Encyclopedia of Signaling Molecules

2012 Edition
| Editors: Sangdun Choi


  • Dimitra Virla
  • Christos Tsatsanis
  • Aristides G. Eliopoulos
Reference work entry
DOI: https://doi.org/10.1007/978-1-4419-0461-4_626


Historical Background

The Tpl2 gene, also known as Cot and MAP3K8 (Vougioukalaki et al. 2011), was independently discovered by three research teams in the early 1990s. Cot (Cancer Ozaka Thyroid) was initially described by Miyoshi et al. as a putative human proto-oncogene found to have a rearranged 3′ end in the last coding exon (Miyoshi et al. 1991). The rat homologue of Cot, named Tumor progression locus (Tpl2) was identified by Tsichlis et al. as a proto-oncogene that is activated by provirus integration in Moloney murine leukemia (MoMuLV) virus-induced T-cell lymphomas (Patriotis et al. 1993). In mice, the Tpl2 gene locus is also targeted by provirus insertion in mouse mammary tumor virus (MMTV)-associated mammary carcinomas (Erny et al. 1996). In both cases, provirus insertion occurs in the last intron of the gene and gives rise to a...
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  1. Aoki M, Hamada F, Sugimoto T, Sumida S, Akiyama T, Toyoshima K. The human cot proto-oncogene encodes two protein serine/threonine kinases with different transforming activities by alternative initiation of translation. J Biol Chem. 1993;268:22723–32.PubMedGoogle Scholar
  2. Banerjee A, Grumont R, Gugasyan R, White C, Strasser A, Gerondakis S. NF-kappaB1 and c-Rel cooperate to promote the survival of TLR4-activated B cells by neutralizing Bim via distinct mechanisms. Blood. 2008;112:5063–73.PubMedGoogle Scholar
  3. Beinke S, Deka J, Lang V, Belich MP, Walker PA, Howell S, Smerdon SJ, Gamblin SJ, Ley SC. NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activity. Mol Cell Biol. 2003;23:4739–52.PubMedGoogle Scholar
  4. Belich MP, Salmeron A, Johnston LH, Ley SC. Tpl-2 kinase regulates the proteolysis of the NF-kB-inhibitory protein NF-kB1 p105. Nature. 1999;397:363–8.PubMedGoogle Scholar
  5. Ceci JD, Patriotis CP, Tsatsanis C, Makris AM, Kovatch R, Swing DA, Jenkins NA, Tsichlis PN, Copeland NG. Tpl-2 is an oncogenic kinase that is activated by carboxy-terminal truncation. Genes Dev. 1997;11:688–700.PubMedGoogle Scholar
  6. Chiariello M, Marinissen MJ, Gutkind JS. Multiple mitogen-activated protein kinase signaling pathways connect the cot oncoprotein to the c-jun promoter and to cellular transformation. Mol Cell Biol. 2000;20:1747–58.PubMedGoogle Scholar
  7. Cho J, Melnick M, Solidakis GP, Tsichlis PN. Tpl2 (tumor progression locus 2) phosphorylation at Thr290 is induced by lipopolysaccharide via an Ikappa-B Kinase-beta-dependent pathway and is required for Tpl2 activation by external signals. J Biol Chem. 2005;280:20442–8.PubMedGoogle Scholar
  8. Choi HS, Kang BS, Shim JH, Cho YY, Choi BY, Bode AM, Dong Z. Cot, a novel kinase of histone H3, induces cellular transformation through up-regulation of c-fos transcriptional activity. FASEB J. 2008;22:113–26.PubMedGoogle Scholar
  9. Das S, Cho J, Lambertz I, Kelliher MA, Eliopoulos AG, Du K, Tsichlis PN. Tpl2/cot signals activate ERK, JNK, and NF-kappaB in a cell-type and stimulus-specific manner. J Biol Chem. 2005;280:23748–57.PubMedGoogle Scholar
  10. Decicco-Skinner KL, Trovato EL, Simmons JK, Lepage PK, Wiest JS. Loss of tumor progression locus 2 (tpl2) enhances tumorigenesis and inflammation in two-stage skin carcinogenesis. Oncogene. 2011;30:389–97.PubMedGoogle Scholar
