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Gene Review

MAPK7  -  mitogen-activated protein kinase 7

Homo sapiens

Synonyms: BMK-1, BMK1, Big MAP kinase 1, ERK-5, ERK4, ...
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Disease relevance of MAPK7


High impact information on MAPK7

  • Expression of a dominant-negative form of Bmk1 blocks EGF-induced cell proliferation and prevents cells from entering the S phase of the cell cycle [6].
  • Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor [6].
  • Big MAP kinase (Bmk1), also known as Erk5, is a member of the MAP kinase family that is activated in cells in response to oxidative stress, hyperosmolarity and treatment with serum [6].
  • ERK5 inhibits the nuclear export of c-Fos by phosphorylating Thr232 in the c-Fos NES(221-233) and disrupts the interaction of c-Fos with UBR1 by phosphorylating Ser32 [7].
  • Moreover, UBR1 depletion in HeLa cells, which constitutively express UBR1 at a high level, enhances both c-Fos expression and cell growth, whereas ERK5 depletion reduces both of them [7].

Chemical compound and disease context of MAPK7

  • The i.t. administration of ERK5 antisense oligodeoxynucleotide reversed heat hyperalgesia, but not mechanical allodynia, produced by capsaicin injection [8].

Biological context of MAPK7


Anatomical context of MAPK7

  • To elucidate molecular functions of ERK5 in the development of vasculature and other tissues, we performed gene profile analyses of erk5-/- mouse embryos and erk5-/- fibroblast cells reconstituted with ERK5 or ERK5(1-740), which lacks the transactivation domain [9].
  • Overexpression of both ERK5 and MEF2 induced a statistically significant increase in cell death of neurotrophin-3-responsive and nonresponsive medulloblastoma cell lines (Daoy-trkC and Daoy) and primary cultures of patched heterozygous mouse medulloblastomas [1].
  • The activation of ERK5 was inhibited by expression of dominant-negative Ras and induced by expression of active Ras in PC12 cells, indicating a requirement for Ras in ERK5 activation [11].
  • Regulation of epidermal growth factor-induced connexin 43 gap junction communication by big mitogen-activated protein kinase1/ERK5 but not ERK1/2 kinase activation [12].
  • Previous data show that BMK1 can be activated by steady laminar flow and is atheroprotective by preventing endothelial cells from undergoing apoptosis [13].

Associations of MAPK7 with chemical compounds

  • Here, we have found that ERK5 is required for mediating the survival of fibroblasts under basal conditions and in response to sorbitol treatment [14].
  • Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases. Identification and characterization of a signaling pathway to the nucleus [11].
  • These data demonstrate an inhibitory function for 14-3-3beta binding to BMK1 and show that serine 486 phosphorylation represents a novel regulatory mechanism for BMK1 [13].
  • Although unique in its structure, ERK5 is activated in analogy to other MAPKs by dual phosphorylation of threonine and tyrosine residues in its activation motif [15].
  • Phosphotyrosine-specific phosphatase PTP-SL regulates the ERK5 signaling pathway [15].

Physical interactions of MAPK7

  • Here, we report the identification of serum and glucocorticoid-inducible kinase (SGK) as a cellular protein that physically interacts with BMK1 [16].

Enzymatic interactions of MAPK7

  • Taken together, these data demonstrate that, upon growth factor induction, BMK1 directly phosphorylates and activates three members of the MEF2 family of transcription factors thereby inducing MEF2-dependent gene expression [17].

Regulatory relationships of MAPK7

  • BMK1 (ERK5) regulates squamous differentiation marker SPRR1B transcription in Clara-like H441 cells [18].
  • Activation of BMK1/ERK5 by epidermal growth factor and H2O2 in Cos7 and HEK293 cells was completely blocked by a kinase-inactive MEKK3 (MEKK3kin(-)), whereas MEKK2kin(-) had no effect [19].
  • The blocking of BMK1 signaling inhibits the epidermal growth factor-dependent activation of these three MEF2 transcription factors [17].
  • We have previously shown that BMK1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor MEF2C [17].
  • The ability of PMA to partially suppress TRAIL- and TNF-induced cell death was inhibited by BMK1/DN [20].

Other interactions of MAPK7

  • Furthermore, by co-immunoprecipitation, we found that BMK1 directly associates with Cx43 in vivo [12].
  • Most of the tumors displayed complex amplification profiles, with frequent involvement of marker D17S2041 in 17p12 and TOP3A in 17p11.2 and, in some cases, very high-level amplification of PMP22 and MAPK7 in 17p11 [21].
  • Here we show that EGF is a potent activator of Bmk1 [6].
  • MEK5 is the upstream BMK1 kinase and exists as naturally occurring splice variants, MEK5alpha and MEK5beta [10].
  • The sites phosphorylated by activated BMK1 were mapped to Ser-355, Thr-312, and Thr-319 of MEF2A and Ser-179 of MEF2D both in vitro and in vivo [17].

