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    MAP3K8 mitogen-activated protein kinase kinase kinase 8 [ Homo sapiens (human) ]

    Gene ID: 1326, updated on 14-Nov-2024

    Summary

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    Official Symbol
    MAP3K8provided by HGNC
    Official Full Name
    mitogen-activated protein kinase kinase kinase 8provided by HGNC
    Primary source
    HGNC:HGNC:6860
    See related
    Ensembl:ENSG00000107968 MIM:191195; AllianceGenome:HGNC:6860
    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
    COT; EST; ESTF; TPL2; AURA2; MEKK8; Tpl-2; c-COT
    Summary
    This gene is an oncogene that encodes a member of the serine/threonine protein kinase family. The encoded protein localizes to the cytoplasm and can activate both the MAP kinase and JNK kinase pathways. This protein was shown to activate IkappaB kinases, and thus induce the nuclear production of NF-kappaB. This protein was also found to promote the production of TNF-alpha and IL-2 during T lymphocyte activation. This gene may also utilize a downstream in-frame translation start codon, and thus produce an isoform containing a shorter N-terminus. The shorter isoform has been shown to display weaker transforming activity. Alternate splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Sep 2011]
    Expression
    Broad expression in bone marrow (RPKM 18.4), appendix (RPKM 6.8) and 17 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See MAP3K8 in Genome Data Viewer
    Location:
    10p11.23
    Exon count:
    13
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 10 NC_000010.11 (30434021..30461833)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 10 NC_060934.1 (30465061..30492876)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 10 NC_000010.10 (30722950..30750762)

    Chromosome 10 - NC_000010.11Genomic Context describing neighboring genes Neighboring gene NIFK pseudogene 1 Neighboring gene cyclin D3 pseudogene 1 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3209 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3210 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3211 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr10:30721100-30721981 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3212 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 2267 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3213 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr10:30724077-30724614 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3214 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr10:30724615-30725150 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3216 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3217 Neighboring gene heterogeneous nuclear ribonucleoprotein A1 pseudogene 32 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3218 Neighboring gene uncharacterized LOC105376478 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 3219 Neighboring gene H3K27ac hESC enhancer GRCh37_chr10:30827242-30827742 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr10:30841700-30842312 Neighboring gene Sharpr-MPRA regulatory region 6088

    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. TPL-2 MEK kinase is not targeted by mutation in diffuse large B cell lymphoma and myeloid leukemia. Shirali S, et al. Leuk Res, 2007 Nov. PMID 17324460
    2. A TPL2 (MAP3K8) disease-risk polymorphism increases TPL2 expression thereby leading to increased pattern recognition receptor-initiated caspase-1 and caspase-8 activation, signalling and cytokine secretion. Hedl M, et al. Gut, 2016 Nov. PMID 26215868, Free PMC Article
    3. The Crystal Structure of Cancer Osaka Thyroid Kinase Reveals an Unexpected Kinase Domain Fold. Gutmann S, et al. J Biol Chem, 2015 Jun 12. PMID 25918157, Free PMC Article
    4. Tumor progression locus 2 (Tpl2) kinase as a novel therapeutic target for cancer: double-sided effects of Tpl2 on cancer. Lee HW, et al. Int J Mol Sci, 2015 Feb 25. PMID 25723737, Free PMC Article
    5. Tpl2 induces castration resistant prostate cancer progression and metastasis. Lee HW, et al. Int J Cancer, 2015 May 1. PMID 25274482

