ID: 4216, updated on 2-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
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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 variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Genotypes

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 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 protein phosphorylation IEA
Inferred from Electronic Annotation
more info
  
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.

Chemical Information
Molecular Biology Databases
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