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Available structures
PDB Ortholog search: PDBe RCSB
Aliases MAP3K8, COT, EST, ESTF, MEKK8, TPL2, Tpl-2, c-COT, AURA2, mitogen-activated protein kinase kinase kinase 8
External IDs MGI: 1346878 HomoloGene: 3812 GeneCards: 1326
Genetically Related Diseases
inflammatory bowel disease[1]
RNA expression pattern
PBB GE MAP3K8 205027 s at tn.png
More reference expression data
Species Human Mouse
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 10: 30.43 – 30.46 Mb Chr 18: 4.33 – 4.35 Mb
PubMed search [2] [3]
View/Edit Human View/Edit Mouse

Mitogen-activated protein kinase kinase kinase 8 is an enzyme that in humans is encoded by the MAP3K8 gene.[4][5][6]


This gene was identified by its oncogenic transforming activity in cells. The encoded protein is a member of the serine/threonine protein kinase family. This kinase can activate both the MAP kinase and JNK kinase pathways. This kinase was shown to activate IkappaB kinases, and thus induce the nuclear production of NF-kappaB. This kinase was also found to promote the production of TNF-alpha and IL-2 during T lymphocyte activation. Studies of a similar gene in rat suggested the direct involvement of this kinase in the proteolysis of NF-kappaB1,p105 (NFKB1). This gene may also start transcription at 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.[6] In mice, this gene is known as Tpl2 and it is a tumor suppressor gene whose absence contributes to the development and progression of cancer.[7]


MAP3K8 has been shown to interact with AKT1,[8] CHUK,[9] NFKB2,[10] NFKB1,[10][11] and C22orf25.[12]


  1. ^ "Diseases that are genetically associated with MAP3K8 view/edit references on wikidata". 
  2. ^ "Human PubMed Reference:". 
  3. ^ "Mouse PubMed Reference:". 
  4. ^ Miyoshi J, Higashi T, Mukai H, Ohuchi T, Kakunaga T (Aug 1991). "Structure and transforming potential of the human cot oncogene encoding a putative protein kinase". Molecular and Cellular Biology. 11 (8): 4088–96. doi:10.1128/mcb.11.8.4088. PMC 361219free to read. PMID 2072910. 
  5. ^ Chan AM, Chedid M, McGovern ES, Popescu NC, Miki T, Aaronson SA (May 1993). "Expression cDNA cloning of a serine kinase transforming gene". Oncogene. 8 (5): 1329–33. PMID 8479752. 
  6. ^ a b "Entrez Gene: MAP3K8 mitogen-activated protein kinase kinase kinase 8". 
  7. ^ DeCicco-Skinner, Kathleen. "Loss of tumor progression locus 2 (tpl2) enhances tumorigenesis and inflammation in two-stage skin carcinogenesis". 
  8. ^ Kane LP, Mollenauer MN, Xu Z, Turck CW, Weiss A (Aug 2002). "Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription". Molecular and Cellular Biology. 22 (16): 5962–74. doi:10.1128/MCB.22.16.5962-5974.2002. PMC 133991free to read. PMID 12138205. 
  9. ^ Lin X, Cunningham ET, Mu Y, Geleziunas R, Greene WC (Feb 1999). "The proto-oncogene Cot kinase participates in CD3/CD28 induction of NF-kappaB acting through the NF-kappaB-inducing kinase and IkappaB kinases". Immunity. 10 (2): 271–80. doi:10.1016/S1074-7613(00)80027-8. PMID 10072079. 
  10. ^ a b Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G (Feb 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nature Cell Biology. 6 (2): 97–105. doi:10.1038/ncb1086. PMID 14743216. 
  11. ^ Belich MP, Salmerón A, Johnston LH, Ley SC (Jan 1999). "TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105". Nature. 397 (6717): 363–8. doi:10.1038/16946. PMID 9950430. 
  12. ^ "Molecular Interaction Database". 

Further reading[edit]