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Gene Review

MAP3K8  -  mitogen-activated protein kinase kinase...

Homo sapiens

Synonyms: COT, Cancer Osaka thyroid oncogene, EST, ESTF, MEKK8, ...
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Disease relevance of MAP3K8


Psychiatry related information on MAP3K8

  • Improving Dietary Habits in Disadvantaged Women With HIV/AIDS: The SMART/EST Women's Project [5].
  • In the SMART/EST II Women's Project 466 disadvantaged women with HIV/AIDS were randomized to one of four groups and received a two-phase training consisting of a coping skills/stress management and nutrition education provided either in a group or individually [5].

High impact information on MAP3K8


Biological context of MAP3K8

  • Depletion of ABIN-2 by RNA interference dramatically reduced steady-state levels of TPL-2 protein without affecting levels of TPL-2 mRNA or p105 protein [8].
  • We demonstrate that knockdown of arrestin-2 leads to enhanced LPS-induced phosphorylation and degradation of p105, enhanced TPL2 release, and enhanced MEK1/2 phosphorylation [9].
  • A 16-mer peptide sequence was obtained from the 12-kDa polypeptide which matched a new open reading frame from a human EST () encoding a hypothetical protein of unknown function [10].
  • Inhibition of Tpl2 kinase and TNF-alpha production with 1,7-naphthyridine-3-carbonitriles: synthesis and structure-activity relationships [11].
  • Approximately 70% of the ESTs generated in this study had not been captured during a previous EST project conducted using a cDNA library constructed from hand-dissected apex tissue that is highly enriched for SAMs [12].

Anatomical context of MAP3K8


Associations of MAP3K8 with chemical compounds

  • The Akt (or protein kinase B) and Cot (or Tpl-2) serine/threonine kinases are associated with cellular transformation [15].
  • The tyrosine kinase Syk regulates TPL2 activation signals [16].
  • The serine/threonine kinase Cot (also known as Tpl2) is a member of the MAP kinase kinase kinase (MAP3K) family that is known to regulate oncogenic and inflammatory pathways; however, the mechanism(s) of its regulation are not precisely known [17].
  • EST dose-dependently inhibited 20K phosphorylation in platelets stimulated by thrombin, ionomycin or collagen [18].
  • By employing a cell penetrating thiol protease inhibitor, EST: ethyl(+)-(2S,3S)-3-[(S)-3-methyl-1-(3-methylbutylcarbamoyl)buty lcarbamoyl]- 2-oxiranecarboxylate, the role of calpain, a major thiol protease in platelets, on 20K protein (myosin light chain) phosphorylation was examined in intact human platelets [18].
  • These inhibitors selectively target Tpl2 in these cells, and they block LPS- and IL-1beta-induced TNFalpha production in both primary human monocytes and human blood [19].
  • Mutation of this conserved residue to alanine (A) blocked the ability of retrovirally expressed TPL-2 to induce the activation of ERK in LPS-stimulated Nfkb1(-/-) macrophages [20].

Regulatory relationships of MAP3K8

  • Together, these data raise the possibility that ABIN-2 functions in the TLR4 signaling pathway which regulates TPL-2 activation [8].

Other interactions of MAP3K8

  • Experiments using dominant-negative Tpl2 suggest this kinase functions distal to TRAFs but proximal to the TAK1/TAB1 signaling complex, within the IKK/NFkappaB activation pathway [21].
  • Serum TNF-alpha levels were increased in all Tpl2/Cot overexpressing patients while serum IL-2 was undetectable in all subjects studied [13].
  • Identification of a novel human kinase supporter of Ras (hKSR-2) that functions as a negative regulator of Cot (Tpl2) signaling [17].
  • The open reading frame of human EST encoded a polypeptide of 107 amino acids with a predicted molecular mass of 12.4 kDa, consistent with the experimental findings. p12 is 25% identical to S pombe Cdm1 [10].
  • Upstream kinases involved in IKK complex activation such as TPL-2/COT, NIK, and IKKepsilon were also shown to play an important role in bpV-mediated NF-kappaB activation [22].

