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Gene Review

MAP2K1  -  mitogen-activated protein kinase kinase 1

Homo sapiens

Synonyms: CFC3, Dual specificity mitogen-activated protein kinase kinase 1, ERK activator kinase 1, MAP kinase kinase 1, MAPK/ERK kinase 1, ...
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Disease relevance of MAP2K1


Psychiatry related information on MAP2K1

  • Additionally, increased levels of Raf-1 are associated with Ras and MEK1 in Alzheimer's disease as evidenced by its coimmunoprecipitation with Ras and Mek1, respectively [6].
  • However, increased diffuse Fas, Fas-L, MEK, ERK and Bax expression, and enhanced granular active caspase-3 immunoreactivity was found in the cytoplasm of Purkinje cells in CJD [7].

High impact information on MAP2K1

  • MEK1, a component of the MAP kinase signaling pathway recently implicated in mitotic Golgi fragmentation, was not required for GM130 phosphorylation or mitotic fragmentation either in vitro or in vivo [8].
  • We propose that Cdc2 is directly involved in mitotic Golgi fragmentation and that signaling via MEK1 is not required for this process [8].
  • Here we show that in cells deficient in the Src-related tyrosine kinase Lyn, stimulation of MAPK kinase and MARPK by Gq-coupled m1 muscarinic acetylcholine receptors (mAChR) is blocked, whereas Gi-coupled m2 mAChR-mediated stimulation is unaffected [9].
  • Here we report that CAP kinase phosphorylates Raf1 on Thr 269, increasing its activity towards MEK (MAP kinase or ERK kinase) [10].
  • A protein called MP1 (MEK Partner 1) was identified that bound specifically to MEK1 and ERK1 and facilitated their activation [11].

Chemical compound and disease context of MAP2K1

  • Furthermore, overexpressing alanine-substituted (S75A) Bad further sensitizes melanoma cells to MEK inhibitor-induced apoptosis [12].
  • In this report, we definitively establish a role for ERK1/2 in oxidative toxicity using dominant negative MEK1 expression in transiently transfected HT22 cells to block glutamate-induced cell death [13].
  • Selective blockade of p42/44 MAPK activity by PD98059 or by transfection of a MEK1 dominant negative adenovirus significantly inhibited the PE-induced scattering of TFG2 cells [14].
  • The role of activated MEK-ERK pathway in quercetin-induced growth inhibition and apoptosis in A549 lung cancer cells [15].
  • Stress-related signaling pathways in epithelial cells are modulated by hypoxia and confer protection from reoxygenation, since hypoxia and chemical inhibition of p38mapk and MEK1/2 similarly increase cytolysis resulting from O2- [16].

Biological context of MAP2K1


Anatomical context of MAP2K1

  • These data indicate that exogenous NO generated from SNP is able to stimulate fetoplacental artery endothelial cell proliferation at least partly via activation of the MAP2K1/2/MAPK3/1 cascade [22].
  • To determine regulatory phosphorylation sites of MAPKK, we isolated a Chinese hamster cDNA, that we epitope-tagged and expressed in fibroblasts [20].
  • Cell lines dependent on the activation of Tyr kinase mitogen receptor targets of the resorcylic acid lactones were unusually sensitive toward hypothemycin and showed the expected inhibition of kinase phosphorylation due to inhibition of the mitogen receptors and/or MEK1/2 and ERK1/2 [23].
  • Myc-tagged cRaf-1, MEK1, and green fluorescent protein-tagged ERK2 coprecipitated with Flag-tagged beta-arrestin-2 from transfected COS-7 cells [24].
  • Normal stress fiber and phosphocofilin levels were restored by the expression of human B-Raf and catalytically active MEK and by the overexpression of LIM kinase (LIMK) [25].

Associations of MAP2K1 with chemical compounds

  • In response to various external stimuli, MAP kinases are activated by phosphorylation on tyrosine and threonine by MAP kinase kinase (MAPKK), a dual specificity kinase [20].
  • Finally, replacing Ser222 with Asp, a negatively charged residue, restored MAPKK activity independently of the upstream kinase [20].
  • Survival signaling by MEK most likely results from the activation of ERKs since expression of a constitutively active form of ERK2 was as effective in protecting NIH 3T3 fibroblasts against doxorubicin-induced cell death as oncogenic MEK [26].
  • Lipopolysaccharide activation of the MEK-ERK1/2 pathway in human monocytic cells mediates tissue factor and tumor necrosis factor alpha expression by inducing Elk-1 phosphorylation and Egr-1 expression [27].
  • Synergistic antileukemic interactions between 17-AAG and UCN-01 involve interruption of RAF/MEK- and AKT-related pathways [28].

