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Gene Review

Map2k1  -  mitogen-activated protein kinase kinase 1

Mus musculus

Synonyms: Dual specificity mitogen-activated protein kinase kinase 1, ERK activator kinase 1, MAP kinase kinase 1, MAPK/ERK kinase 1, MAPKK 1, ...
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Disease relevance of Map2k1


High impact information on Map2k1

  • Conditional expression of a dominant-negative form of MEK1 in the postnatal murine forebrain inhibited ERK activation and caused selective deficits in hippocampal memory retention and the translation-dependent, transcription-independent phase of hippocampal L-LTP [5].
  • The transforming-growth-factor-beta-activated kinase TAK1 is a member of the mitogen-activated protein kinase kinase kinase family, which couples extracellular stimuli to gene transcription [6].
  • These data indicate that MEK inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer [7].
  • Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1 [8].
  • Here we report that MAPK-K as well as Erk1 and 2 are constitutively active in v-raf-transformed cells [9].

Chemical compound and disease context of Map2k1


Biological context of Map2k1


Anatomical context of Map2k1


Associations of Map2k1 with chemical compounds


Physical interactions of Map2k1


Enzymatic interactions of Map2k1

  • MEK-1 is a dual threonine and tyrosine recognition kinase that phosphorylates and activates mitogen-activated protein kinase (MAPK) [26].
  • Furthermore, the MEK-phosphorylating activity of protein kinase Czeta (PKCzeta) was also enhanced after TPO stimulation of T69Mpl, contributing to ERK activity [27].
  • The Mek1 dual specificity protein kinase phosphorylates and activates the mitogen-activated protein kinases Erk1 and Erk2 in response to mitogenic stimulation [28].

Regulatory relationships of Map2k1


Other interactions of Map2k1


Analytical, diagnostic and therapeutic context of Map2k1

  • MEK1 transgenic mice showed a dramatic increase in cardiac function, as measured by echocardiography and isolated working heart preparation, without signs of decompensation over time [1].
  • Laser scanning cytometry and flow cytometry were used to determine: (1) whether expression of phosphorylated ERKs was cell cycle-related; and (2) whether cell-cycle alterations by agents could be modified after addition of the mitogen-activated protein kinase/ERK kinase (MEK) 1 inhibitor PD98059 [38].
  • Immunoprecipitation experiments have shown that the time courses of activation and deactivation of both isoforms of MAPKK were superimposed [39].
  • Western blots analysis was performed to determine the levels of proteins involved in the MEK-MAPK and apoptotic pathways [40].
  • Studying the protein expression profile of seven HCC xenografts revealed that their growth rate was positively correlated with the levels of phosphorylated MEK [41].