Analytical, diagnostic and therapeutic context of MAP3K8

  • With powerful reverse genetics methods, a large collection of EST sequences and a new cDNA microarray, Gerbera has become a model plant of the sunflower family [23].
  • Tpl-2 was found overexpressed in 14 of the 35 breast tumours tested using a semi-quantitative RT - PCR method [24].
  • METHODS: In 46 patients with ApHCM, we measured CO time on M-mode echocardiography and corrected it by the R-R interval (cCOT) [25].
  • EST/cDNA sequencing and microarray analysis show that nearly 70% are represented in embryo RNA [26].
  • Although typical poly(A) sites are located between 0 and 2 kb from the stop codon, EST sequence analyses have identified sites located at unexpectedly long ranges (5-10 kb) in a number of genes [27].


  1. Mutational activation of the MAP3K8 protooncogene in lung cancer. Clark, A.M., Reynolds, S.H., Anderson, M., Wiest, J.S. Genes Chromosomes Cancer (2004) [Pubmed]
  2. 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. Eliopoulos, A.G., Davies, C., Blake, S.S., Murray, P., Najafipour, S., Tsichlis, P.N., Young, L.S. J. Virol. (2002) [Pubmed]
  3. Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase. Salmeron, A., Ahmad, T.B., Carlile, G.W., Pappin, D., Narsimhan, R.P., Ley, S.C. EMBO J. (1996) [Pubmed]
  4. 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]
  5. Improving Dietary Habits in Disadvantaged Women With HIV/AIDS: The SMART/EST Women's Project. Segal-Isaacson, C.J., Tobin, J.N., Weiss, S.M., Brondolo, E., Vaughn, A., Wang, C., Camille, J., Gousse, Y., Ishii, M., Jones, D., Laperriere, A., Lydston, D., Schneiderman, N., Ironson, G. AIDS and behavior. (2006) [Pubmed]
  6. The proto-oncogene Cot kinase participates in CD3/CD28 induction of NF-kappaB acting through the NF-kappaB-inducing kinase and IkappaB kinases. Lin, X., Cunningham, E.T., Mu, Y., Geleziunas, R., Greene, W.C. Immunity (1999) [Pubmed]
  7. Brain response to putative pheromones in lesbian women. Berglund, H., Lindström, P., Savic, I. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  8. ABIN-2 forms a ternary complex with TPL-2 and NF-kappa B1 p105 and is essential for TPL-2 protein stability. Lang, V., Symons, A., Watton, S.J., Janzen, J., Soneji, Y., Beinke, S., Howell, S., Ley, S.C. Mol. Cell. Biol. (2004) [Pubmed]
  9. Arrestin-2 and G Protein-coupled Receptor Kinase 5 Interact with NF{kappa}B1 p105 and Negatively Regulate Lipopolysaccharide-stimulated ERK1/2 Activation in Macrophages. Parameswaran, N., Pao, C.S., Leonhard, K.S., Kang, D.S., Kratz, M., Ley, S.C., Benovic, J.L. J. Biol. Chem. (2006) [Pubmed]
  10. Identification of a fourth subunit of mammalian DNA polymerase delta. Liu, L., Mo, J., Rodriguez-Belmonte, E.M., Lee, M.Y. J. Biol. Chem. (2000) [Pubmed]
  11. Inhibition of Tpl2 kinase and TNF-alpha production with 1,7-naphthyridine-3-carbonitriles: synthesis and structure-activity relationships. Gavrin, L.K., Green, N., Hu, Y., Janz, K., Kaila, N., Li, H.Q., Tam, S.Y., Thomason, J.R., Gopalsamy, A., Ciszewski, G., Cuozzo, J.W., Hall, J.P., Hsu, S., Telliez, J.B., Lin, L.L. Bioorg. Med. Chem. Lett. (2005) [Pubmed]
