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Gene Review

Map2k3  -  mitogen-activated protein kinase kinase 3

Mus musculus

Synonyms: AW212142, Dual specificity mitogen-activated protein kinase kinase 3, MAP kinase kinase 3, MAPK/ERK kinase 3, MAPKK 3, ...
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Disease relevance of Map2k3

  • To modulate p38 function but potentially minimize toxicity, we evaluated the utility of targeting MKK3 by using MKK3(-/-) mice [1].
  • Mice deficient for MKK3, an upstream activator of p38 mitogen-activated protein (MAP) kinase, develop a lower Th1 response and exhibit an impaired ability to produce proinflammatory cytokines upon infection with the spirochete [2].
  • Langendorff perfused murine hearts exposed to antimycin A or vehicle prior to global ischemia with p38-MAPK and HSP27 phosphorylation examined in the presence and absence of SB203580 or the presence (mkk3(+/+)) and absence (mkk3(-/-)) of MKK3 [3].
  • Anthrax lethal factor cleaves MKK3 in macrophages and inhibits the LPS/IFNgamma-induced release of NO and TNFalpha [4].

High impact information on Map2k3

  • We show that MKK3 and MKK6are essential for tumor necrosis factor-stimulated p38 MAPK activation [5].
  • Mkk3(-/-) mice were viable and fertile; however, they were defective in interleukin-12 (IL-12) production by macrophages and dendritic cells [6].
  • Finally, of the three scaffold proteins of the JIP family expressed in brown adipocytes, only JIP2 co-immunoprecipitates p38alpha MAPK and MKK3 [7].
  • In contrast, the expression levels of the p38 activators MKK3 and MKK4 are not affected in p38alpha-deficient cells [8].
  • 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 [9].

Biological context of Map2k3


Anatomical context of Map2k3


Associations of Map2k3 with chemical compounds

  • MKK3 mitogen-activated protein kinase pathway mediates carbon monoxide-induced protection against oxidant-induced lung injury [18].
  • MKK4 was phosphorylated only in response to sorbitol, and neither of the stimuli caused phosphorylation of MKK3 or 6 [19].
  • Peroxynitrite-induced phosphorylation of p38alpha in the approximately 85-kDa complex is independent from MKK3/6 because only phospho-p38alpha not associated with the disulfide complex was diminished in MKK3/6 DKO cells [20].
  • We show that TAB1-mediated p38alpha phosphorylation in MEF cells did not need MKK3/4/6, and it accounted for a small portion of the total p38alpha phosphorylation that was induced by hyperosmolarity and anisomycin [20].
  • Antimycin A induced cardioprotection is dependent on pre-ischemic p38-MAPK activation but independent of MKK3 [3].

Regulatory relationships of Map2k3


Other interactions of Map2k3

  • To examine the relative roles of these protein kinases in the mechanism of p38 MAP kinase activation in vivo, we examined the effect of disruption of the murine Mkk3, Mkk4, and Mkk6 genes on the p38 MAPK signaling pathway [5].
  • In peripheral CD4(+)T cells, MKK3 is induced upon stimulation, whereas MKK6 is downregulated [10].
  • Furthermore, all three MAPKs were phosphorylated by the upstream activation of MEK1/2, MKK3/6, and MKK4, respectively [23].
  • Under conditions of constant coronary flow, the p38-MAPK activation and contractile depression induced by TNFalpha, though attenuated, remained sensitive to the absence of MKK3 or the presence of SB203580 [21].
  • Our studies have shown that the basal kinase activities of p38 alpha, its upstream activator, MKK3, and its downstream substrate, ATF-2, are elevated in livers of aged C57BL/6 male mice and that these kinase activities, which are induced by 3-NPA in young livers, do not occur in aged livers [24].

