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    MAP2K4 mitogen-activated protein kinase kinase 4 [ Homo sapiens (human) ]

    Gene ID: 6416, updated on 4-Jan-2025

    Summary

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    Official Symbol
    MAP2K4provided by HGNC
    Official Full Name
    mitogen-activated protein kinase kinase 4provided by HGNC
    Primary source
    HGNC:HGNC:6844
    See related
    Ensembl:ENSG00000065559 MIM:601335; AllianceGenome:HGNC:6844
    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
    JNKK; MEK4; MKK4; SEK1; SKK1; JNKK1; SERK1; MAPKK4; PRKMK4; SAPKK1; SAPKK-1
    Summary
    This gene encodes a member of the mitogen-activated protein kinase (MAPK) family. Members of this family act as an integration point for multiple biochemical signals and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation, and development. They form a three-tiered signaling module composed of MAPKKKs, MAPKKs, and MAPKs. This protein is phosphorylated at serine and threonine residues by MAPKKKs and subsequently phosphorylates downstream MAPK targets at threonine and tyrosine residues. A similar protein in mouse has been reported to play a role in liver organogenesis. A pseudogene of this gene is located on the long arm of chromosome X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
    Expression
    Ubiquitous expression in brain (RPKM 23.5), thyroid (RPKM 10.1) and 25 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See MAP2K4 in Genome Data Viewer
    Location:
    17p12
    Exon count:
    15
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 17 NC_000017.11 (12020877..12143828)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 17 NC_060941.1 (11928859..12051837)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 17 NC_000017.10 (11924194..12047145)

    Chromosome 17 - NC_000017.11Genomic Context describing neighboring genes Neighboring gene dynein axonemal heavy chain 9 Neighboring gene uncharacterized LOC124903928 Neighboring gene NANOG-H3K27ac hESC enhancer GRCh37_chr17:11879623-11880182 Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chr17:11894608-11895262 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr17:11900873-11901856 Neighboring gene H3K27ac hESC enhancer GRCh37_chr17:11923994-11924494 Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chr17:11949815-11950698 Neighboring gene ribosomal protein L21 pseudogene 122 Neighboring gene uncharacterized LOC124904155 Neighboring gene zinc finger protein 18 Neighboring gene RNA, U11 small nuclear 2, pseudogene Neighboring gene dynein light chain Tctex-type 1 pseudogene Neighboring gene microRNA 744 Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chr17:12125284-12125872 Neighboring gene ReSE screen-validated silencer GRCh37_chr17:12287658-12287861 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 11736 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr17:12358360-12358972 Neighboring gene Sharpr-MPRA regulatory region 9419 Neighboring gene uncharacterized LOC105371540 Neighboring gene long intergenic non-protein coding RNA 670 Neighboring gene BRD4-independent group 4 enhancer GRCh37_chr17:12533784-12534983 Neighboring gene H3K27ac hESC enhancer GRCh37_chr17:12540895-12541394 Neighboring gene H3K27ac hESC enhancer GRCh37_chr17:12591458-12591958 Neighboring gene H3K27ac hESC enhancer GRCh37_chr17:12591959-12592459 Neighboring gene Neanderthal introgressed variant-containing enhancer experimental_46971 Neighboring gene MYOCD antisense RNA 1 Neighboring gene myocardin

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: Tissue-specific circular RNA induction during human fetal development
    • Description: 35 human fetal samples from 6 tissues (3 - 7 replicates per tissue) collected between 10 and 20 weeks gestational time were sequenced using Illumina TruSeq Stranded Total RNA
    • BioProject: PRJNA270632
    • Publication: PMID 26076956
    • Analysis date: Mon Apr 2 22:54:59 2018

    Bibliography

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    Related articles in PubMed

    1. Functional variant (-1304T>G) in the MKK4 promoter is associated with decreased risk of acute myeloid leukemia in a southern Chinese population. Jiang L, et al. Cancer Sci, 2011 Aug. PMID 21518142
    2. Acetylation regulates the MKK4-JNK pathway in T cell receptor signaling. Matsui Y, et al. Immunol Lett, 2018 Feb. PMID 29248490
    3. MEK4 function, genistein treatment, and invasion of human prostate cancer cells. Xu L, et al. J Natl Cancer Inst, 2009 Aug 19. PMID 19638505, Free PMC Article
    4. Increased MKK4 abundance with replicative senescence is linked to the joint reduction of multiple microRNAs. Marasa BS, et al. Sci Signal, 2009 Oct 27. PMID 19861690, Free PMC Article
    5. Downregulation of phosphorylated MKK4 is associated with a poor prognosis in colorectal cancer patients. Wang PN, et al. Oncotarget, 2017 May 23. PMID 28423721, Free PMC Article

