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Gene Review

MAP2K3  -  mitogen-activated protein kinase kinase 3

Homo sapiens

Synonyms: Dual specificity mitogen-activated protein kinase kinase 3, MAP kinase kinase 3, MAPK/ERK kinase 3, MAPKK 3, MAPKK3, ...
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Disease relevance of MAP2K3


High impact information on MAP2K3

  • Moreover, expressing a constitutively active form of MKK3, a direct activator of p38 MAP kinase promoted Bax translocation and cell death in the absence of SNP [6].
  • Dominant negative mutants of Cdc42, MKK3, and MKK4 prevented alpha2beta1 integrin-mediated activation of p38alpha [7].
  • We also determined the phosphorylation/activation of p38alpha, MAPK kinase 3/6, and MAPKAP-2 in response to erythropoietin and stem cell factor [8].
  • Constitutive activation of p38 by active MKK3 or MKK6 induces senescence [9].
  • In the present study, we provide evidence that the kinases MAPK kinase 3 (Mkk3) and Mkk6 are activated during treatment of leukemic cell lines with As(2)O(3) to regulate downstream engagement of the p38 mitogen-activated protein kinase [10].

Biological context of MAP2K3


Anatomical context of MAP2K3

  • MEK6 is highly expressed in skeletal muscle like many other members of this family, but in contrast to MKK3 its expression in leukocytes is very low [16].
  • H-Ras-specific activation of Rac-MKK3/6-p38 pathway: its critical role in invasion and migration of breast epithelial cells [17].
  • Like p150(Glued), MKK3/6 directly associate with microtubules [13].
  • Similarly, induction of As(2)O(3)-dependent apoptosis is enhanced in mouse embryonic fibroblasts (MEF) with targeted disruption of both the Mkk3 and Mkk6 genes, establishing a key role for this pathway in the regulation of As(2)O(3)-induced apoptosis [10].
  • However, phosphorylated MKK3/6 expression was significantly higher in RA synovium and was localized to the sublining mononuclear cells and the intimal lining [18].

Associations of MAP2K3 with chemical compounds

  • Gbetagamma-induced MKK3 and MKK6 activations were dependent on a tyrosine kinase other than c-Src [19].
  • To firmly establish the role of the p38 MAPK signaling pathway, clonal lines of LLC-PK1-FBPase+ cells that express constitutively active (ca) and dominant negative (dn) forms of MKK3 and MKK6 from a tetracycline-responsive promoter were developed [20].
  • Overexpression of a MKK3 construct, but not MKK1, stimulated SB202190-sensitive p53 Ser(15) phosphorylation [21].
  • IgE-dependent activation of p38 MAPK and MKK3/6 was affected by LY 294002 and wortmannin, suggesting that these kinases are targets for phosphatidylinositol 3 kinase (PI 3-K) [22].
  • Tetracaine alone, but not the other local anesthetics, inhibited LPS activation of p38 mitogen-activated protein kinase (MAPK) and MAPK kinase 3 (kinases in the LPS signaling pathway) [23].

Physical interactions of MAP2K3


Regulatory relationships of MAP2K3

  • Expression of kinase-inactive PKR (K296R) in cells inhibited the poly(IC)-induced phosphorylation of MKK3/6 detected by phosphospecific antiserum but did not affect the poly(IC)-induced gel migration retardation of MKK3 [25].
  • Consistent with these observations, immunoprecipitated MEKK2 directly activated recombinant MKK4 in vitro but failed to activate MKK3 [26].
  • Furthermore, IL-1beta-induced IL-8, IL-6, and matrix metalloproteinase-3 protein production was significantly inhibited in DN MKK3/DN MKK6-transfected cells [27].
  • In vitro kinase assays on IL-1-stimulated FLS also showed that the combination of DN MKK3 and DN MKK6 markedly decreased kinase activity compared with empty vector or the individual DN plasmids [27].
  • MKK3 and -6-dependent activation of p38alpha MAP kinase is required for cytoskeletal changes in pulmonary microvascular endothelial cells induced by ICAM-1 ligation [28].

