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Gene Review

Map2k1  -  mitogen activated protein kinase kinase 1

Rattus norvegicus

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


Psychiatry related information on Map2k1


High impact information on Map2k1

  • Interestingly, we find a Golgi-associated ERK, which we propose as the likely target for MEK1 in Golgi fragmentation [10].
  • However, the known cytoplasmic substrates for MEK1, ERK1, and ERK2 are not required for this process [10].
  • Signaling via mitogen-activated protein kinase kinase (MEK1) is required for Golgi fragmentation during mitosis [10].
  • Thus the forming of complexes containing MAPKK activity and Raf-1 protein are dependent upon the activity of Ras [11].
  • Downstream effectors of CaMKI include the MAP-kinase pathway of Ras/MEK/ERK and the transcription factor CREB [12].

Chemical compound and disease context of Map2k1


Biological context of Map2k1


Anatomical context of Map2k1


Associations of Map2k1 with chemical compounds

  • Phosphorylation of serine 105 enhanced the transcriptional potency of GATA4, which was sensitive to U0126 (MEK1 inhibitor) but not SB202190 (p38 inhibitor) [2].
  • In retrogradely perfused hearts, high coronary perfusion pressure (120 mm Hg for 5 minutes), norepinephrine (50 mumol/L for 5 minutes), or isoproterenol (50 mumol/L for 5 minutes) stimulated MAPK and MEK approximately 2- to 5-fold [25].
  • Finally, FHL2 partially antagonized the cardiac hypertrophic response induced by activated MEK-1, GATA4, and phenylephrine agonist stimulation [26].
  • Similarly, these inhibitors as well as inhibitors of MEK 1/2 counteracted the loss in gap-junctional communication elicited by menadione [27].
  • Contraction-stimulated phosphorylation of ERK1/2 and p38(MAPK) was completely inhibited by pretreatment with PD98059 (MAPK kinase inhibitor) and SB203580 (p38(MAPK) inhibitor), respectively [28].

Physical interactions of Map2k1


Enzymatic interactions of Map2k1


Regulatory relationships of Map2k1


Other interactions of Map2k1

  • The effect of ET-1 and PDGF BB on MEK-1 mRNA expression was maximal after 24 h (3.3-fold) or 6 h (2.9-fold) [36].
  • Incubation with PD 98059 blocked angiotensin II (AII)-dependent phosphorylation and enzymatic activity of both MEK1 and MEK2 isoforms, leading to inhibition of the phosphorylation and activation of p44(mapk) and p42(mapk) [22].
  • The rapid induction of ERK1/2 phosphorylation was completely blocked by pretreatment with a MEK1 inhibitor and was associated with a nearly complete inhibition of insulin-stimulated induction of both Egr-1and Krox20, indicating this pathway is necessary for insulin's effect on these genes [37].
  • Furthermore, cAMP response element-binding protein, a transcription factor, was also activated by suramin in a MEK-dependent manner [38].
  • Manganese-induced up-regulation of caspase-3 mRNA was partially attenuated by the pretreatment with the MEK inhibitor U0126, but not with the c-Jun N-terminal kinase (JNK) inhibitor SP600125 [39].

Analytical, diagnostic and therapeutic context of Map2k1

  • Immunoblotting showed that the relative abundances of MAPK and MEK protein in ventricles declined to < 20% of their postpartal abundances after 50 days [25].
  • Third, a correlation between the mid-late G(1) MEK/ERK activation in hepatocytes in vivo after partial hepatectomy and the mitogen-independent proliferation capacity of these cells in vitro was established [19].
  • These results gave a new insight of the dynamics of ERK2 and MEK in the nuclear shuttling of RBL-2H3 cells after the ligation of IgE receptors [40].
  • MATERIALS AND METHODS: Using a rat calvarial organ culture system, the inhibition of ERK phosphorylation by PD98059, a MAPK/ERK kinase 1 (MEK1) inhibitor, was assayed by immunoblotting [41].
  • Immunohistochemistry revealed that clozapine treatment elevated the number of cells in the prefrontal cortex positive for phosphoERK, the downstream substrate of MEK1/2 [42].