    See all (210) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Hsa_circ_0081069 facilitates tongue squamous cell carcinoma progression by modulating MAP2K4 expression via miR-634.
      Title: Hsa_circ_0081069 facilitates tongue squamous cell carcinoma progression by modulating MAP2K4 expression via miR-634.
    2. PCAT19 Regulates the Proliferation and Apoptosis of Lung Cancer Cells by Inhibiting miR-25-3p via Targeting the MAP2K4 Signal Axis.
      Title: PCAT19 Regulates the Proliferation and Apoptosis of Lung Cancer Cells by Inhibiting miR-25-3p via Targeting the MAP2K4 Signal Axis.
    3. Is there any correlation among MKK4 (mitogen-activated protein kinase kinase 4) expression, clinicopathological features, and KRAS/NRAS mutation in colorectal cancer.
      Title: Is there any correlation among MKK4 (mitogen-activated protein kinase kinase 4) expression, clinicopathological features, and KRAS/NRAS mutation in colorectal cancer.
    4. A new prognosis prediction model combining TNM stage with MAP2K4 and JNK in postoperative pancreatic cancer patients.
      Title: A new prognosis prediction model combining TNM stage with MAP2K4 and JNK in postoperative pancreatic cancer patients.
    5. Long noncoding RNA HNF1A-AS1 regulates proliferation and apoptosis of glioma through activation of the JNK signaling pathway via miR-363-3p/MAP2K4.
      Title: Long noncoding RNA HNF1A-AS1 regulates proliferation and apoptosis of glioma through activation of the JNK signaling pathway via miR-363-3p/MAP2K4.
    6. microRNA-124-3p inhibits tumourigenesis by targeting mitogen-activated protein kinase 4 in papillary thyroid carcinoma.
      Title: microRNA-124-3p inhibits tumourigenesis by targeting mitogen-activated protein kinase 4 in papillary thyroid carcinoma.
    7. MAP2K4 interacts with Vimentin to activate the PI3K/AKT pathway and promotes breast cancer pathogenesis.
      Title: MAP2K4 interacts with Vimentin to activate the PI3K/AKT pathway and promotes breast cancer pathogenesis.
    8. The ensemble structures provided more detailed mechanisms for regulating MAP2K4 in addition to those delineated only by the crystal structures in three states.
      Title: Ensemble structural analyses depict the regulatory mechanism of non-phosphorylated human MAP2K4.
    9. The initial characterization of tumor-suppressing kinases- in particular members of the protein kinase C (PKC) family, MKK4 of the mitogen-activated protein kinase kinase family, and DAPK3 of the death-associated protein kinase family- laid the foundation for bioinformatic approaches that enable the identification of other tumor-suppressing kinases.
      Title: Orange is the new black: Kinases are the new master regulators of tumor suppression.
    10. high MKK4 expression and its combination with high MKK7 expression both predicted favorable prognosis in resectable pancreatic ductal adenocarcinoma.
      Title: Clinicopathological and prognostic significance of MKK4 and MKK7 in resectable pancreatic ductal adenocarcinoma.
    Submit: New GeneRIF Correction See all GeneRIFs (104)

    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
    Genome-wide association study of d-amphetamine response in healthy volunteers identifies putative associations, including cadherin 13 (CDH13).
    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)

    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

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables ATP binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables JUN kinase kinase activity TAS
    Traceable Author Statement
    more info
    		  
    enables MAP kinase kinase activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables histone H2AXY142 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H3Y41 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables molecular adaptor activity EXP
    Inferred from Experiment
    more info
    		 PubMed 
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables protein kinase activity TAS
    Traceable Author Statement
    more info
    		 PubMed 
    enables protein serine kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables protein serine/threonine kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    Process Evidence Code Pubs
    involved_in Fc-epsilon receptor signaling pathway TAS
    Traceable Author Statement
    more info
    		  
    involved_in JNK cascade TAS
    Traceable Author Statement
    more info
    		  
    involved_in MAPK cascade IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in cell growth involved in cardiac muscle cell development IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in cellular response to mechanical stimulus IEP
    Inferred from Expression Pattern
    more info
    		 PubMed 
    involved_in cellular response to sorbitol IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in cellular senescence TAS
    Traceable Author Statement
    more info
    		  
    involved_in chromatin remodeling IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in intrinsic apoptotic signaling pathway in response to hydrogen peroxide IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in negative regulation of motor neuron apoptotic process IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in positive regulation of DNA replication IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in positive regulation of JNK cascade IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in positive regulation of neuron apoptotic process IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in response to wounding IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in signal transduction TAS
    Traceable Author Statement
    more info
    		 PubMed 
    involved_in smooth muscle cell apoptotic process IEA
    Inferred from Electronic Annotation
    more info
    		  