    See all (136) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Spitz melanoma with MAP3K8::ABLIM1 rearrangement: a case report with review of the literature.
      Title: Spitz melanoma with MAP3K8::ABLIM1 rearrangement: a case report with review of the literature.
    2. The TRIM4 E3 ubiquitin ligase degrades TPL2 and is modulated by oncogenic KRAS.
      Title: The TRIM4 E3 ubiquitin ligase degrades TPL2 and is modulated by oncogenic KRAS.
    3. Clinical, Morphologic, and Molecular Features of MAP3K8 Rearranged Spitz Neoplasms: A Retrospective Study Documenting That Bonafide Spitz Melanomas Are Rare.
      Title: Clinical, Morphologic, and Molecular Features of MAP3K8 Rearranged Spitz Neoplasms: A Retrospective Study Documenting That Bonafide Spitz Melanomas Are Rare.
    4. Overexpression of TPL2 may be a predictor of good prognosis in patients with breast invasive ductal carcinoma.
      Title: Overexpression of TPL2 may be a predictor of good prognosis in patients with breast invasive ductal carcinoma.
    5. Tumor progression locus 2 (TPL2): A Cot-plicated progression from inflammation to chronic liver disease.
      Title: Tumor progression locus 2 (TPL2): A Cot-plicated progression from inflammation to chronic liver disease.
    6. Epigenetic Regulation of MAP3K8 in EBV-Associated Gastric Carcinoma.
      Title: Epigenetic Regulation of MAP3K8 in EBV-Associated Gastric Carcinoma.
    7. ALKBH5/MAP3K8 axis regulates PD-L1+ macrophage infiltration and promotes hepatocellular carcinoma progression.
      Title: ALKBH5/MAP3K8 axis regulates PD-L1+ macrophage infiltration and promotes hepatocellular carcinoma progression.
    8. Loss of Tpl2 activates compensatory signaling and resistance to EGFR/MET dual inhibition in v-RAS transduced keratinocytes.
      Title: Loss of Tpl2 activates compensatory signaling and resistance to EGFR/MET dual inhibition in v-RAS transduced keratinocytes.
    9. Cell adhesion tunes inflammatory TPL2 kinase signal transduction.
      Title: Cell adhesion tunes inflammatory TPL2 kinase signal transduction.
    10. Unravelling the Impact of the Genetic Variant rs1042058 within the TPL2 Risk Gene Locus on Molecular and Clinical Disease Course Patients with Inflammatory Bowel Disease.
      Title: Unravelling the Impact of the Genetic Variant rs1042058 within the TPL2 Risk Gene Locus on Molecular and Clinical Disease Course Patients with Inflammatory Bowel Disease.
    Submit: New GeneRIF Correction See all GeneRIFs (96)

    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

    Associated conditions

    Description Tests
    Lung cancer
    MedGen: C0242379 OMIM: 211980 GeneReviews: Not available
    		not available

    EBI GWAS Catalog

    Description
    Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.
    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

    Clone Names

    • FLJ10486

    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 MAP kinase kinase kinase activity TAS
    Traceable Author Statement
    more info
    		  
    enables magnesium 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
    		  
    enables protein serine/threonine kinase activity TAS
    Traceable Author Statement
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in MAPK cascade IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in MAPK cascade IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in T cell costimulation TAS
    Traceable Author Statement
    more info
    		  
    involved_in positive regulation of inflammatory response IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in protein phosphorylation TAS
    Traceable Author Statement
    more info
    		 PubMed 
    Component Evidence Code Pubs
    is_active_in cytoplasm IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in cytosol IDA
    Inferred from Direct Assay
    more info
    		  
    located_in cytosol TAS
    Traceable Author Statement
    more info
    		  

    General protein information

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    Preferred Names
    mitogen-activated protein kinase kinase kinase 8
    Names
    Ewing sarcoma transformant
    augmented in rheumatoid arthritis 2
    cot (cancer Osaka thyroid) oncogene
    proto-oncogene c-Cot
    proto-oncogene serine/threoine protein kinase
    tumor progression locus 2
    NP_001231063.1
    NP_001307890.1
    NP_005195.2
    XP_016871198.1
    XP_016871199.1
    XP_016871203.1
    XP_047280578.1
    XP_047280579.1
    XP_047280580.1
    XP_054220805.1
    XP_054220806.1
    XP_054220807.1
    XP_054220808.1
    XP_054220809.1

    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_029984.2 RefSeqGene

      Range
      5165..32814
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_001244134.1 → NP_001231063.1  mitogen-activated protein kinase kinase kinase 8

      See identical proteins and their annotated locations for NP_001231063.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) differs in the 5' UTR compared to variant 1. Both variants 1 and 2 encode the same protein. Variants 1-3 encode the same protein.
      Source sequence(s)
      AK290320, AL161651, DB271664
      Consensus CDS
      CCDS7166.1
      UniProtKB/Swiss-Prot
      A8K2Q5, D3DRX1, P41279, Q14275, Q5T855, Q9HC81
      UniProtKB/TrEMBL
      B2R8A5, Q6FG25
      Related
      ENSP00000443610.1, ENST00000542547.5
      Conserved Domains (1) summary
      cd13995
      Location:133 → 388
      STKc_MAP3K8; Catalytic domain of the Serine/Threonine kinase, Mitogen-Activated Protein Kinase (MAPK) Kinase Kinase 8

    2. NM_001320961.2 → NP_001307890.1  mitogen-activated protein kinase kinase kinase 8

      Status: REVIEWED

      Source sequence(s)
      AL161651
      Consensus CDS
      CCDS7166.1
      UniProtKB/Swiss-Prot
      A8K2Q5, D3DRX1, P41279, Q14275, Q5T855, Q9HC81
      UniProtKB/TrEMBL
      B2R8A5, Q6FG25
      Related
      ENSP00000364470.1, ENST00000375321.1
      Conserved Domains (1) summary
      cd13995
      Location:133 → 388
      STKc_MAP3K8; Catalytic domain of the Serine/Threonine kinase, Mitogen-Activated Protein Kinase (MAPK) Kinase Kinase 8

