Available structures
PDBOrtholog search: PDBe RCSB
AliasesMAP3K8, COT, EST, ESTF, MEKK8, TPL2, Tpl-2, c-COT, AURA2, mitogen-activated protein kinase kinase kinase 8, Tpl2
External IDsOMIM: 191195 MGI: 1346878 HomoloGene: 3812 GeneCards: MAP3K8
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 10: 30.43 – 30.46 MbChr 18: 4.33 – 4.35 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

Mitogen-activated protein kinase kinase kinase 8 is an enzyme that in humans is encoded by the MAP3K8 gene.[5][6][7]


The gene was identified by its oncogenic transforming activity in cells. The encoded protein is a member of the serine/threonine-specific protein kinase family. This kinase can activate ERK1, ERK2 and p38 MAP kinases.[8][9] 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.[7] In mice, the gene is known as TPL2 and is a tumor-suppressor gene whose absence contributes to the development and progression of cancer.[10]


MAP3K8 has been shown to interact with AKT1,[11] CHUK,[12] NFKB2,[13] NFKB1,[13][14] C22orf25[15] and TNIP2.[16]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000107968 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024235 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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 361219. PMID 2072910.
  6. ^ 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.
  7. ^ a b "Entrez Gene: MAP3K8 mitogen-activated protein kinase kinase kinase 8".
  8. ^ Arthur JS, Ley SC (Sep 2013). "Mitogen-activated protein kinases in innate immunity". Nature Reviews Immunology. 13 (9): 679–92. doi:10.1038/nri3495. PMID 23954936. S2CID 12049695.
  9. ^ Pattison MJ, Mitchell O, Flynn HR, Chen CS, Yang HT, Ben-Addi H, Boeing S, Snijders AP, Ley SC (Sep 2016). "TLR and TNF-R1 activation of the MKK3/MKK6-p38α axis in macrophages is mediated by TPL-2 kinase". Biochemical Journal. 473 (18): 2845–61. doi:10.1042/BCJ20160502. PMC 5095906. PMID 27402796.
  10. ^ DeCicco-Skinner, Kathleen (2011). "Loss of tumor progression locus 2 (tpl2) enhances tumorigenesis and inflammation in two-stage skin carcinogenesis". Oncogene. 30 (4): 389–97. doi:10.1038/onc.2010.447. PMC 3460638. PMID 20935675.
  11. ^ 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 133991. PMID 12138205.
  12. ^ 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.
  13. ^ 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. S2CID 11683986.
  14. ^ 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. S2CID 4391108.
  15. ^ "Molecular Interaction Database". Archived from the original on 2006-05-06. Retrieved 2012-05-08.
  16. ^ Lang V, Symons A, Watton SJ, Janzen J, Soneji Y, Beinke S, Howell S, Ley SC (Jun 2004). "ABIN-2 forms a ternary complex with TPL-2 and NF-kappa B1 p105 and is essential for TPL-2 protein stability". Molecular and Cellular Biology. 24 (12): 5235–48. doi:10.1128/MCB.24.12.5235-5248.2004. PMC 419892. PMID 15169888.

Further reading