  11. Dumitru CD, Ceci JD, Tsatsanis C, Kontoyiannis D, Stamatakis K, Lin JH, Patriotis C, Jenkins NA, Copeland NG, Kollias G, Tsichlis PN. TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell. 2000;103:1071–83.PubMedGoogle Scholar
  12. Eliopoulos AG, Dumitru CD, Wang C-C, Cho J, Tsichlis PN. Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals. EMBO J. 2002;21:4831–40.PubMedGoogle Scholar
  13. Eliopoulos AG, Wang CC, Dumitru CD, Tsichlis PN. Tpl2 transduces CD40 and TNF signals that activate ERK and regulates IgE induction by CD40. EMBO J. 2003;22:3855–64.PubMedGoogle Scholar
  14. Erny KM, Peli J, Lambert JF, Muller V, Diggelmann H. Involvement of the Tpl-2/cot oncogene in MMTV tumorigenesis. Oncogene. 1996;13:2015–20.PubMedGoogle Scholar
  15. Gandara ML, Lopez P, Hernando R, Castano JG, Alemany S. The COOH-terminal domain of wild-type Cot regulates its stability and kinase specific activity. Mol Cell Biol. 2003;23:7377–90.PubMedGoogle Scholar
  16. Gomez-Casero E, San-Antonio B, Iniguez MA, Fresno M. Cot/Tpl2 and PKCzeta cooperate in the regulation of the transcriptional activity of NFATc2 through the phosphorylation of its amino-terminal domain. Cell Signal. 2007;19:1652–61.PubMedGoogle Scholar
  17. Jager J, Gremeaux T, Gonzalez T, Bonnafous S, Debard C, Laville M, Vidal H, Tran A, Gual P, Le Marchand-Brustel Y, Cormont M, Tanti JF. Tpl2 kinase is upregulated in adipose tissue in obesity and may mediate interleukin-1beta and tumor necrosis factor-{alpha} effects on extracellular signal-regulated kinase activation and lipolysis. Diabetes. 2009;59:61–70.PubMedGoogle Scholar
  18. Jeong JH, Bhatia A, Z Z, Oh S, Inn KS, Liao CP, Roy-Burman P, et al. TPL2/COT/MAP3K8 (TPL2) activation promotes androgen depletion-independent (ADI) prostate cancer growth. PLoS One. 2011;6:e16205.Google Scholar
  19. Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, Emery CM, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468:968–72.PubMedGoogle Scholar
  20. Khanal P, Lee KY, Kang KW, Kang BS, Choi HS. Tpl-2 kinase downregulates the activity of p53 and enhances signaling pathways leading to activation of activator protein 1 induced by EGF. Carcinogenesis. 2009;30:682–9.PubMedGoogle Scholar
  21. Kontoyiannis D, Boulougouris G, Manoloukos M, Armaka M, Apostolaki M, Pizarro T, Kotlyarov A, Forster I, Flavell R, Gaestel M, Tsichlis P, Cominelli F, Kollias G. Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor-induced Crohn’s-like inflammatory bowel disease. J Exp Med. 2002;196:1563–74.PubMedGoogle Scholar
  22. Lin X, Cunningham ET, Mu Y, Geleziunas R, Greene WC. The proto-oncogene Cot kinase participates in CD3/CD28 induction of NF-kB acting through the NF-kB-inducing kinase and IkB kinases. Immunity. 1999;10:271–80.PubMedGoogle Scholar
  23. Mieulet V, Yan L, Choisy C, Sully K, Procter J, Kouroumalis A, Krywawych S, Pende M, Ley SC, Moinard C, Lamb RF. TPL-2-mediated activation of MAPK downstream of TLR4 signaling is coupled to arginine availability. Sci Signal. 2010;3:ra61.PubMedGoogle Scholar
  24. Miyoshi J, Higashi T, Mukai H, Ohuchi T, Kakunaga T. Structure and transforming potential of the human Cot oncogene encoding a putative protein kinase. Mol Cell Biol. 1991;11:4088–96.PubMedGoogle Scholar
  25. Ohnishi T, Okamoto A, Kakimoto K, Bandow K, Chiba N, Matsuguchi T. Involvement of Cot/Tp12 in bone loss during periodontitis. J Dent Res. 2010;89:192–7.PubMedGoogle Scholar
  26. Papoutsopoulou S, Symons A, Tharmalingham T, Belich MP, Kaiser F, Kioussis D, O'Garra, et al. ABIN-2 is required for optimal activation of Erk MAP kinase in innate immune responses. Nat Immunol. 2006;7:606–15.PubMedGoogle Scholar
