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Gene Review

Map3k8  -  mitogen-activated protein kinase kinase...

Mus musculus

Synonyms: Cancer Osaka thyroid oncogene, Cot, Cot/Tpl2, Est, Estf, ...
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Disease relevance of Map3k8


High impact information on Map3k8


Biological context of Map3k8

  • Recent studies revealed that Tpl2 undergoes phosphorylation at Thr-290 and that phosphorylation at this site is required for activation [7].
  • The serine-threonine protein kinase encoded by the Tpl2 protooncogene transduces Toll-like and death receptor signals in a variety of cell types and plays an important role in innate immunity and inflammation [7].
  • Here, we show that overexpression of the cot proto-oncogene is sufficient to stimulate the expression of c-jun and that, in turn, the activity of c-Jun is required for Cot-induced transformation [8].
  • In contrast, the contribution of NIK to the transactivation function of p65/RelA seems to be negligible and more importantly NIK-KD did not inhibit induction by Cot and PKCzeta [9].
  • The oncoprotein kinase Tpl2 plays an essential role in macrophage activation by the bacterial component lipopolysaccharide (LPS) [10].

Anatomical context of Map3k8


Associations of Map3k8 with chemical compounds

  • We also showed that Tpl2 activation by TNF-alpha depends on a tyrosine kinase activity that is detected in TNF-alpha-stimulated cells [14].
  • The Cot sequence contains a conserved threonine at position 290 in the activation loop of the kinase domain [15].
  • Considering these data, we propose that the inhibition of LPS-induced Cot activation is one mechanism by which 15-deoxy-Delta12,14-prostaglandin J2 acts as an anti-inflammatory [16].
  • 15-Deoxy-Delta12,14-prostaglandin J2, but not rosiglitazone, blocks Cot activation by LPS [16].
  • The core DNA population that contains satellite sequences was then purified from total core DNA by denaturation of the DNA, reassociation to a low Cot value and hydroxyapatite chromatography to separate the renatured satellite fraction [17].

Regulatory relationships of Map3k8


Other interactions of Map3k8

  • IkappaB kinase is an essential component of the Tpl2 signaling pathway [19].
  • In addition, we show that the activation of Tpl2 by TNF-alpha depends on signals transduced by both TRAF2 and RIP1 [11].
  • Differential translational initiation of the Tpl2 mRNA gives rise to 58-kDa (p58) and 52-kDa (p52) isoforms [7].
  • Interestingly, a large pool of Tpl2/Cot is liberated from p105 and exhibits constitutive kinase activity in HTLV-I-transformed T cells [1].
  • We conclude that Tpl2 phosphorylation at Thr(290) is induced by LPS, depends on IKKbeta, and is required for the physiological activation of Tpl2 by external signals [20].

Analytical, diagnostic and therapeutic context of Map3k8

  • These results indicate that Cot/Tpl2 is an important negative regulator of Th1-type adaptive immunity, that it achieves this regulation by inhibiting IL-12 production from accessory cells, and that it might be a potential target molecule in CpG-DNA-guided vaccination [6].