  12. Gene discovery and annotation using LCM-454 transcriptome sequencing. Emrich, S.J., Barbazuk, W.B., Li, L., Schnable, P.S. Genome Res. (2007) [Pubmed]
  13. Expression of the Tpl2/Cot oncogene in human T-cell neoplasias. Christoforidou, A.V., Papadaki, H.A., Margioris, A.N., Eliopoulos, G.D., Tsatsanis, C. Mol. Cancer (2004) [Pubmed]
  14. Sex-specific differences in olfactory sensitivity for putative human pheromones in nonhuman primates. Laska, M., Wieser, A., Salazar, L.T. Journal of comparative psychology (Washington, D.C. : 1983) (2006) [Pubmed]
  15. Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription. Kane, L.P., Mollenauer, M.N., Xu, Z., Turck, C.W., Weiss, A. Mol. Cell. Biol. (2002) [Pubmed]
  16. The tyrosine kinase Syk regulates TPL2 activation signals. Eliopoulos, A.G., Das, S., Tsichlis, P.N. J. Biol. Chem. (2006) [Pubmed]
  17. Identification of a novel human kinase supporter of Ras (hKSR-2) that functions as a negative regulator of Cot (Tpl2) signaling. Channavajhala, P.L., Wu, L., Cuozzo, J.W., Hall, J.P., Liu, W., Lin, L.L., Zhang, Y. J. Biol. Chem. (2003) [Pubmed]
  18. Studies on myosin light chain phosphorylation in intact platelets, utilizing a cell-penetrating thiol protease inhibitor. Tsujinaka, T., Kajiwara, Y., Kambayashi, J., Sakon, M., Mori, T. Thromb. Res. (1988) [Pubmed]
  19. Pharmacologic inhibition of tpl2 blocks inflammatory responses in primary human monocytes, synoviocytes, and blood. Hall, J.P., Kurdi, Y., Hsu, S., Cuozzo, J., Liu, J., Telliez, J.B., Seidl, K.J., Winkler, A., Hu, Y., Green, N., Askew, G.R., Tam, S., Clark, J.D., Lin, L.L. J. Biol. Chem. (2007) [Pubmed]
  20. Phosphorylation of TPL-2 on serine 400 is essential for lipopolysaccharide activation of extracellular signal-regulated kinase in macrophages. Robinson, M.J., Beinke, S., Kouroumalis, A., Tsichlis, P.N., Ley, S.C. Mol. Cell. Biol. (2007) [Pubmed]
  21. TRAF-dependent association of protein kinase Tpl2/COT1 (MAP3K8) with CD40. Chan, H., Reed, J.C. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  22. NF-kappaB induction by bisperoxovanadium compounds requires CD45, p36(LAT), PKC, and IKK activity and exhibits kinetics of activation comparable to those of TCR/CD28 coengagement. Ouellet, M., Roy, J., Barbeau, B., Geleziunas, R., Tremblay, M.J. Biochemistry (2003) [Pubmed]
  23. Mining plant diversity: Gerbera as a model system for plant developmental and biosynthetic research. Teeri, T.H., Elomaa, P., Kotilainen, M., Albert, V.A. Bioessays (2006) [Pubmed]
  24. Overexpression of the Tpl-2/Cot oncogene in human breast cancer. Sourvinos, G., Tsatsanis, C., Spandidos, D.A. Oncogene (1999) [Pubmed]
  25. Sustained cavity obliteration and apical aneurysm formation in apical hypertrophic cardiomyopathy. Matsubara, K., Nakamura, T., Kuribayashi, T., Azuma, A., Nakagawa, M. J. Am. Coll. Cardiol. (2003) [Pubmed]
  26. Sea urchin metalloproteases: A genomic survey of the BMP-1/tolloid-like, MMP and ADAM families. Angerer, L., Hussain, S., Wei, Z., Livingston, B.T. Dev. Biol. (2006) [Pubmed]
  27. The disparate nature of "intergenic" polyadenylation sites. Lopez, F., Granjeaud, S., Ara, T., Ghattas, B., Gautheret, D. RNA (2006) [Pubmed]
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