Physical interactions of MAP2K1

  • Pull-down assays showed that Plk3 physically interacted with MEK1 and ERK2 [29].
  • Both wild type and constitutively active MEK1 coimmunoprecipitated with Raf-1 whether or not the insert was present [30].
  • These results support the concept that MP1 functions as a regulator of MAP kinase signaling by binding to MEK1 and regulating its association with a larger signaling complex that may sequentially service multiple molecules of ERK [31].
  • It is concluded that ouabain stimulates proliferation in ADPKD cells by binding to the Na,K-ATPase with high affinity and via activation of the MEK-ERK pathway [32].
  • We then identified two conserved hydrophobic residues on ERK2 that play roles in docking with MEK1 [33].

Enzymatic interactions of MAP2K1

  • These findings indicate that MAPKK-1* phosphorylates p42 MAPK by a two-collision, distributive mechanism rather than a single-collision, processive mechanism, and provide a mechanistic basis for understanding how MAP kinase can convert graded inputs into switch-like outputs [34].
  • This could be partly explained by the inability of Raf-1 to phosphorylate MKK1 C-terminal deletion mutants even though the phosphorylation sites were intact in these mutants [35].
  • Here we report that MLK3 can phosphorylate and activate MEK-1 directly in vitro and also can induce MEK phosphorylation on its activation sites in vivo in COS-7 cells [36].
  • Treatment of these cells with the MAPK kinase inhibitor PD98059 prior to infection blocked the increase in phosphorylated ERK1/2 seen with infection [37].
  • Western blot analysis demonstrated that IL-6 indeed increased the activation of phosphorylated MEK and p38 MAPK in GH3 cells [38].

Regulatory relationships of MAP2K1

  • However, only S222A/MAPKK showed a reduction in phosphorylation in response to active MAPKKK and exerted a dominant negative effect on the serum-stimulated endogenous MAPKK [20].
  • The MEK1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases ERK1 and ERK2 in mammalian cells [30].
  • Although c-Raf and B-Raf have been implicated in growth factor-induced MEK activation, little is known about A-Raf [39].
  • Furthermore, overexpression of the constitutively active MEK1 induced IL-8 and MIP3alpha protein production [40].
  • Blockade of MEK1 by PD98059 suppresses c-Fos and Fra-1 expression and, thus, affects two counteractive signals for IL-8 mRNA synthesis simultaneously [41].

Other interactions of MAP2K1

  • A conserved docking site, termed DVD, is found in the mammalian MAP kinase kinases (MAPKKs) belonging to the three major subfamilies, namely MEK1, MKK4/7, and MKK3/6 [19].
  • These results strongly suggest that Ser222 represents one key MAPKKK-dependent phosphorylation site switching on and off the activity of MAPKK, an event crucial for growth control [20].
  • Here we show that MEK, the molecule immediately upstream of ERK in the Ras/mitogen-activated protein (MAP) kinase signaling cascade, also interacts directly with IQGAP1 [42].
  • These findings suggest that drugs that target the BRAF/MEK pathway could be combined with agents that target TNF-alpha and/or NF-kappaB signaling to provide exciting new therapeutic opportunities for the treatment of melanoma [43].
  • In particular, MEK-2 was considerably more sensitive than MEK-1 to the phosphatidylinositol 3-kinase inhibitor wortmannin [44].

Analytical, diagnostic and therapeutic context of MAP2K1

  • Microarray analysis reveals that some genes are precociously expressed in mek1(-) and erk1(-) cells [45].
  • No modifications in the expression of non-phosphorylated MEK-1, ERK2 and GSK-3alpha/beta, as revealed by immunohistochemistry, were seen in AGD, but sarkosyl-insoluble fractions were particularly enriched in JNK-1 and alphaCaM kinase II [46].
  • Immunofluorescence analysis of MKK1 mutants revealed a loss of homogenous cytosolic distribution that is typically observed with MKK1 wild type, suggesting this region regulates MKK1 cellular localization [35].
  • Furthermore, compared with platelets and cells expressing the Leu(33) isoform, the Pro(33) variant showed greater alpha-granule release, clot retraction, and adhesion to fibrinogen under shear stress, and these functional differences were abolished by MLCK and MAPK kinase inhibition [47].
  • Quantitative evaluation of the steady state kinetics of MEK inhibition by these compounds reveals that U0126 has approximately 100-fold higher affinity for deltaN3-S218E/S222D MEK than does PD098059 [48].