  1. The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. Bueno, O.F., De Windt, L.J., Tymitz, K.M., Witt, S.A., Kimball, T.R., Klevitsky, R., Hewett, T.E., Jones, S.P., Lefer, D.J., Peng, C.F., Kitsis, R.N., Molkentin, J.D. EMBO J. (2000) [Pubmed]
  2. Mitogen-activated protein kinase (MAPK) activation by butylated hydroxytoluene hydroperoxide: implications for cellular survival and tumor promotion. Guyton, K.Z., Gorospe, M., Kensler, T.W., Holbrook, N.J. Cancer Res. (1996) [Pubmed]
  3. Induction of ornithine decarboxylase activity is a necessary step for mitogen-activated protein kinase kinase-induced skin tumorigenesis. Feith, D.J., Bol, D.K., Carboni, J.M., Lynch, M.J., Sass-Kuhn, S., Shoop, P.L., Shantz, L.M. Cancer Res. (2005) [Pubmed]
  4. Activation of extracellular signal-regulated kinases, NF-kappa B, and cyclic adenosine 5'-monophosphate response element-binding protein in lung neutrophils occurs by differing mechanisms after hemorrhage or endotoxemia. Abraham, E., Arcaroli, J., Shenkar, R. J. Immunol. (2001) [Pubmed]
  5. Translational control by MAPK signaling in long-term synaptic plasticity and memory. Kelleher, R.J., Govindarajan, A., Jung, H.Y., Kang, H., Tonegawa, S. Cell (2004) [Pubmed]
  6. TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice. Zhang, D., Gaussin, V., Taffet, G.E., Belaguli, N.S., Yamada, M., Schwartz, R.J., Michael, L.H., Overbeek, P.A., Schneider, M.D. Nat. Med. (2000) [Pubmed]
  7. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Sebolt-Leopold, J.S., Dudley, D.T., Herrera, R., Van Becelaere, K., Wiland, A., Gowan, R.C., Tecle, H., Barrett, S.D., Bridges, A., Przybranowski, S., Leopold, W.R., Saltiel, A.R. Nat. Med. (1999) [Pubmed]
  8. Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1. Yan, M., Dai, T., Deak, J.C., Kyriakis, J.M., Zon, L.I., Woodgett, J.R., Templeton, D.J. Nature (1994) [Pubmed]
  9. Raf-1 activates MAP kinase-kinase. Kyriakis, J.M., App, H., Zhang, X.F., Banerjee, P., Brautigan, D.L., Rapp, U.R., Avruch, J. Nature (1992) [Pubmed]
  10. Vitamin D(3)-induced apoptosis of murine squamous cell carcinoma cells. Selective induction of caspase-dependent MEK cleavage and up-regulation of MEKK-1. McGuire, T.F., Trump, D.L., Johnson, C.S. J. Biol. Chem. (2001) [Pubmed]
  11. Hydralazine may induce autoimmunity by inhibiting extracellular signal-regulated kinase pathway signaling. Deng, C., Lu, Q., Zhang, Z., Rao, T., Attwood, J., Yung, R., Richardson, B. Arthritis Rheum. (2003) [Pubmed]
  12. Role of a mitogen-activated protein kinase pathway in the induction of phase II detoxifying enzymes by chemicals. Yu, R., Lei, W., Mandlekar, S., Weber, M.J., Der, C.J., Wu, J., Kong, A.T. J. Biol. Chem. (1999) [Pubmed]
  13. Anthrax lethal factor causes proteolytic inactivation of mitogen-activated protein kinase kinase. Duesbery, N.S., Vande Woude, G.F. J. Appl. Microbiol. (1999) [Pubmed]
  14. MEK1-ERK2 signaling pathway protects myocardium from ischemic injury in vivo. Lips, D.J., Bueno, O.F., Wilkins, B.J., Purcell, N.H., Kaiser, R.A., Lorenz, J.N., Voisin, L., Saba-El-Leil, M.K., Meloche, S., Pouysségur, J., Pagès, G., De Windt, L.J., Doevendans, P.A., Molkentin, J.D. Circulation (2004) [Pubmed]
  15. Requirement for Map2k1 (Mek1) in extra-embryonic ectoderm during placentogenesis. Bissonauth, V., Roy, S., Gravel, M., Guillemette, S., Charron, J. Development (2006) [Pubmed]
  16. Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption. Yujiri, T., Sather, S., Fanger, G.R., Johnson, G.L. Science (1998) [Pubmed]
  17. A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Lange-Carter, C.A., Pleiman, C.M., Gardner, A.M., Blumer, K.J., Johnson, G.L. Science (1993) [Pubmed]
  18. Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype. Murakami, S., Balmes, G., McKinney, S., Zhang, Z., Givol, D., de Crombrugghe, B. Genes Dev. (2004) [Pubmed]
  19. Mitogen-activated protein kinase kinase activity is required for the G(2)/M transition of the cell cycle in mammalian fibroblasts. Wright, J.H., Munar, E., Jameson, D.R., Andreassen, P.R., Margolis, R.L., Seger, R., Krebs, E.G. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  20. MEK kinase 1 gene disruption alters cell migration and c-Jun NH2-terminal kinase regulation but does not cause a measurable defect in NF-kappa B activation. Yujiri, T., Ware, M., Widmann, C., Oyer, R., Russell, D., Chan, E., Zaitsu, Y., Clarke, P., Tyler, K., Oka, Y., Fanger, G.R., Henson, P., Johnson, G.L. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  21. Erythropoietin regulation of Raf-1 and MEK: evidence for a Ras-independent mechanism. Chen, C., Sytkowski, A.J. Blood (2004) [Pubmed]
