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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
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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
Compare labs

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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