  1. Inhibition of the mitogen-activated protein kinase kinase superfamily by a Yersinia effector. Orth, K., Palmer, L.E., Bao, Z.Q., Stewart, S., Rudolph, A.E., Bliska, J.B., Dixon, J.E. Science (1999) [Pubmed]
  2. The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. Sumimoto, H., Imabayashi, F., Iwata, T., Kawakami, Y. J. Exp. Med. (2006) [Pubmed]
  3. Signal transduction pathways involved in soluble fractalkine-induced monocytic cell adhesion. Cambien, B., Pomeranz, M., Schmid-Antomarchi, H., Millet, M.A., Breittmayer, V., Rossi, B., Schmid-Alliana, A. Blood (2001) [Pubmed]
  4. Cell-cycle-dependent activation of mitogen-activated protein kinase kinase (MEK-1/2) in myeloid leukemia cell lines and induction of growth inhibition and apoptosis by inhibitors of RAS signaling. Morgan, M.A., Dolp, O., Reuter, C.W. Blood (2001) [Pubmed]
  5. Blocking the Raf/MEK/ERK pathway sensitizes acute myelogenous leukemia cells to lovastatin-induced apoptosis. Wu, J., Wong, W.W., Khosravi, F., Minden, M.D., Penn, L.Z. Cancer Res. (2004) [Pubmed]
  6. Distribution, levels and phosphorylation of Raf-1 in Alzheimer's disease. Mei, M., Su, B., Harrison, K., Chao, M., Siedlak, S.L., Previll, L.A., Jackson, L., Cai, D.X., Zhu, X. J. Neurochem. (2006) [Pubmed]
  7. Cell death signaling in the cerebellum in Creutzfeldt-Jakob disease. Puig, B., Ferrer, I. Acta Neuropathol. (2001) [Pubmed]
  8. Cdc2 kinase directly phosphorylates the cis-Golgi matrix protein GM130 and is required for Golgi fragmentation in mitosis. Lowe, M., Rabouille, C., Nakamura, N., Watson, R., Jackman, M., Jämsä, E., Rahman, D., Pappin, D.J., Warren, G. Cell (1998) [Pubmed]
  9. Tyrosine kinases in activation of the MAP kinase cascade by G-protein-coupled receptors. Wan, Y., Kurosaki, T., Huang, X.Y. Nature (1996) [Pubmed]
  10. Phosphorylation of Raf by ceramide-activated protein kinase. Yao, B., Zhang, Y., Delikat, S., Mathias, S., Basu, S., Kolesnick, R. Nature (1995) [Pubmed]
  11. MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. Schaeffer, H.J., Catling, A.D., Eblen, S.T., Collier, L.S., Krauss, A., Weber, M.J. Science (1998) [Pubmed]
  12. Mitogen-activated protein kinase pathway-dependent tumor-specific survival signaling in melanoma cells through inactivation of the proapoptotic protein bad. Eisenmann, K.M., VanBrocklin, M.W., Staffend, N.A., Kitchen, S.M., Koo, H.M. Cancer Res. (2003) [Pubmed]
  13. Opposing roles for ERK1/2 in neuronal oxidative toxicity: distinct mechanisms of ERK1/2 action at early versus late phases of oxidative stress. Luo, Y., DeFranco, D.B. J. Biol. Chem. (2006) [Pubmed]
  14. Activation of mitogen-activated protein kinases is required for alpha1-adrenergic agonist-induced cell scattering in transfected HepG2 cells. Spector, M., Nguyen, V.A., Sheng, X., He, L., Woodward, J., Fan, S., Baumgarten, C.M., Kunos, G., Dent, P., Gao, B. Exp. Cell Res. (2000) [Pubmed]
  15. The role of activated MEK-ERK pathway in quercetin-induced growth inhibition and apoptosis in A549 lung cancer cells. Nguyen, T.T., Tran, E., Nguyen, T.H., Do, P.T., Huynh, T.H., Huynh, H. Carcinogenesis (2004) [Pubmed]
  16. 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]
  17. Chromosome mapping of the human genes encoding the MAP kinase kinase MEK1 (MAP2K1) to 15q21 and MEK2 (MAP2K2) to 7q32. Meloche, S., Gopalbhai, K., Beatty, B.G., Scherer, S.W., Pellerin, J. Cytogenet. Cell Genet. (2000) [Pubmed]