  1. A specific activation of the mitogen-activated protein kinase kinase 1 (MEK1) is required for Golgi fragmentation during mitosis. Colanzi, A., Deerinck, T.J., Ellisman, M.H., Malhotra, V. J. Cell Biol. (2000) [Pubmed]
  2. The transcription factor GATA4 is activated by extracellular signal-regulated kinase 1- and 2-mediated phosphorylation of serine 105 in cardiomyocytes. Liang, Q., Wiese, R.J., Bueno, O.F., Dai, Y.S., Markham, B.E., Molkentin, J.D. Mol. Cell. Biol. (2001) [Pubmed]
  3. Identification of MEK1 as a novel target for the treatment of neuropathic pain. Ciruela, A., Dixon, A.K., Bramwell, S., Gonzalez, M.I., Pinnock, R.D., Lee, K. Br. J. Pharmacol. (2003) [Pubmed]
  4. Baicalein inhibits Raf-1-mediated phosphorylation of MEK-1 in C6 rat glioma cells. Nakahata, N., Tsuchiya, C., Nakatani, K., Ohizumi, Y., Ohkubo, S. Eur. J. Pharmacol. (2003) [Pubmed]
  5. Different effects of amlodipine and enalapril on the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase pathway for induction of vascular smooth muscle cell differentiation in vivo. Umemoto, S., Kawahara, S., Hashimoto, R., Umeji, K., Matsuda, S., Tanaka, M., Kubo, M., Matsuzaki, M. Hypertens. Res. (2006) [Pubmed]
  6. Okadaic-acid-induced inhibition of protein phosphatase 2A produces activation of mitogen-activated protein kinases ERK1/2, MEK1/2, and p70 S6, similar to that in Alzheimer's disease. Pei, J.J., Gong, C.X., An, W.L., Winblad, B., Cowburn, R.F., Grundke-Iqbal, I., Iqbal, K. Am. J. Pathol. (2003) [Pubmed]
  7. Inhibition of the phosphodiesterase 4 (PDE4) enzyme reverses memory deficits produced by infusion of the MEK inhibitor U0126 into the CA1 subregion of the rat hippocampus. Zhang, H.T., Zhao, Y., Huang, Y., Dorairaj, N.R., Chandler, L.J., O'Donnell, J.M. Neuropsychopharmacology (2004) [Pubmed]
  8. Role of hippocampal signaling pathways in long-term memory formation of a nonassociative learning task in the rat. Vianna, M.R., Alonso, M., Viola, H., Quevedo, J., de Paris, F., Furman, M., de Stein, M.L., Medina, J.H., Izquierdo, I. Learn. Mem. (2000) [Pubmed]
  9. Electroconvulsive shock increases the phosphorylation of Pyk2 in the rat hippocampus. Jeon, S.H., Oh, S.W., Kang, U.G., Ahn, Y.M., Bae, C.D., Park, J.B., Kim, Y.S. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  10. Signaling via mitogen-activated protein kinase kinase (MEK1) is required for Golgi fragmentation during mitosis. Acharya, U., Mallabiabarrena, A., Acharya, J.K., Malhotra, V. Cell (1998) [Pubmed]
  11. Complexes of Ras.GTP with Raf-1 and mitogen-activated protein kinase kinase. Moodie, S.A., Willumsen, B.M., Weber, M.J., Wolfman, A. Science (1993) [Pubmed]
  12. Activity-dependent dendritic arborization mediated by CaM-kinase I activation and enhanced CREB-dependent transcription of Wnt-2. Wayman, G.A., Impey, S., Marks, D., Saneyoshi, T., Grant, W.F., Derkach, V., Soderling, T.R. Neuron (2006) [Pubmed]
  13. Nuclear mitogen-activated protein kinase activation by protein kinase czeta during reoxygenation after ischemic hypoxia. Mizukami, Y., Kobayashi, S., Uberall, F., Hellbert, K., Kobayashi, N., Yoshida, K. J. Biol. Chem. (2000) [Pubmed]
  14. Renal ischemia/reperfusion and ATP depletion/repletion in LLC-PK(1) cells result in phosphorylation of FKHR and FKHRL1. Andreucci, M., Michael, A., Kramers, C., Park, K.M., Chen, A., Matthaeus, T., Alessandrini, A., Haq, S., Force, T., Bonventre, J.V. Kidney Int. (2003) [Pubmed]
