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    MAP3K6 mitogen-activated protein kinase kinase kinase 6 [ Homo sapiens (human) ]

    Gene ID: 9064, updated on 5-Mar-2024

    Summary

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    Official Symbol
    MAP3K6provided by HGNC
    Official Full Name
    mitogen-activated protein kinase kinase kinase 6provided by HGNC
    Primary source
    HGNC:HGNC:6858
    See related
    Ensembl:ENSG00000142733 MIM:604468; AllianceGenome:HGNC:6858
    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
    ASK2; MEKK6; MAPKKK6
    Summary
    This gene encodes a serine/threonine protein kinase that forms a component of protein kinase-mediated signal transduction cascades. The encoded kinase participates in the regulation of vascular endothelial growth factor (VEGF) expression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]
    Expression
    Broad expression in skin (RPKM 18.7), fat (RPKM 11.6) and 21 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    Location:
    1p36.11
    Exon count:
    30
    Annotation release Status Assembly Chr Location
    RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 1 NC_000001.11 (27355184..27366961, complement)
    RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 1 NC_060925.1 (27196422..27208199, complement)
    105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 1 NC_000001.10 (27681675..27693452, complement)

    Chromosome 1 - NC_000001.11Genomic Context describing neighboring genes Neighboring gene transmembrane protein 222 Neighboring gene actin gamma 1 pseudogene 20 Neighboring gene RNA, U6 small nuclear 48, pseudogene Neighboring gene ATAC-STARR-seq lymphoblastoid active region 543 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 544 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr1:27669148-27669765 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 545 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr1:27673548-27674088 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr1:27674089-27674627 Neighboring gene synaptotagmin like 1 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 508 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 509 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr1:27685945-27686480 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr1:27686481-27687016 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 546 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 510 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 511 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr1:27692433-27693376 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr1:27693377-27694318 Neighboring gene ficolin 3 Neighboring gene CD164 molecule like 2

    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
    • 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. Germline mutations in MAP3K6 are associated with familial gastric cancer. Gaston D, et al. PLoS Genet, 2014 Oct. PMID 25340522, Free PMC Article
    2. Heteromeric complex formation of ASK2 and ASK1 regulates stress-induced signaling. Ortner E, et al. Biochem Biophys Res Commun, 2007 Oct 19. PMID 17714688
    3. Structure-based mechanism of preferential complex formation by apoptosis signal-regulating kinases. Trevelyan SJ, et al. Sci Signal, 2020 Mar 10. PMID 32156783
    4. Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility. Weren RDA, et al. J Med Genet, 2018 Oct. PMID 29330337, Free PMC Article
    5. Dual engagement of 14-3-3 proteins controls signal relay from ASK2 to the ASK1 signalosome. Cockrell LM, et al. Oncogene, 2010 Feb 11. PMID 19935702

    See all (31) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Structure-based mechanism of preferential complex formation by apoptosis signal-regulating kinases.
      Title: Structure-based mechanism of preferential complex formation by apoptosis signal-regulating kinases.
    2. MAP3K6 should no longer be considered a gastric cancer (GC) predisposition gene, whereas deleterious CTNNA1 variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88 germline mutations are at most a very rare cause of GC susceptibility.
      Title: Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility.
    3. Data show that the MAPKKK6 ASK2, a modulator of MAPKKK5 ASK1 signaling, was essential for ASK1-dependent apoptosis, but not for inducing interferon-beta (IFNB) expression.
      Title: The ASK family kinases differentially mediate induction of type I interferon and apoptosis during the antiviral response.
    4. MAP3K6 acts as a tumor suppressor, and studies showing the presence of somatic mutations in MAP3K6 in non-hereditary gastric cancers and gastric cancer cell lines, point towards MAP3K6 variants as a predisposing factor for familial gastric cancer
      Title: Germline mutations in MAP3K6 are associated with familial gastric cancer.
    5. Observational study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator)
      Title: Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study.
    6. regulation of VEGF by MAP3K6 may play a crucial role in both angiogenesis and tumorigenesis.
      Title: Mitogen-activated protein 3 kinase 6 mediates angiogenic and tumorigenic effects via vascular endothelial growth factor expression.
    7. Observational study of gene-disease association. (HuGE Navigator)
      Title: Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.
    8. Apoptosis signal-regulating kinase (ASK) 2 functions as a mitogen-activated protein kinase kinase kinase in a heteromeric complex with ASK1.
      Title: Apoptosis signal-regulating kinase (ASK) 2 functions as a mitogen-activated protein kinase kinase kinase in a heteromeric complex with ASK1.
    Submit: New GeneRIF Correction