  18. Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Dérijard, B., Raingeaud, J., Barrett, T., Wu, I.H., Han, J., Ulevitch, R.J., Davis, R.J. Science (1995) [Pubmed]
  19. Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases. Takekawa, M., Tatebayashi, K., Saito, H. Mol. Cell (2005) [Pubmed]
  20. Constitutive mutant and putative regulatory serine phosphorylation site of mammalian MAP kinase kinase (MEK1). Pagès, G., Brunet, A., L'Allemain, G., Pouysségur, J. EMBO J. (1994) [Pubmed]
  21. Anti-apoptotic signaling by hepatocyte growth factor/Met via the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. Xiao, G.H., Jeffers, M., Bellacosa, A., Mitsuuchi, Y., Vande Woude , G.F., Testa, J.R. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  22. Exogenous nitric oxide stimulates cell proliferation via activation of a mitogen-activated protein kinase pathway in ovine fetoplacental artery endothelial cells. Zheng, J., Wen, Y., Austin, J.L., Chen, D.B. Biol. Reprod. (2006) [Pubmed]
  23. Targeted covalent inactivation of protein kinases by resorcylic acid lactone polyketides. Schirmer, A., Kennedy, J., Murli, S., Reid, R., Santi, D.V. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  24. Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Luttrell, L.M., Roudabush, F.L., Choy, E.W., Miller, W.E., Field, M.E., Pierce, K.L., Lefkowitz, R.J. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  25. B-Raf acts via the ROCKII/LIMK/cofilin pathway to maintain actin stress fibers in fibroblasts. Pritchard, C.A., Hayes, L., Wojnowski, L., Zimmer, A., Marais, R.M., Norman, J.C. Mol. Cell. Biol. (2004) [Pubmed]
  26. Apoptosis suppression by Raf-1 and MEK1 requires MEK- and phosphatidylinositol 3-kinase-dependent signals. von Gise, A., Lorenz, P., Wellbrock, C., Hemmings, B., Berberich-Siebelt, F., Rapp, U.R., Troppmair, J. Mol. Cell. Biol. (2001) [Pubmed]
  27. Lipopolysaccharide activation of the MEK-ERK1/2 pathway in human monocytic cells mediates tissue factor and tumor necrosis factor alpha expression by inducing Elk-1 phosphorylation and Egr-1 expression. Guha, M., O'Connell, M.A., Pawlinski, R., Hollis, A., McGovern, P., Yan, S.F., Stern, D., Mackman, N. Blood (2001) [Pubmed]
  28. Synergistic antileukemic interactions between 17-AAG and UCN-01 involve interruption of RAF/MEK- and AKT-related pathways. Jia, W., Yu, C., Rahmani, M., Krystal, G., Sausville, E.A., Dent, P., Grant, S. Blood (2003) [Pubmed]
  29. MEK1-induced Golgi dynamics during cell cycle progression is partly mediated by Polo-like kinase-3. Xie, S., Wang, Q., Ruan, Q., Liu, T., Jhanwar-Uniyal, M., Guan, K., Dai, W. Oncogene (2004) [Pubmed]
  30. The MEK1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases ERK1 and ERK2 in mammalian cells. Dang, A., Frost, J.A., Cobb, M.H. J. Biol. Chem. (1998) [Pubmed]
  31. MEK partner 1 (MP1): regulation of oligomerization in MAP kinase signaling. Sharma, C., Vomastek, T., Tarcsafalvi, A., Catling, A.D., Schaeffer, H.J., Eblen, S.T., Weber, M.J. J. Cell. Biochem. (2005) [Pubmed]
  32. Ouabain Binds with High Affinity to the Na,K-ATPase in Human Polycystic Kidney Cells and Induces Extracellular Signal-Regulated Kinase Activation and Cell Proliferation. Nguyen, A.N., Wallace, D.P., Blanco, G. J. Am. Soc. Nephrol. (2007) [Pubmed]
  33. Hydrophobic as well as charged residues in both MEK1 and ERK2 are important for their proper docking. Xu Be, n.u.l.l., Stippec, S., Robinson, F.L., Cobb, M.H. J. Biol. Chem. (2001) [Pubmed]