  15. Activation of ERK1 and ERK2 is required for manganese-induced neurite outgrowth in rat pheochromocytoma (PC12) cells. Walowitz, J.L., Roth, J.A. J. Neurosci. Res. (1999) [Pubmed]
  16. Acrolein activates mitogen-activated protein kinase signal transduction pathways in rat vascular smooth muscle cells. Ranganna, K., Yousefipour, Z., Nasif, R., Yatsu, F.M., Milton, S.G., Hayes, B.E. Mol. Cell. Biochem. (2002) [Pubmed]
  17. alpha 2B-adrenergic receptor activates MAPK via a pathway involving arachidonic acid metabolism, matrix metalloproteinases, and epidermal growth factor receptor transactivation. Cussac, D., Schaak, S., Denis, C., Paris, H. J. Biol. Chem. (2002) [Pubmed]
  18. Nuclear export of MAP kinase (ERK) involves a MAP kinase kinase (MEK)-dependent active transport mechanism. Adachi, M., Fukuda, M., Nishida, E. J. Cell Biol. (2000) [Pubmed]
  19. The mitogen-activated protein kinase kinase/extracellular signal-regulated kinase cascade activation is a key signalling pathway involved in the regulation of G(1) phase progression in proliferating hepatocytes. Talarmin, H., Rescan, C., Cariou, S., Glaise, D., Zanninelli, G., Bilodeau, M., Loyer, P., Guguen-Guillouzo, C., Baffet, G. Mol. Cell. Biol. (1999) [Pubmed]
  20. Simian virus 40 small t antigen cooperates with mitogen-activated kinases to stimulate AP-1 activity. Frost, J.A., Alberts, A.S., Sontag, E., Guan, K., Mumby, M.C., Feramisco, J.R. Mol. Cell. Biol. (1994) [Pubmed]
  21. Induction of neurite extension and survival in pheochromocytoma cells by the Rit GTPase. Spencer, M.L., Shao, H., Andres, D.A. J. Biol. Chem. (2002) [Pubmed]
  22. Inhibition of growth factor-induced protein synthesis by a selective MEK inhibitor in aortic smooth muscle cells. Servant, M.J., Giasson, E., Meloche, S. J. Biol. Chem. (1996) [Pubmed]
  23. MEK-ERK signaling is involved in interferon-gamma-induced death of oligodendroglial progenitor cells. Horiuchi, M., Itoh, A., Pleasure, D., Itoh, T. J. Biol. Chem. (2006) [Pubmed]
  24. MEK and ERK activation in ras-disabled RBL-2H3 mast cells and novel roles for geranylgeranylated and farnesylated proteins in Fc epsilonRI-mediated signaling. Graham, T.E., Pfeiffer, J.R., Lee, R.J., Kusewitt, D.F., Martinez, A.M., Foutz, T., Wilson, B.S., Oliver, J.M. J. Immunol. (1998) [Pubmed]
  25. Regulation of mitogen-activated protein kinase cascade in adult rat heart preparations in vitro. Lazou, A., Bogoyevitch, M.A., Clerk, A., Fuller, S.J., Marshall C, J., Sugden, P.H. Circ. Res. (1994) [Pubmed]
  26. Extracellular signal-regulated kinase 2 interacts with and is negatively regulated by the LIM-only protein FHL2 in cardiomyocytes. Purcell, N.H., Darwis, D., Bueno, O.F., Müller, J.M., Schüle, R., Molkentin, J.D. Mol. Cell. Biol. (2004) [Pubmed]
  27. 2-Methyl-1,4-naphthoquinone, vitamin K(3), decreases gap-junctional intercellular communication via activation of the epidermal growth factor receptor/extracellular signal-regulated kinase cascade. Klotz, L.O., Patak, P., Ale-Agha, N., Buchczyk, D.P., Abdelmohsen, K., Gerber, P.A., von Montfort, C., Sies, H. Cancer Res. (2002) [Pubmed]
  28. Effect of contraction on mitogen-activated protein kinase signal transduction in skeletal muscle. Involvement Of the mitogen- and stress-activated protein kinase 1. Ryder, J.W., Fahlman, R., Wallberg-Henriksson, H., Alessi, D.R., Krook, A., Zierath, J.R. J. Biol. Chem. (2000) [Pubmed]