  22. Kinase suppressor of ras is necessary for tumor necrosis factor alpha activation of extracellular signal-regulated kinase/mitogen-activated protein kinase in intestinal epithelial cells. Yan, F., Polk, D.B. Cancer Res. (2001) [Pubmed]
  23. Raf-1 forms a stable complex with Mek1 and activates Mek1 by serine phosphorylation. Huang, W., Alessandrini, A., Crews, C.M., Erikson, R.L. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  24. Growth hormone alters epidermal growth factor receptor binding affinity via activation of extracellular signal-regulated kinases in 3T3-F442A cells. Huang, Y., Chang, Y., Wang, X., Jiang, J., Frank, S.J. Endocrinology (2004) [Pubmed]
  25. Activated MEK1 binds the nuclear MyoD transcriptional complex to repress transactivation. Perry, R.L., Parker, M.H., Rudnicki, M.A. Mol. Cell (2001) [Pubmed]
  26. MEK-1 phosphorylation by MEK kinase, Raf, and mitogen-activated protein kinase: analysis of phosphopeptides and regulation of activity. Gardner, A.M., Vaillancourt, R.R., Lange-Carter, C.A., Johnson, G.L. Mol. Biol. Cell (1994) [Pubmed]
  27. The roles of phosphatidylinositol 3-kinase and protein kinase Czeta for thrombopoietin-induced mitogen-activated protein kinase activation in primary murine megakaryocytes. Rojnuckarin, P., Miyakawa, Y., Fox, N.E., Deou, J., Daum, G., Kaushansky, K. J. Biol. Chem. (2001) [Pubmed]
  28. An analysis of Mek1 signaling in cell proliferation and transformation. Greulich, H., Erikson, R.L. J. Biol. Chem. (1998) [Pubmed]
  29. Mast cell tumor necrosis factor alpha production is regulated by MEK kinases. Ishizuka, T., Terada, N., Gerwins, P., Hamelmann, E., Oshiba, A., Fanger, G.R., Johnson, G.L., Gelfand, E.W. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  30. Skeletal muscle cell activation by low-energy laser irradiation: a role for the MAPK/ERK pathway. Shefer, G., Oron, U., Irintchev, A., Wernig, A., Halevy, O. J. Cell. Physiol. (2001) [Pubmed]
  31. MEKK1 plays a critical role in activating the transcription factor C/EBP-beta-dependent gene expression in response to IFN-gamma. Roy, S.K., Hu, J., Meng, Q., Xia, Y., Shapiro, P.S., Reddy, S.P., Platanias, L.C., Lindner, D.J., Johnson, P.F., Pritchard, C., Pagés, G., Pouyssegur, J., Kalvakolanu, D.V. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  32. Growth hormone stimulates phosphorylation and activation of elk-1 and expression of c-fos, egr-1, and junB through activation of extracellular signal-regulated kinases 1 and 2. Hodge, C., Liao, J., Stofega, M., Guan, K., Carter-Su, C., Schwartz, J. J. Biol. Chem. (1998) [Pubmed]
  33. Induction of PER1 mRNA expression in immortalized gonadotropes by gonadotropin-releasing hormone (GnRH): involvement of protein kinase C and MAP kinase signaling. Olcese, J., Sikes, H.E., Resuehr, D. Chronobiol. Int. (2006) [Pubmed]
  34. Rac-PAK signaling stimulates extracellular signal-regulated kinase (ERK) activation by regulating formation of MEK1-ERK complexes. Eblen, S.T., Slack, J.K., Weber, M.J., Catling, A.D. Mol. Cell. Biol. (2002) [Pubmed]
  35. The JNK/SAPK activator mixed lineage kinase 3 (MLK3) transforms NIH 3T3 cells in a MEK-dependent fashion. Hartkamp, J., Troppmair, J., Rapp, U.R. Cancer Res. (1999) [Pubmed]
  36. Expression of c-Myc in response to colony-stimulating factor-1 requires mitogen-activated protein kinase kinase-1. Cheng, M., Wang, D., Roussel, M.F. J. Biol. Chem. (1999) [Pubmed]
  37. Murine Ksr interacts with MEK and inhibits Ras-induced transformation. Denouel-Galy, A., Douville, E.M., Warne, P.H., Papin, C., Laugier, D., Calothy, G., Downward, J., Eychène, A. Curr. Biol. (1998) [Pubmed]
  38. Different accumulation of activated extracellular signal-regulated kinases (ERK 1/2) and role in cell-cycle alterations by epidermal growth factor, hydrogen peroxide, or asbestos in pulmonary epithelial cells. Buder-Hoffmann, S., Palmer, C., Vacek, P., Taatjes, D., Mossman, B. Am. J. Respir. Cell Mol. Biol. (2001) [Pubmed]
  39. Activation of two isoforms of mitogen-activated protein kinase kinase in response to epidermal growth factor and nerve growth factor. Moriguchi, T., Gotoh, Y., Nishida, E. Eur. J. Biochem. (1995) [Pubmed]
  40. Over-expression of the mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK in hepatocellular carcinoma: its role in tumor progression and apoptosis. Huynh, H., Nguyen, T.T., Chow, K.H., Tan, P.H., Soo, K.C., Tran, E. BMC gastroenterology [electronic resource]. (2003) [Pubmed]
  41. Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma. Huynh, H., Soo, K.C., Chow, P.K., Tran, E. Mol. Cancer Ther. (2007) [Pubmed]
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