Skip to main content
SpringerLink
Log in

TPL2

  • Reference work entry
Encyclopedia of Signaling Molecules

  • 103 Accesses

Synonyms

Cancer Osaka thyroid oncogene; COT; Map3k8; Mitogen-activated protein kinase kinase kinase 8; Tumor progression locus 2

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 carboxy-terminally...

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Vougioukalaki M, Kanellis DC, Gkouskou K, Eliopoulos AG. Tpl2 kinase signal transduction in inflammation and cancer. Cancer Lett. 2011;304:80–9.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecular & Cellular Biology Laboratory, Division of Basic Sciences, University of Crete Medical School, Heraklion, Crete, Greece

    Dimitra Virla & Aristides G. Eliopoulos

  2. Institute for Molecular Biology & Biotechnology, Foundation of Research & Technology Hellas (FORTH), Heraklion, Crete, Greece

    Aristides G. Eliopoulos

  3. Department of Clinical Chemistry, University of Crete Medical School, Heraklion, Crete, Greece

    Dr. Christos Tsatsanis

Authors
  1. Dimitra Virla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dr. Christos Tsatsanis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aristides G. Eliopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christos Tsatsanis .

Editor information

Editors and Affiliations

  1. Department of Molecular Science and Technology, Ajou University, Suwon, Korea

    Sangdun Choi

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this entry

Cite this entry

Virla, D., Tsatsanis, C., Eliopoulos, A.G. (2012). TPL2. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0461-4_626

Download citation

Publish with us

Policies and ethics

Search

Navigation