  1. Deregulated activation of oncoprotein kinase Tpl2/Cot in HTLV-I-transformed T cells. Babu, G., Waterfield, M., Chang, M., Wu, X., Sun, S.C. J. Biol. Chem. (2006) [Pubmed]
  2. Tpl-2 is an oncogenic kinase that is activated by carboxy-terminal truncation. Ceci, J.D., Patriotis, C.P., Tsatsanis, C., Makris, A.M., Kovatch, R., Swing, D.A., Jenkins, N.A., Tsichlis, P.N., Copeland, N.G. Genes Dev. (1997) [Pubmed]
  3. Overexpression of the Tpl-2/Cot oncogene in human breast cancer. Sourvinos, G., Tsatsanis, C., Spandidos, D.A. Oncogene (1999) [Pubmed]
  4. TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Dumitru, C.D., Ceci, J.D., Tsatsanis, C., Kontoyiannis, D., Stamatakis, K., Lin, J.H., Patriotis, C., Jenkins, N.A., Copeland, N.G., Kollias, G., Tsichlis, P.N. Cell (2000) [Pubmed]
  5. NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase. Waterfield, M.R., Zhang, M., Norman, L.P., Sun, S.C. Mol. Cell (2003) [Pubmed]
  6. A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA-induced IL-12 production and Th cell differentiation. Sugimoto, K., Ohata, M., Miyoshi, J., Ishizaki, H., Tsuboi, N., Masuda, A., Yoshikai, Y., Takamoto, M., Sugane, K., Matsuo, S., Shimada, Y., Matsuguchi, T. J. Clin. Invest. (2004) [Pubmed]
  7. Phosphorylation at Thr-290 regulates Tpl2 binding to NF-kappaB1/p105 and Tpl2 activation and degradation by lipopolysaccharide. Cho, J., Tsichlis, P.N. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  8. Multiple mitogen-activated protein kinase signaling pathways connect the cot oncoprotein to the c-jun promoter and to cellular transformation. Chiariello, M., Marinissen, M.J., Gutkind, J.S. Mol. Cell. Biol. (2000) [Pubmed]
  9. Differential regulation of p65 and c-Rel NF-kappaB transactivating activity by Cot, protein kinase C zeta and NIK protein kinases in CD3/CD28 activated T cells. Sánchez-Valdepeñas, C., Punzón, C., San-Antonio, B., Martin, A.G., Fresno, M. Cell. Signal. (2007) [Pubmed]
  10. Phosphorylation of NF-kappaB1/p105 by oncoprotein kinase Tpl2: implications for a novel mechanism of Tpl2 regulation. Babu, G.R., Jin, W., Norman, L., Waterfield, M., Chang, M., Wu, X., Zhang, M., Sun, S.C. Biochim. Biophys. Acta (2006) [Pubmed]
  11. Tpl2/cot signals activate ERK, JNK, and NF-kappaB in a cell-type and stimulus-specific manner. Das, S., Cho, J., Lambertz, I., Kelliher, M.A., Eliopoulos, A.G., Du, K., Tsichlis, P.N. J. Biol. Chem. (2005) [Pubmed]
  12. Cot/Tpl2 is essential for RANKL induction by lipid A in osteoblasts. Kikuchi, T., Yoshikai, Y., Miyoshi, J., Katsuki, M., Musikacharoen, T., Mitani, A., Tanaka, S., Noguchi, T., Matsuguchi, T. J. Dent. Res. (2003) [Pubmed]
  13. Tpl2 transduces CD40 and TNF signals that activate ERK and regulates IgE induction by CD40. Eliopoulos, A.G., Wang, C.C., Dumitru, C.D., Tsichlis, P.N. EMBO J. (2003) [Pubmed]
  14. The tyrosine kinase Syk regulates TPL2 activation signals. Eliopoulos, A.G., Das, S., Tsichlis, P.N. J. Biol. Chem. (2006) [Pubmed]
  15. Phosphorylation of threonine 290 in the activation loop of Tpl2/Cot is necessary but not sufficient for kinase activity. Luciano, B.S., Hsu, S., Channavajhala, P.L., Lin, L.L., Cuozzo, J.W. J. Biol. Chem. (2004) [Pubmed]
  16. 15-Deoxy-Delta12,14-prostaglandin J2 regulates endogenous Cot MAPK kinase kinase 1 activity induced by lipopolysaccharide. Caivano, M., Rodriguez, C., Cohen, P., Alemany, S. J. Biol. Chem. (2003) [Pubmed]
  17. Nucleosomes are positioned on mouse satellite DNA in multiple highly specific frames that are correlated with a diverged subrepeat of nine base-pairs. Zhang, X.Y., Hörz, W. J. Mol. Biol. (1984) [Pubmed]
  18. Diverse Toll-like receptors utilize Tpl2 to activate extracellular signal-regulated kinase (ERK) in hemopoietic cells. Banerjee, A., Gugasyan, R., McMahon, M., Gerondakis, S. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  19. IkappaB kinase is an essential component of the Tpl2 signaling pathway. Waterfield, M., Jin, W., Reiley, W., Zhang, M., Sun, S.C. Mol. Cell. Biol. (2004) [Pubmed]
  20. 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. Cho, J., Melnick, M., Solidakis, G.P., Tsichlis, P.N. J. Biol. Chem. (2005) [Pubmed]
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