    3. NM_005204.4 → NP_005195.2  mitogen-activated protein kinase kinase kinase 8

      See identical proteins and their annotated locations for NP_005195.2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the longest transcript. Variants 1-3 encode the same protein.
      Source sequence(s)
      AL161651
      Consensus CDS
      CCDS7166.1
      UniProtKB/Swiss-Prot
      A8K2Q5, D3DRX1, P41279, Q14275, Q5T855, Q9HC81
      UniProtKB/TrEMBL
      B2R8A5, Q6FG25
      Related
      ENSP00000263056.1, ENST00000263056.6
      Conserved Domains (1) summary
      cd13995
      Location:133 → 388
      STKc_MAP3K8; Catalytic domain of the Serine/Threonine kinase, Mitogen-Activated Protein Kinase (MAPK) Kinase Kinase 8

    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_000010.11 Reference GRCh38.p14 Primary Assembly

      Range
      30434021..30461833
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_047424624.1 → XP_047280580.1  mitogen-activated protein kinase kinase kinase 8 isoform X1

      UniProtKB/Swiss-Prot
      A8K2Q5, D3DRX1, P41279, Q14275, Q5T855, Q9HC81

    2. XM_047424623.1 → XP_047280579.1  mitogen-activated protein kinase kinase kinase 8 isoform X1

      UniProtKB/Swiss-Prot
      A8K2Q5, D3DRX1, P41279, Q14275, Q5T855, Q9HC81

    3. XM_047424622.1 → XP_047280578.1  mitogen-activated protein kinase kinase kinase 8 isoform X1

      UniProtKB/Swiss-Prot
      A8K2Q5, D3DRX1, P41279, Q14275, Q5T855, Q9HC81

    4. XM_017015709.3 → XP_016871198.1  mitogen-activated protein kinase kinase kinase 8 isoform X1

      UniProtKB/Swiss-Prot
      A8K2Q5, D3DRX1, P41279, Q14275, Q5T855, Q9HC81
      UniProtKB/TrEMBL
      B2R8A5, Q6FG25
      Conserved Domains (1) summary
      cd13995
      Location:133 → 388
      STKc_MAP3K8; Catalytic domain of the Serine/Threonine kinase, Mitogen-Activated Protein Kinase (MAPK) Kinase Kinase 8

    5. XM_017015710.1 → XP_016871199.1  mitogen-activated protein kinase kinase kinase 8 isoform X1

      UniProtKB/Swiss-Prot
      A8K2Q5, D3DRX1, P41279, Q14275, Q5T855, Q9HC81
      UniProtKB/TrEMBL
      B2R8A5, Q6FG25
      Conserved Domains (1) summary
      cd13995
      Location:133 → 388
      STKc_MAP3K8; Catalytic domain of the Serine/Threonine kinase, Mitogen-Activated Protein Kinase (MAPK) Kinase Kinase 8

    6. XM_017015714.2 → XP_016871203.1  mitogen-activated protein kinase kinase kinase 8 isoform X2

      Conserved Domains (1) summary
      cl21453
      Location:1 → 225
      PKc_like; Protein Kinases, catalytic domain

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060934.1 Alternate T2T-CHM13v2.0

      Range
      30465061..30492876
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054364833.1 → XP_054220808.1  mitogen-activated protein kinase kinase kinase 8 isoform X1

      UniProtKB/Swiss-Prot
      A8K2Q5, D3DRX1, P41279, Q14275, Q5T855, Q9HC81

    2. XM_054364831.1 → XP_054220806.1  mitogen-activated protein kinase kinase kinase 8 isoform X1

      UniProtKB/Swiss-Prot
      A8K2Q5, D3DRX1, P41279, Q14275, Q5T855, Q9HC81

    3. XM_054364830.1 → XP_054220805.1  mitogen-activated protein kinase kinase kinase 8 isoform X1

      UniProtKB/Swiss-Prot
      A8K2Q5, D3DRX1, P41279, Q14275, Q5T855, Q9HC81

    4. XM_054364832.1 → XP_054220807.1  mitogen-activated protein kinase kinase kinase 8 isoform X1

      UniProtKB/Swiss-Prot
      A8K2Q5, D3DRX1, P41279, Q14275, Q5T855, Q9HC81

    5. XM_054364834.1 → XP_054220809.1  mitogen-activated protein kinase kinase kinase 8 isoform X2

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    P41279.2 GenPept UniProtKB/Swiss-Prot:P41279

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