    Component Evidence Code Pubs
    located_in axon IEA
    Inferred from Electronic Annotation
    more info
    		  
    located_in cytosol TAS
    Traceable Author Statement
    more info
    		  
    located_in dendrite cytoplasm IEA
    Inferred from Electronic Annotation
    more info
    		  
    located_in nucleus IEA
    Inferred from Electronic Annotation
    more info
    		  
    located_in perikaryon IEA
    Inferred from Electronic Annotation
    more info
    		  

    General protein information

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    Preferred Names
    dual specificity mitogen-activated protein kinase kinase 4
    Names
    JNK-activated kinase 1
    JNK-activating kinase 1
    MAP kinase kinase 4
    MAPK/ERK kinase 4
    MAPKK 4
    MEK 4
    SAPK/ERK kinase 1
    c-Jun N-terminal kinase kinase 1
    c-Jun NH2-terminal kinase kinase 1
    stress-activated protein kinase kinase 1
    NP_001268364.1
    NP_003001.1
    XP_005256810.1
    XP_011522278.1
    XP_054172877.1
    XP_054172878.1

    NCBI Reference Sequences (RefSeq)

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    NEW Try the new Transcript table

    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.

    Genomic

    1. NG_033952.1 RefSeqGene

      Range
      5060..128011
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_001281435.2 → NP_001268364.1  dual specificity mitogen-activated protein kinase kinase 4 isoform 2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) contains an alternate in-frame exon in the 5' coding region compared to variant 1. It encodes isoform 2 which is longer compared to isoform 1.
      Source sequence(s)
      AC005244, AC005410, AK131544
      Consensus CDS
      CCDS62095.1
      UniProtKB/TrEMBL
      B4DH44
      Related
      ENSP00000410402.3, ENST00000415385.7
      Conserved Domains (1) summary
      cd06616
      Location:106 → 396
      PKc_MKK4; Catalytic domain of the dual-specificity Protein Kinase, Mitogen-activated protein Kinase Kinase 4

    2. NM_003010.4 → NP_003001.1  dual specificity mitogen-activated protein kinase kinase 4 isoform 1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) encodes isoform 1.
      Source sequence(s)
      AU150695, BC036032, BQ028457, L36870
      Consensus CDS
      CCDS11162.1
      UniProtKB/Swiss-Prot
      B2R7N7, B3KYB2, D3DTS5, P45985, Q5U0B8, Q6FHX4, Q6P9H2, Q6PIE6
      UniProtKB/TrEMBL
      B4DH44
      Related
      ENSP00000262445.5, ENST00000353533.10
      Conserved Domains (1) summary
      cd06616
      Location:95 → 385
      PKc_MKK4; Catalytic domain of the dual-specificity Protein Kinase, Mitogen-activated protein Kinase Kinase 4

    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_000017.11 Reference GRCh38.p14 Primary Assembly

      Range
      12020877..12143828
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_011523976.3 → XP_011522278.1  dual specificity mitogen-activated protein kinase kinase 4 isoform X1

      Conserved Domains (2) summary
      smart00220
      Location:114 → 310
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      cl21453
      Location:106 → 309
      PKc_like; Protein Kinases, catalytic domain

    2. XM_005256753.4 → XP_005256810.1  dual specificity mitogen-activated protein kinase kinase 4 isoform X2

      UniProtKB/TrEMBL
      B7Z9Y5
      Conserved Domains (1) summary
      cd06616
      Location:1 → 267
      PKc_MKK4; Catalytic domain of the dual-specificity Protein Kinase, Mitogen-activated protein Kinase Kinase 4

    RNA

    1. XR_007065381.1 RNA Sequence

    2. XR_007065382.1 RNA Sequence

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060941.1 Alternate T2T-CHM13v2.0

      Range
      11928859..12051837
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054316902.1 → XP_054172877.1  dual specificity mitogen-activated protein kinase kinase 4 isoform X1

    2. XM_054316903.1 → XP_054172878.1  dual specificity mitogen-activated protein kinase kinase 4 isoform X2

      UniProtKB/TrEMBL
      B7Z9Y5

    RNA

    1. XR_008484871.1 RNA Sequence

    2. XR_008484872.1 RNA Sequence

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    P45985.1 GenPept UniProtKB/Swiss-Prot:P45985

    Gene LinkOut

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

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