Other interactions of MAP2K3


Analytical, diagnostic and therapeutic context of MAP2K3


  1. Isolation of TAO1, a protein kinase that activates MEKs in stress-activated protein kinase cascades. Hutchison, M., Berman, K.S., Cobb, M.H. J. Biol. Chem. (1998) [Pubmed]
  2. Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor. Vitale, G., Bernardi, L., Napolitani, G., Mock, M., Montecucco, C. Biochem. J. (2000) [Pubmed]
  3. Involvement of p38 mitogen-activated protein kinase in gemcitabine-induced apoptosis in human pancreatic cancer cells. Habiro, A., Tanno, S., Koizumi, K., Izawa, T., Nakano, Y., Osanai, M., Mizukami, Y., Okumura, T., Kohgo, Y. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  4. p38 Kinase-dependent MAPKAPK-2 activation functions as 3-phosphoinositide-dependent kinase-2 for Akt in human neutrophils. Rane, M.J., Coxon, P.Y., Powell, D.W., Webster, R., Klein, J.B., Pierce, W., Ping, P., McLeish, K.R. J. Biol. Chem. (2001) [Pubmed]
  5. p38mapk and MEK1/2 inhibition contribute to cellular oxidant injury after hypoxia. Powell, C.S., Wright, M.M., Jackson, R.M. Am. J. Physiol. Lung Cell Mol. Physiol. (2004) [Pubmed]
  6. p38 MAP kinase mediates bax translocation in nitric oxide-induced apoptosis in neurons. Ghatan, S., Larner, S., Kinoshita, Y., Hetman, M., Patel, L., Xia, Z., Youle, R.J., Morrison, R.S. J. Cell Biol. (2000) [Pubmed]
  7. Integrin alpha2beta1 mediates isoform-specific activation of p38 and upregulation of collagen gene transcription by a mechanism involving the alpha2 cytoplasmic tail. Ivaska, J., Reunanen, H., Westermarck, J., Koivisto, L., Kähäri, V.M., Heino, J. J. Cell Biol. (1999) [Pubmed]
  8. Differentiation stage-specific activation of p38 mitogen-activated protein kinase isoforms in primary human erythroid cells. Uddin, S., Ah-Kang, J., Ulaszek, J., Mahmud, D., Wickrema, A. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  9. Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Wang, W., Chen, J.X., Liao, R., Deng, Q., Zhou, J.J., Huang, S., Sun, P. Mol. Cell. Biol. (2002) [Pubmed]
  10. Role of the p38 mitogen-activated protein kinase pathway in the generation of arsenic trioxide-dependent cellular responses. Giafis, N., Katsoulidis, E., Sassano, A., Tallman, M.S., Higgins, L.S., Nebreda, A.R., Davis, R.J., Platanias, L.C. Cancer Res. (2006) [Pubmed]
  11. Selective activation of p38 mitogen-activated protein kinase cascade in human neutrophils stimulated by IL-1beta. Suzuki, K., Hino, M., Kutsuna, H., Hato, F., Sakamoto, C., Takahashi, T., Tatsumi, N., Kitagawa, S. J. Immunol. (2001) [Pubmed]
  12. Human mitogen-activated protein kinase kinase kinase mediates the stress-induced activation of mitogen-activated protein kinase cascades. Chan-Hui, P.Y., Weaver, R. Biochem. J. (1998) [Pubmed]
  13. p150(Glued), Dynein, and microtubules are specifically required for activation of MKK3/6 and p38 MAPKs. Cheung, P.Y., Zhang, Y., Long, J., Lin, S., Zhang, M., Jiang, Y., Wu, Z. J. Biol. Chem. (2004) [Pubmed]
  14. The p38 MAP kinase inhibitor SB203580 enhances nuclear factor-kappa B transcriptional activity by a non-specific effect upon the ERK pathway. Birkenkamp, K.U., Tuyt, L.M., Lummen, C., Wierenga, A.T., Kruijer, W., Vellenga, E. Br. J. Pharmacol. (2000) [Pubmed]
  15. Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6. Enslen, H., Raingeaud, J., Davis, R.J. J. Biol. Chem. (1998) [Pubmed]
  16. Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade. Stein, B., Brady, H., Yang, M.X., Young, D.B., Barbosa, M.S. J. Biol. Chem. (1996) [Pubmed]