  29. Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway leading to cyclic AMP response element-binding protein phosphorylation is required for the long-term facilitation process of aversive olfactory learning in young rats. Zhang, J.J., Okutani, F., Inoue, S., Kaba, H. Neuroscience (2003) [Pubmed]
  30. Association of MEK1 with p21ras.GMPPNP is dependent on B-Raf. Moodie, S.A., Paris, M.J., Kolch, W., Wolfman, A. Mol. Cell. Biol. (1994) [Pubmed]
  31. Involvement of Ras and Raf in the Gi-coupled acetylcholine muscarinic m2 receptor activation of mitogen-activated protein (MAP) kinase kinase and MAP kinase. Winitz, S., Russell, M., Qian, N.X., Gardner, A., Dwyer, L., Johnson, G.L. J. Biol. Chem. (1993) [Pubmed]
  32. Nerve growth factor stimulates a novel protein kinase in PC-12 cells that phosphorylates and activates mitogen-activated protein kinase kinase (MEK). Pang, L., Zheng, C.F., Guan, K.L., Saltiel, A.R. Biochem. J. (1995) [Pubmed]
  33. Role of protein phosphatase 2A in mGluR5-regulated MEK/ERK phosphorylation in neurons. Mao, L., Yang, L., Arora, A., Choe, E.S., Zhang, G., Liu, Z., Fibuch, E.E., Wang, J.Q. J. Biol. Chem. (2005) [Pubmed]
  34. p42/p44 mitogen-activated protein kinases activation is required for the insulin-like growth factor-I/insulin induced proliferation, but inhibits differentiation, in rat fetal brown adipocytes. Porras, A., Alvarez, A.M., Valladares, A., Benito, M. Mol. Endocrinol. (1998) [Pubmed]
  35. AUF-1 mediates inhibition by nitric oxide of lipopolysaccharide-induced matrix metalloproteinase-9 expression in cultured astrocytes. Liu, W., Rosenberg, G.A., Liu, K.J. J. Neurosci. Res. (2006) [Pubmed]
  36. ET-1 and PDGF BB induce MEK mRNA and protein expression in mesangial cells. Schramek, H., Sorokin, A., Watson, R.D., Dunn, M.J. J. Cardiovasc. Pharmacol. (1995) [Pubmed]
  37. Insulin-regulated expression of Egr-1 and Krox20: dependence on ERK1/2 and interaction with p38 and PI3-kinase pathways. Keeton, A.B., Bortoff, K.D., Bennett, W.L., Franklin, J.L., Venable, D.Y., Messina, J.L. Endocrinology (2003) [Pubmed]
  38. Stimulation of extracellular signal-regulated kinase pathway by suramin with concomitant activation of DNA synthesis in cultured cells. Nakata, H. J. Pharmacol. Exp. Ther. (2004) [Pubmed]
  39. p44/42 MAP kinase and c-Jun N-terminal kinase contribute to the up-regulation of caspase-3 in manganese-induced apoptosis in PC12 cells. Ito, Y., Oh-Hashi, K., Kiuchi, K., Hirata, Y. Brain Res. (2006) [Pubmed]
  40. Nuclear shuttling of mitogen-activated protein (MAP) kinase (extracellular signal-regulated kinase (ERK) 2) was dynamically controlled by MAP/ERK kinase after antigen stimulation in RBL-2H3 cells. Furuno, T., Hirashima, N., Onizawa, S., Sagiya, N., Nakanishi, M. J. Immunol. (2001) [Pubmed]
  41. Role of osteoclast extracellular signal-regulated kinase (ERK) in cell survival and maintenance of cell polarity. Nakamura, H., Hirata, A., Tsuji, T., Yamamoto, T. J. Bone Miner. Res. (2003) [Pubmed]
  42. Clozapine and the mitogen-activated protein kinase signal transduction pathway: implications for antipsychotic actions. Browning, J.L., Patel, T., Brandt, P.C., Young, K.A., Holcomb, L.A., Hicks, P.B. Biol. Psychiatry (2005) [Pubmed]
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