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Gene Review

Map2k6  -  mitogen-activated protein kinase kinase 6

Mus musculus

Synonyms: Dual specificity mitogen-activated protein kinase kinase 6, MAP kinase kinase 6, MAPK/ERK kinase 6, MAPKK 6, MEK 6, ...
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Disease relevance of Map2k6

  • While overexpression of the p38 isoforms alpha and beta did not protect L929 cells from TNF-induced toxicity, overexpression of constitutively active MKK6 decreased TNF-induced cell death [1].
  • Deletion of TCRalphabeta(int)CD4hiCD8hi cells by injecting antigenic lymphocytic chorio-meningitis virus (LCMV) peptide into LCMV-specific TCR-transgenic mice was incomplete in MKK6-deficient mice [2].

High impact information on Map2k6


Biological context of Map2k6


Anatomical context of Map2k6

  • On assessing functional consequences of these reductions, we found that MKK6 mouse heart mitochondria exhibited 50% lower oxidative respiration and I/R-mediated reactive oxygen species (ROS) generation, both of which are predicted consequences of decreased oxidative phosphorylation complex proteins [6].
  • To examine this possibility, we employed the multidimensional protein identification technology MudPIT to characterize changes in levels of proteins in MKK6 transgenic mouse hearts, focusing on proteins in mitochondria, which play key roles in mediating I/R injury in the heart [6].
  • In addition, suppression of p38 MAPK activation by overexpression of a dominant negative p38 MAPK or MKK6 mutant did not diminish insulin-induced glucose uptake by 3T3-L1 adipocytes [10].
  • The tubulogenic defects imparted by RGS4 in epithelial cells, including its reduction in VEGF expression, were rescued by overexpression of constitutively active MKK6, an activator of p38 MAPK [11].
  • In this report, we have directly addressed these questions by analyzing 3T3-L1 cell lines harboring a specific upstream activator of p38 (a constitutively active mitogen-activated protein kinase kinase 6 (MKK6) mutant, MKK6(Glu)) under the control of an inducible promoter [9].

Associations of Map2k6 with chemical compounds

  • Constitutively active MKK6/3 mutants up-regulated GLUT1 expression and down-regulated GLUT4 expression, thereby significantly increasing basal glucose transport but diminishing transport induced by insulin [10].
  • Our findings suggest that MKK6 downregulates NADPH oxidase activity by enhancing Rac-GTPase activity [12].

Regulatory relationships of Map2k6

  • In addition, elevated levels of COX-2 protein were identified in the hearts of transgenic mice with cardiac-restricted expression of wild-type or constitutively activated MKK6, in comparison with nontransgenic littermates [13].

Other interactions of Map2k6


Analytical, diagnostic and therapeutic context of Map2k6

  • Cellular death of TCRalphabeta(int) fetal thymocytes induced by adding an antigenic peptide into an in vitro fetal thymic organ culture system was also diminished in MKK6-deficient TCR-transgenic thymi [2].


  1. Inhibition of p38 mitogen-activated protein kinase reduces TNF-induced activation of NF-kappaB, elicits caspase activity, and enhances cytotoxicity. Lüschen, S., Scherer, G., Ussat, S., Ungefroren, H., Adam-Klages, S. Exp. Cell Res. (2004) [Pubmed]
  2. Involvement of MKK6 in TCRalphabeta(int)CD69lo: a target population for apoptotic cell death in thymocytes. Suzuki, H., Wu, J., Hossain, K., Ohhata, T., Du, J., Akhand, A.A., Hayakawa, A., Kimura, H., Hagiwara, M., Nakashima, I. FASEB J. (2003) [Pubmed]
  3. Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling. Braz, J.C., Bueno, O.F., Liang, Q., Wilkins, B.J., Dai, Y.S., Parsons, S., Braunwart, J., Glascock, B.J., Klevitsky, R., Kimball, T.F., Hewett, T.E., Molkentin, J.D. J. Clin. Invest. (2003) [Pubmed]
  4. 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]
  5. The cJun N-terminal kinase (JNK) signaling pathway mediates induction of urokinase-type plasminogen activator (uPA) by the alkylating agent MNNG. Parra, M., Lluís, F., Miralles, F., Caelles, C., Muñoz-Cánoves, P. Blood (2000) [Pubmed]
  6. Alterations in oxidative phosphorylation complex proteins in the hearts of transgenic mice that overexpress the p38 MAP kinase activator, MAP kinase kinase 6. Wall, J.A., Wei, J., Ly, M., Belmont, P., Martindale, J.J., Tran, D., Sun, J., Chen, W.J., Yu, W., Oeller, P., Briggs, S., Gustafsson, A.B., Sayen, M.R., Gottlieb, R.A., Glembotski, C.C. Am. J. Physiol. Heart Circ. Physiol. (2006) [Pubmed]
  7. 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]
  8. Microphthalmia transcription factor and PU.1 synergistically induce the leukocyte receptor osteoclast-associated receptor gene expression. So, H., Rho, J., Jeong, D., Park, R., Fisher, D.E., Ostrowski, M.C., Choi, Y., Kim, N. J. Biol. Chem. (2003) [Pubmed]
  9. Constitutively active mitogen-activated protein kinase kinase 6 (MKK6) or salicylate induces spontaneous 3T3-L1 adipogenesis. Engelman, J.A., Berg, A.H., Lewis, R.Y., Lin, A., Lisanti, M.P., Scherer, P.E. J. Biol. Chem. (1999) [Pubmed]
  10. MKK6/3 and p38 MAPK pathway activation is not necessary for insulin-induced glucose uptake but regulates glucose transporter expression. Fujishiro, M., Gotoh, Y., Katagiri, H., Sakoda, H., Ogihara, T., Anai, M., Onishi, Y., Ono, H., Funaki, M., Inukai, K., Fukushima, Y., Kikuchi, M., Oka, Y., Asano, T. J. Biol. Chem. (2001) [Pubmed]
  11. Identification and characterization of regulator of G protein signaling 4 (RGS4) as a novel inhibitor of tubulogenesis: RGS4 inhibits mitogen-activated protein kinases and vascular endothelial growth factor signaling. Albig, A.R., Schiemann, W.P. Mol. Biol. Cell (2005) [Pubmed]
  12. MKK6 phosphorylation regulates production of superoxide by enhancing Rac GTPase activity. Harraz, M.M., Park, A., Abbott, D., Zhou, W., Zhang, Y., Engelhardt, J.F. Antioxid. Redox Signal. (2007) [Pubmed]
  13. MAP kinase kinase 6-p38 MAP kinase signaling cascade regulates cyclooxygenase-2 expression in cardiac myocytes in vitro and in vivo. Degousee, N., Martindale, J., Stefanski, E., Cieslak, M., Lindsay, T.F., Fish, J.E., Marsden, P.A., Thuerauf, D.J., Glembotski, C.C., Rubin, B.B. Circ. Res. (2003) [Pubmed]
  14. 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]
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