  17. H-Ras-specific activation of Rac-MKK3/6-p38 pathway: its critical role in invasion and migration of breast epithelial cells. Shin, I., Kim, S., Song, H., Kim, H.R., Moon, A. J. Biol. Chem. (2005) [Pubmed]
  18. Expression and activation of mitogen-activated protein kinase kinases-3 and -6 in rheumatoid arthritis. Chabaud-Riou, M., Firestein, G.S. Am. J. Pathol. (2004) [Pubmed]
  19. Parallel regulation of mitogen-activated protein kinase kinase 3 (MKK3) and MKK6 in Gq-signaling cascade. Yamauchi, J., Tsujimoto, G., Kaziro, Y., Itoh, H. J. Biol. Chem. (2001) [Pubmed]
  20. Effects of constitutively active and dominant negative MAPK kinase (MKK) 3 and MKK6 on the pH-responsive increase in phosphoenolpyruvate carboxykinase mRNA. O'Hayre, M., Taylor, L., Andratsch, M., Feifel, E., Gstraunthaler, G., Curthoys, N.P. J. Biol. Chem. (2006) [Pubmed]
  21. Prostaglandin E2 stimulates p53 transactivational activity through specific serine 15 phosphorylation in human synovial fibroblasts. Role in suppression of c/EBP/NF-kappaB-mediated MEKK1-induced MMP-1 expression. Faour, W.H., He, Q., Mancini, A., Jovanovic, D., Antoniou, J., Di Battista, J.A. J. Biol. Chem. (2006) [Pubmed]
  22. Regulation of mediator secretion in human basophils by p38 mitogen-activated protein kinase: phosphorylation is sensitive to the effects of phosphatidylinositol 3-kinase inhibitors and calcium mobilization. Gibbs, B.F., Plath, K.E., Wolff, H.H., Grabbe, J. J. Leukoc. Biol. (2002) [Pubmed]
  23. Local anesthetics inhibit priming of neutrophils by lipopolysaccharide for enhanced release of superoxide: suppression of cytochrome b558 expression by disparate mechanisms. Jinnouchi, A., Aida, Y., Nozoe, K., Maeda, K., Pabst, M.J. J. Leukoc. Biol. (2005) [Pubmed]
  24. Phospholipase C-beta 2 interacts with mitogen-activated protein kinase kinase 3. Barr, A.J., Marjoram, R., Xu, J., Snyderman, R. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  25. Protein kinase R (PKR) interacts with and activates mitogen-activated protein kinase kinase 6 (MKK6) in response to double-stranded RNA stimulation. Silva, A.M., Whitmore, M., Xu, Z., Jiang, Z., Li, X., Williams, B.R. J. Biol. Chem. (2004) [Pubmed]
  26. Characterization of the mitogen-activated protein kinase kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK3/p38 pathways regulated by MEK kinases 2 and 3. MEK kinase 3 activates MKK3 but does not cause activation of p38 kinase in vivo. Deacon, K., Blank, J.L. J. Biol. Chem. (1997) [Pubmed]
  27. Regulation of p38 MAPK by MAPK kinases 3 and 6 in fibroblast-like synoviocytes. Inoue, T., Hammaker, D., Boyle, D.L., Firestein, G.S. J. Immunol. (2005) [Pubmed]
  28. MKK3 and -6-dependent activation of p38alpha MAP kinase is required for cytoskeletal changes in pulmonary microvascular endothelial cells induced by ICAM-1 ligation. Wang, Q., Yerukhimovich, M., Gaarde, W.A., Popoff, I.J., Doerschuk, C.M. Am. J. Physiol. Lung Cell Mol. Physiol. (2005) [Pubmed]
  29. A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. Moriguchi, T., Kuroyanagi, N., Yamaguchi, K., Gotoh, Y., Irie, K., Kano, T., Shirakabe, K., Muro, Y., Shibuya, H., Matsumoto, K., Nishida, E., Hagiwara, M. J. Biol. Chem. (1996) [Pubmed]
  30. Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. Lavoie, J.N., L'Allemain, G., Brunet, A., Müller, R., Pouysségur, J. J. Biol. Chem. (1996) [Pubmed]
  31. Identification and characterization of a predominant isoform of human MKK3. Han, J., Wang, X., Jiang, Y., Ulevitch, R.J., Lin, S. FEBS Lett. (1997) [Pubmed]
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