Analytical, diagnostic and therapeutic context of Map2k3


  1. Mitogen-activated protein kinase kinase 3 is a pivotal pathway regulating p38 activation in inflammatory arthritis. Inoue, T., Boyle, D.L., Corr, M., Hammaker, D., Davis, R.J., Flavell, R.A., Firestein, G.S. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  2. Control of Borrelia burgdorferi-Specific CD4+-T-Cell Effector Function by Interleukin-12- and T-Cell Receptor-Induced p38 Mitogen-Activated Protein Kinase Activity. Hedrick, M.N., Olson, C.M., Conze, D.B., Bates, T.C., Rincón, M., Anguita, J. Infect. Immun. (2006) [Pubmed]
  3. Antimycin A induced cardioprotection is dependent on pre-ischemic p38-MAPK activation but independent of MKK3. Kabir, A.M., Cao, X., Gorog, D.A., Tanno, M., Bassi, R., Bellahcene, M., Quinlan, R.A., Davis, R.J., Flavell, R.A., Shattock, M.J., Marber, M.S. J. Mol. Cell. Cardiol. (2005) [Pubmed]
  4. Anthrax lethal factor cleaves MKK3 in macrophages and inhibits the LPS/IFNgamma-induced release of NO and TNFalpha. Pellizzari, R., Guidi-Rontani, C., Vitale, G., Mock, M., Montecucco, C. FEBS Lett. (1999) [Pubmed]
  5. Mechanism of p38 MAP kinase activation in vivo. Brancho, D., Tanaka, N., Jaeschke, A., Ventura, J.J., Kelkar, N., Tanaka, Y., Kyuuma, M., Takeshita, T., Flavell, R.A., Davis, R.J. Genes Dev. (2003) [Pubmed]
  6. Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. Lu, H.T., Yang, D.D., Wysk, M., Gatti, E., Mellman, I., Davis, R.J., Flavell, R.A. EMBO J. (1999) [Pubmed]
  7. Selective activation of mitogen-activated protein (MAP) kinase kinase 3 and p38alpha MAP kinase is essential for cyclic AMP-dependent UCP1 expression in adipocytes. Robidoux, J., Cao, W., Quan, H., Daniel, K.W., Moukdar, F., Bai, X., Floering, L.M., Collins, S. Mol. Cell. Biol. (2005) [Pubmed]
  8. Negative feedback regulation of MKK6 mRNA stability by p38alpha mitogen-activated protein kinase. Ambrosino, C., Mace, G., Galban, S., Fritsch, C., Vintersten, K., Black, E., Gorospe, M., Nebreda, A.R. Mol. Cell. Biol. (2003) [Pubmed]
  9. 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]
  10. Differential involvement of p38 mitogen-activated protein kinase kinases MKK3 and MKK6 in T-cell apoptosis. Tanaka, N., Kamanaka, M., Enslen, H., Dong, C., Wysk, M., Davis, R.J., Flavell, R.A. EMBO Rep. (2002) [Pubmed]
  11. Angiotensin II stimulates the synthesis of vascular endothelial growth factor through the p38 mitogen activated protein kinase pathway in cultured mouse podocytes. Kang, Y.S., Park, Y.G., Kim, B.K., Han, S.Y., Jee, Y.H., Han, K.H., Lee, M.H., Song, H.K., Cha, D.R., Kang, S.W., Han, D.S. J. Mol. Endocrinol. (2006) [Pubmed]
  12. Pathways regulating Na+/Ca2+ exchanger expression in the heart. Menick, D.R., Xu, L., Kappler, C., Jiang, W., Withers, P., Shepherd, N., Conway, S.J., Müller, J.G. Ann. N. Y. Acad. Sci. (2002) [Pubmed]
  13. p38 MAPK regulates IL-1beta induced IL-6 expression through mRNA stability in osteoblasts. Patil, C., Zhu, X., Rossa, C., Kim, Y.J., Kirkwood, K.L. Immunol. Invest. (2004) [Pubmed]