  34. Mechanistic studies of the dual phosphorylation of mitogen-activated protein kinase. Ferrell, J.E., Bhatt, R.R. J. Biol. Chem. (1997) [Pubmed]
  35. Identification of a C-terminal region that regulates mitogen-activated protein kinase kinase-1 cytoplasmic localization and ERK activation. Cha, H., Lee, E.K., Shapiro, P. J. Biol. Chem. (2001) [Pubmed]
  36. Cross-talk between JNK/SAPK and ERK/MAPK pathways: sustained activation of JNK blocks ERK activation by mitogenic factors. Shen, Y.H., Godlewski, J., Zhu, J., Sathyanarayana, P., Leaner, V., Birrer, M.J., Rana, A., Tzivion, G. J. Biol. Chem. (2003) [Pubmed]
  37. Trypanosoma cruzi infection activates extracellular signal-regulated kinase in cultured endothelial and smooth muscle cells. Mukherjee, S., Huang, H., Petkova, S.B., Albanese, C., Pestell, R.G., Braunstein, V.L., Christ, G.J., Wittner, M., Lisanti, M.P., Berman, J.W., Weiss, L.M., Tanowitz, H.B. Infect. Immun. (2004) [Pubmed]
  38. The regulatory mechanism by which interleukin-6 stimulates GH-gene expression in rat GH3 cells. Gong, F.Y., Shi, Y.F., Deng, J.Y. J. Endocrinol. (2006) [Pubmed]
  39. Selective activation of MEK1 but not MEK2 by A-Raf from epidermal growth factor-stimulated Hela cells. Wu, X., Noh, S.J., Zhou, G., Dixon, J.E., Guan, K.L. J. Biol. Chem. (1996) [Pubmed]
  40. MEK is a key modulator for TLR5-induced interleukin-8 and MIP3alpha gene expression in non-transformed human colonic epithelial cells. Rhee, S.H., Keates, A.C., Moyer, M.P., Pothoulakis, C. J. Biol. Chem. (2004) [Pubmed]
  41. MEK1-dependent delayed expression of Fos-related antigen-1 counteracts c-Fos and p65 NF-kappaB-mediated interleukin-8 transcription in response to cytokines or growth factors. Hoffmann, E., Thiefes, A., Buhrow, D., Dittrich-Breiholz, O., Schneider, H., Resch, K., Kracht, M. J. Biol. Chem. (2005) [Pubmed]
  42. IQGAP1 is a scaffold for mitogen-activated protein kinase signaling. Roy, M., Li, Z., Sacks, D.B. Mol. Cell. Biol. (2005) [Pubmed]
  43. Tumor Necrosis Factor-{alpha} Blocks Apoptosis in Melanoma Cells when BRAF Signaling Is Inhibited. Gray-Schopfer, V.C., Karasarides, M., Hayward, R., Marais, R. Cancer Res. (2007) [Pubmed]
  44. Chemotactic peptide-induced activation of MEK-2, the predominant isoform in human neutrophils. Inhibition by wortmannin. Downey, G.P., Butler, J.R., Brumell, J., Borregaard, N., Kjeldsen, L., Sue-A-Quan, A.K., Grinstein, S. J. Biol. Chem. (1996) [Pubmed]
  45. Loss of SMEK, a novel, conserved protein, suppresses MEK1 null cell polarity, chemotaxis, and gene expression defects. Mendoza, M.C., Du, F., Iranfar, N., Tang, N., Ma, H., Loomis, W.F., Firtel, R.A. Mol. Cell. Biol. (2005) [Pubmed]
  46. Phosphorylated protein kinases associated with neuronal and glial tau deposits in argyrophilic grain disease. Ferrer, I., Barrachina, M., Tolnay, M., Rey, M.J., Vidal, N., Carmona, M., Blanco, R., Puig, B. Brain Pathol. (2003) [Pubmed]
  47. Enhanced activation of mitogen-activated protein kinase and myosin light chain kinase by the Pro33 polymorphism of integrin beta 3. Vijayan, K.V., Liu, Y., Dong, J.F., Bray, P.F. J. Biol. Chem. (2003) [Pubmed]
  48. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. Favata, M.F., Horiuchi, K.Y., Manos, E.J., Daulerio, A.J., Stradley, D.A., Feeser, W.S., Van Dyk, D.E., Pitts, W.J., Earl, R.A., Hobbs, F., Copeland, R.A., Magolda, R.L., Scherle, P.A., Trzaskos, J.M. J. Biol. Chem. (1998) [Pubmed]
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