  27. Patriotis C, Makris A, Bear SE, Tsichlis PN. Tumor progression locus 2 (Tpl-2) encodes a protein kinase involved in the progression of rodent T-cell lymphomas and in T-cell activation. Proc Natl Acad Sci USA. 1993;90:2251–5.PubMedGoogle Scholar
  28. Robinson MJ, Beinke S, Kouroumalis A, Tsichlis PN, Ley SC. Phosphorylation of TPL-2 on serine 400 is essential for lipopolysaccharide activation of extracellular signal-regulated kinase in macrophages. Mol Cell Biol. 2007;27:7355–64.PubMedGoogle Scholar
  29. Rousseau S, Papoutsopoulou M, Symons A, Cook D, Lucocq JM, Prescott AR, O’Garra A, Ley SC, Cohen P. TPL2-mediated activation of ERK1 and ERK2 regulates the processing of pre-TNF alpha in LPS-stimulated macrophages. J Cell Sci. 2008;121:149–54.PubMedGoogle Scholar
  30. Salmeron A, Ahmad TB, Carlile GW, Pappin D, Narsimhan RP, Ley SC. Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase. EMBO J. 1996;15:817–26.PubMedGoogle Scholar
  31. Stafford MJ, Morrice NA, Peggie MW, Cohen P. Interleukin-1 stimulated activation of the COT catalytic subunit through the phosphorylation of Thr290 and Ser62. FEBS Lett. 2006;580:4010–14.PubMedGoogle Scholar
  32. Sugimoto K, Ohata M, Miyoshi J, Ishizaki H, Tsuboi N, Masuda A, Yoshikai Y, et al. A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA-induced IL-12 production and Th cell differentiation. J Clin Invest. 2004;114:857–66.PubMedGoogle Scholar
  33. Tsatsanis C, Patriotis C, Bear SE, Tsichlis PN. The Tpl-2 protooncoprotein activates the nuclear factor of activated T cells and induces interleukin 2 expression in T cells. Proc Natl Acad Sci USA. 1998a;95:3827–32.PubMedGoogle Scholar
  34. Tsatsanis C, Patriotis C, Tsichlis PN. Tpl-2 induces IL-2 expression in T cell lines by triggering multiple signaling pathways that activate NFAT and NF-kB. Oncogene. 1998b;17:2609–18.PubMedGoogle Scholar
  35. Tsatsanis C, Vaporidi K, Zacharioudaki V, Androulidaki A, Sykulev Y, Margioris AN, Tsichlis PN. Tpl2 and ERK transduce antiproliferative T cell receptor signals and inhibit transformation of chronically stimulated T cells. Proc Natl Acad Sci USA. 2008;105:2987–92.PubMedGoogle Scholar
  36. Vougioukalaki M, Kanellis DC, Gkouskou K, Eliopoulos AG. Tpl2 kinase signal transduction in inflammation and cancer. Cancer Lett. 2011;304:80–9.PubMedGoogle Scholar
  37. Waterfield MR, Zhang M, Norman LP, Sun SC. NF-kappaB1/p105 Regulates Lipopolysaccharide-Stimulated MAP Kinase Signaling by Governing the Stability and Function of the Tpl2 Kinase. Mol Cell. 2003;11:685–94.PubMedGoogle Scholar
  38. Watford WT, Hissong BD, Durant LR, Yamane H, Muul LM, Kanno Y, Tato CM, et al. Tpl2 kinase regulates T cell interferon-gamma production and host resistance to Toxoplasma gondii. J Exp Med. 2008;205:2803–12.PubMedGoogle Scholar
  39. Watford WT, Wang CC, Tsatsanis C, Mielke LA, Eliopoulos AG, Daskalakis C, Charles N, Odom S, Rivera J, O’Shea J, Tsichlis PN. Ablation of tumor progression locus 2 promotes a type 2 Th cell response in ovalbumin-immunized mice. J Immunol. 2010;184:105–13.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Dimitra Virla
    • 1
  • Christos Tsatsanis
    • 3
  • Aristides G. Eliopoulos
    • 1
    • 2
  1. 1.Molecular & Cellular Biology Laboratory, Division of Basic SciencesUniversity of Crete Medical SchoolHeraklionGreece
  2. 2.Institute for Molecular Biology & BiotechnologyFoundation of Research & Technology Hellas (FORTH)HeraklionGreece
  3. 3.Department of Clinical ChemistryUniversity of Crete Medical SchoolHeraklionGreece