  14. Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for tumor necrosis factor-induced cytokine expression. Wysk, M., Yang, D.D., Lu, H.T., Flavell, R.A., Davis, R.J. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  15. Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for activation of p38alpha and p38delta MAPK isoforms by TGF-beta 1 in murine mesangial cells. Wang, L., Ma, R., Flavell, R.A., Choi, M.E. J. Biol. Chem. (2002) [Pubmed]
  16. Actinobacillus actinomycetemcomitans lipopolysaccharide induces interleukin-6 expression through multiple mitogen-activated protein kinase pathways in periodontal ligament fibroblasts. Patil, C., Rossa, C., Kirkwood, K.L. Oral Microbiol. Immunol. (2006) [Pubmed]
  17. p38 MAPK-mediated signals are required for inducing osteoclast differentiation but not for osteoclast function. Li, X., Udagawa, N., Itoh, K., Suda, K., Murase, Y., Nishihara, T., Suda, T., Takahashi, N. Endocrinology (2002) [Pubmed]
  18. MKK3 mitogen-activated protein kinase pathway mediates carbon monoxide-induced protection against oxidant-induced lung injury. Otterbein, L.E., Otterbein, S.L., Ifedigbo, E., Liu, F., Morse, D.E., Fearns, C., Ulevitch, R.J., Knickelbein, R., Flavell, R.A., Choi, A.M. Am. J. Pathol. (2003) [Pubmed]
  19. Stimulation of MAPK cascades by insulin and osmotic shock: lack of an involvement of p38 mitogen-activated protein kinase in glucose transport in 3T3-L1 adipocytes. Kayali, A.G., Austin, D.A., Webster, N.J. Diabetes (2000) [Pubmed]
  20. Multiple activation mechanisms of p38alpha mitogen-activated protein kinase. Kang, Y.J., Seit-Nebi, A., Davis, R.J., Han, J. J. Biol. Chem. (2006) [Pubmed]
  21. Activation of p38 mitogen-activated protein kinase contributes to the early cardiodepressant action of tumor necrosis factor. Bellahcene, M., Jacquet, S., Cao, X.B., Tanno, M., Haworth, R.S., Layland, J., Kabir, A.M., Gaestel, M., Davis, R.J., Flavell, R.A., Shah, A.M., Avkiran, M., Marber, M.S. J. Am. Coll. Cardiol. (2006) [Pubmed]
  22. Galectin-3 expression in macrophages is signaled by Ras/MAP kinase pathway and up-regulated by modified lipoproteins. Kim, K., Mayer, E.P., Nachtigal, M. Biochim. Biophys. Acta (2003) [Pubmed]
  23. Hypertonicity-induced aquaporin-1 (AQP1) expression is mediated by the activation of MAPK pathways and hypertonicity-responsive element in the AQP1 gene. Umenishi, F., Schrier, R.W. J. Biol. Chem. (2003) [Pubmed]
  24. The effect of aging on p38 signaling pathway activity in the mouse liver and in response to ROS generated by 3-nitropropionic acid. Hsieh, C.C., Papaconstantinou, J. Mech. Ageing Dev. (2002) [Pubmed]
  25. Purification and identification of a major activator for p38 from osmotically shocked cells. Activation of mitogen-activated protein kinase kinase 6 by osmotic shock, tumor necrosis factor-alpha, and H2O2. Moriguchi, T., Toyoshima, F., Gotoh, Y., Iwamatsu, A., Irie, K., Mori, E., Kuroyanagi, N., Hagiwara, M., Matsumoto, K., Nishida, E. J. Biol. Chem. (1996) [Pubmed]
  26. Inhibition of apoptosis signal-regulating kinase 1 by nitric oxide through a thiol redox mechanism. Park, H.S., Yu, J.W., Cho, J.H., Kim, M.S., Huh, S.H., Ryoo, K., Choi, E.J. J. Biol. Chem. (2004) [Pubmed]
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