    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

    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

    • MGC20114, MGC125653

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables ATP binding IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables MAP kinase kinase kinase activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables MAP kinase kinase kinase activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables magnesium ion binding IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    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 IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in cellular response to stress IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in protein phosphorylation IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in signal transduction TAS
    Traceable Author Statement
    more info
    		 PubMed 

    General protein information

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    Preferred Names
    mitogen-activated protein kinase kinase kinase 6
    Names
    apoptosis signal-regulating kinase 2
    NP_001284538.1
    NP_004663.3
    XP_016858261.1
    XP_047289645.1
    XP_047289648.1
    XP_047289651.1
    XP_054195489.1
    XP_054195490.1
    XP_054195491.1
    XP_054195492.1

    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.

    Genomic

    1. NG_051309.1 RefSeqGene

      Range
      6077..17854
      Download
      GenBank, FASTA, Sequence Viewer (Graphics), LRG_1086

    mRNA and Protein(s)

    1. NM_001297609.2 → NP_001284538.1  mitogen-activated protein kinase kinase kinase 6 isoform 2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) lacks an alternate in-frame exon in the 5' coding region, compared to variant 1. The encoded isoform (2) is shorter than isoform 1.
      Source sequence(s)
      AB208805, AI658745, AW771625, FO393419
      Consensus CDS
      CCDS72738.1
      UniProtKB/Swiss-Prot
      O95382
      Related
      ENSP00000363152.2, ENST00000374040.7
      Conserved Domains (3) summary
      smart00220
      Location:645 → 898
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      cd06624
      Location:631 → 898
      STKc_ASK; Catalytic domain of the Serine/Threonine Kinase, Apoptosis signal-regulating kinase
      pfam13281
      Location:129 → 498
      DUF4071; Domain of unknown function (DUF4071)

    2. NM_004672.5 → NP_004663.3  mitogen-activated protein kinase kinase kinase 6 isoform 1

      See identical proteins and their annotated locations for NP_004663.3

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1).
      Source sequence(s)
      AB167411, AF100318, AW771625, FO393419
      Consensus CDS
      CCDS299.1
      UniProtKB/Swiss-Prot
      A2ACE8, A2VDG4, A2VDG5, O95382, Q59HF4, Q5SSD4, Q75PK3, Q96B75
      Related
      ENSP00000350195.2, ENST00000357582.3
      Conserved Domains (3) summary
      smart00220
      Location:653 → 906
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      cd06624
      Location:639 → 906
      STKc_ASK; Catalytic domain of the Serine/Threonine Kinase, Apoptosis signal-regulating kinase
      pfam13281
      Location:129 → 506
      DUF4071; Domain of unknown function (DUF4071)

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

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

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000001.11 Reference GRCh38.p14 Primary Assembly

      Range
      27355184..27366961 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_047433689.1 → XP_047289645.1  mitogen-activated protein kinase kinase kinase 6 isoform X1

      Related
      ENST00000493901.6

    2. XM_047433695.1 → XP_047289651.1  mitogen-activated protein kinase kinase kinase 6 isoform X3

    3. XM_047433692.1 → XP_047289648.1  mitogen-activated protein kinase kinase kinase 6 isoform X2

    4. XM_017002772.2 → XP_016858261.1  mitogen-activated protein kinase kinase kinase 6 isoform X4

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060925.1 Alternate T2T-CHM13v2.0

      Range
      27196422..27208199 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054339514.1 → XP_054195489.1  mitogen-activated protein kinase kinase kinase 6 isoform X1

    2. XM_054339516.1 → XP_054195491.1  mitogen-activated protein kinase kinase kinase 6 isoform X3

    3. XM_054339515.1 → XP_054195490.1  mitogen-activated protein kinase kinase kinase 6 isoform X2

    4. XM_054339517.1 → XP_054195492.1  mitogen-activated protein kinase kinase kinase 6 isoform X4

    Suppressed Reference Sequence(s)

    The following Reference Sequences have been suppressed. Explain

    1. NM_145319.1: Suppressed sequence

      Description
      NM_145319.1: This RefSeq record was removed by NCBI staff. Contact info@ncbi.nlm.nih.gov for further information.
    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    O95382.3 GenPept UniProtKB/Swiss-Prot:O95382

    Gene LinkOut

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

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