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Mitogen-activated protein kinase kinase kinase 8
Symbols MAP3K8; COT; EST; ESTF; FLJ10486; TPL2; Tpl-2; c-COT
External IDs OMIM191195 MGI1346878 HomoloGene3812 GeneCards: MAP3K8 Gene
RNA expression pattern
PBB GE MAP3K8 205027 s at tn.png
More reference expression data
Species Human Mouse
Entrez 1326 26410
Ensembl ENSG00000107968 ENSMUSG00000024235
UniProt P41279 Q3T9M0
RefSeq (mRNA) NM_005204 NM_007746
RefSeq (protein) NP_005195 NP_031772
Location (UCSC) Chr 10:
30.76 - 30.79 Mb
Chr 18:
4.33 - 4.35 Mb
PubMed search [1] [2]

Mitogen-activated protein kinase kinase kinase 8 is an enzyme that in humans is encoded by the MAP3K8 gene.[1][2][3]

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 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.[3]


MAP3K8 has been shown to interact with AKT1,[4] CHUK,[5] NFKB2[6] and NFKB1.[7][6]


  1. ^ 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". Mol Cell Biol 11 (8): 4088–96. PMID 2072910.  
  2. ^ 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.  
  3. ^ a b "Entrez Gene: MAP3K8 mitogen-activated protein kinase kinase kinase 8".  
  4. ^ Kane, Lawrence P; Mollenauer Marianne N, Xu Zheng, Turck Christoph W, Weiss Arthur (Aug. 2002). "Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription". Mol. Cell. Biol. (United States) 22 (16): 5962–74. ISSN 0270-7306. PMID 12138205.  
  5. ^ Lin, X; Cunningham E T, Mu Y, Geleziunas R, Greene W C (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 (UNITED STATES) 10 (2): 271–80. ISSN 1074-7613. PMID 10072079.  
  6. ^ a b Bouwmeester, Tewis; Bauch Angela, Ruffner Heinz, Angrand Pierre-Olivier, Bergamini Giovanna, Croughton Karen, Cruciat Cristina, Eberhard Dirk, Gagneur Julien, Ghidelli Sonja, Hopf Carsten, Huhse Bettina, Mangano Raffaella, Michon Anne-Marie, Schirle Markus, Schlegl Judith, Schwab Markus, Stein Martin A, Bauer Andreas, Casari Georg, Drewes Gerard, Gavin Anne-Claude, Jackson David B, Joberty Gerard, Neubauer Gitte, Rick Jens, Kuster Bernhard, Superti-Furga Giulio (Feb. 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nat. Cell Biol. (England) 6 (2): 97–105. doi:10.1038/ncb1086. ISSN 1465-7392. PMID 14755267.  
  7. ^ Belich, M P; Salmerón A, Johnston L H, Ley S C (Jan. 1999). "TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105". Nature (ENGLAND) 397 (6717): 363–8. doi:10.1038/16946. ISSN 0028-0836. PMID 9950430.  

Further reading

  • Aoki M, Akiyama T, Miyoshi J, Toyoshima K (1991). "Identification and characterization of protein products of the cot oncogene with serine kinase activity.". Oncogene 6 (9): 1515–9. PMID 1833717.  
  • Aoki M, Hamada F, Sugimoto T, et al. (1993). "The human cot proto-oncogene encodes two protein serine/threonine kinases with different transforming activities by alternative initiation of translation.". J. Biol. Chem. 268 (30): 22723–32. PMID 8226782.  
  • Salmeron A, Ahmad TB, Carlile GW, et al. (1996). "Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase.". Embo J. 15 (4): 817–26. PMID 8631303.  
  • Ballester A, Tobeña R, Lisbona C, et al. (1997). "Cot kinase regulation of IL-2 production in Jurkat T cells.". J. Immunol. 159 (4): 1613–8. PMID 9257820.  
  • Ballester A, Velasco A, Tobeña R, Alemany S (1998). "Cot kinase activates tumor necrosis factor-alpha gene expression in a cyclosporin A-resistant manner.". J. Biol. Chem. 273 (23): 14099–106. doi:10.1074/jbc.273.23.14099. PMID 9603908.  
  • Lin X, Mu Y, Cunningham ET, et al. (1998). "Molecular determinants of NF-kappaB-inducing kinase action.". Mol. Cell. Biol. 18 (10): 5899–907. PMID 9742107.  
  • Belich MP, Salmerón A, Johnston LH, Ley SC (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.  
  • Lin X, Cunningham ET, Mu Y, et al. (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.  
  • Chiariello M, Marinissen MJ, Gutkind JS (2000). "Multiple mitogen-activated protein kinase signaling pathways connect the cot oncoprotein to the c-jun promoter and to cellular transformation.". Mol. Cell. Biol. 20 (5): 1747–58. doi:10.1128/MCB.20.5.1747-1758.2000. PMID 10669751.  
  • Sánchez-Góngora E, Lisbona C, de Gregorio R, et al. (2000). "COT kinase proto-oncogene expression in T cells: implication of the JNK/SAPK signal transduction pathway in COT promoter activation.". J. Biol. Chem. 275 (40): 31379–86. doi:10.1074/jbc.M000382200. PMID 10896655.  
  • Luftig MA, Cahir-McFarland E, Mosialos G, Kieff E (2001). "Effects of the NIK aly mutation on NF-kappaB activation by the Epstein-Barr virus latent infection membrane protein, lymphotoxin beta receptor, and CD40.". J. Biol. Chem. 276 (18): 14602–6. doi:10.1074/jbc.C100103200. PMID 11278268.  
  • Eliopoulos AG, Davies C, Blake SS, et al. (2002). "The oncogenic protein kinase Tpl-2/Cot contributes to Epstein-Barr virus-encoded latent infection membrane protein 1-induced NF-kappaB signaling downstream of TRAF2.". J. Virol. 76 (9): 4567–79. doi:10.1128/JVI.76.9.4567-4579.2002. PMID 11932422.  
  • Kane LP, Mollenauer MN, Xu Z, et al. (2002). "Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription.". Mol. Cell. Biol. 22 (16): 5962–74. doi:10.1128/MCB.22.16.5962-5974.2002. PMID 12138205.  
  • Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMID 12477932.  
  • Waterfield MR, Zhang M, Norman LP, Sun SC (2003). "NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase.". Mol. Cell 11 (3): 685–94. doi:10.1016/S1097-2765(03)00070-4. PMID 12667451.  
  • Channavajhala PL, Wu L, Cuozzo JW, et al. (2004). "Identification of a novel human kinase supporter of Ras (hKSR-2) that functions as a negative regulator of Cot (Tpl2) signaling.". J. Biol. Chem. 278 (47): 47089–97. doi:10.1074/jbc.M306002200. PMID 12975377.  
  • Gándara ML, López P, Hernando R, et al. (2003). "The COOH-terminal domain of wild-type Cot regulates its stability and kinase specific activity.". Mol. Cell. Biol. 23 (20): 7377–90. doi:10.1128/MCB.23.20.7377-7390.2003. PMID 14517305.  
  • Bouwmeester T, Bauch A, Ruffner H, et al. (2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.". Nat. Cell Biol. 6 (2): 97–105. doi:10.1038/ncb1086. PMID 14743216.  


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