Analytical, diagnostic and therapeutic context of MAPK7


  1. A novel role for extracellular signal-regulated kinase 5 and myocyte enhancer factor 2 in medulloblastoma cell death. Sturla, L.M., Cowan, C.W., Guenther, L., Castellino, R.C., Kim, J.Y., Pomeroy, S.L. Cancer Res. (2005) [Pubmed]
  2. Multifunctional role of Erk5 in multiple myeloma. Carvajal-Vergara, X., Tabera, S., Montero, J.C., Esparís-Ogando, A., López-Pérez, R., Mateo, G., Gutiérrez, N., Parmo-Cabañas, M., Teixidó, J., San Miguel, J.F., Pandiella, A. Blood (2005) [Pubmed]
  3. Activated MEK5 induces serial assembly of sarcomeres and eccentric cardiac hypertrophy. Nicol, R.L., Frey, N., Pearson, G., Cobb, M., Richardson, J., Olson, E.N. EMBO J. (2001) [Pubmed]
  4. Erk5 participates in neuregulin signal transduction and is constitutively active in breast cancer cells overexpressing ErbB2. Esparís-Ogando, A., Díaz-Rodríguez, E., Montero, J.C., Yuste, L., Crespo, P., Pandiella, A. Mol. Cell. Biol. (2002) [Pubmed]
  5. Global gene expression analysis of ERK5 and ERK1/2 signaling reveals a role for HIF-1 in ERK5-mediated responses. Schweppe, R.E., Cheung, T.H., Ahn, N.G. J. Biol. Chem. (2006) [Pubmed]
  6. Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor. Kato, Y., Tapping, R.I., Huang, S., Watson, M.H., Ulevitch, R.J., Lee, J.D. Nature (1998) [Pubmed]
  7. Spatiotemporal Regulation of c-Fos by ERK5 and the E3 Ubiquitin Ligase UBR1, and Its Biological Role. Sasaki, T., Kojima, H., Kishimoto, R., Ikeda, A., Kunimoto, H., Nakajima, K. Mol. Cell (2006) [Pubmed]
  8. Intensity-dependent activation of extracellular signal-regulated protein kinase 5 in sensory neurons contributes to pain hypersensitivity. Mizushima, T., Obata, K., Katsura, H., Sakurai, J., Kobayashi, K., Yamanaka, H., Dai, Y., Fukuoka, T., Mashimo, T., Noguchi, K. J. Pharmacol. Exp. Ther. (2007) [Pubmed]
  9. Transcriptional regulation of tissue-specific genes by the ERK5 mitogen-activated protein kinase. Sohn, S.J., Li, D., Lee, L.K., Winoto, A. Mol. Cell. Biol. (2005) [Pubmed]
  10. Differential role of MEK5alpha and MEK5beta in BMK1/ERK5 activation. Cameron, S.J., Abe, J., Malik, S., Che, W., Yang, J. J. Biol. Chem. (2004) [Pubmed]
  11. Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases. Identification and characterization of a signaling pathway to the nucleus. Kamakura, S., Moriguchi, T., Nishida, E. J. Biol. Chem. (1999) [Pubmed]
  12. Regulation of epidermal growth factor-induced connexin 43 gap junction communication by big mitogen-activated protein kinase1/ERK5 but not ERK1/2 kinase activation. Cameron, S.J., Malik, S., Akaike, M., Lerner-Marmarosh, N., Yan, C., Lee, J.D., Abe, J., Yang, J. J. Biol. Chem. (2003) [Pubmed]
  13. 14-3-3beta binds to big mitogen-activated protein kinase 1 (BMK1/ERK5) and regulates BMK1 function. Zheng, Q., Yin, G., Yan, C., Cavet, M., Berk, B.C. J. Biol. Chem. (2004) [Pubmed]
  14. Activation of extracellular signal-regulated protein kinase 5 downregulates FasL upon osmotic stress. Wang, X., Finegan, K.G., Robinson, A.C., Knowles, L., Khosravi-Far, R., Hinchliffe, K.A., Boot-Handford, R.P., Tournier, C. Cell Death Differ. (2006) [Pubmed]
  15. Phosphotyrosine-specific phosphatase PTP-SL regulates the ERK5 signaling pathway. Buschbeck, M., Eickhoff, J., Sommer, M.N., Ullrich, A. J. Biol. Chem. (2002) [Pubmed]
  16. BMK1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinase. Hayashi, M., Tapping, R.I., Chao, T.H., Lo, J.F., King, C.C., Yang, Y., Lee, J.D. J. Biol. Chem. (2001) [Pubmed]
  17. Big mitogen-activated kinase regulates multiple members of the MEF2 protein family. Kato, Y., Zhao, M., Morikawa, A., Sugiyama, T., Chakravortty, D., Koide, N., Yoshida, T., Tapping, R.I., Yang, Y., Yokochi, T., Lee, J.D. J. Biol. Chem. (2000) [Pubmed]
  18. BMK1 (ERK5) regulates squamous differentiation marker SPRR1B transcription in Clara-like H441 cells. Reddy, S.P., Adiseshaiah, P., Shapiro, P., Vuong, H. Am. J. Respir. Cell Mol. Biol. (2002) [Pubmed]
  19. MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway. Sun, W., Kesavan, K., Schaefer, B.C., Garrington, T.P., Ware, M., Johnson, N.L., Gelfand, E.W., Johnson, G.L. J. Biol. Chem. (2001) [Pubmed]
  20. Identification of mitogen-activated protein kinase kinase as a chemoresistant pathway in MCF-7 cells by using gene expression microarray. Weldon, C.B., Scandurro, A.B., Rolfe, K.W., Clayton, J.L., Elliott, S., Butler, N.N., Melnik, L.I., Alam, J., McLachlan, J.A., Jaffe, B.M., Beckman, B.S., Burow, M.E. Surgery (2002) [Pubmed]
  21. Amplification of 17p11.2 approximately p12, including PMP22, TOP3A, and MAPK7, in high-grade osteosarcoma. van Dartel, M., Cornelissen, P.W., Redeker, S., Tarkkanen, M., Knuutila, S., Hogendoorn, P.C., Westerveld, A., Gomes, I., Bras, J., Hulsebos, T.J. Cancer Genet. Cytogenet. (2002) [Pubmed]
  22. Preconditioning-induced activation of ERK5 is dependent on moderate Ca(2+) influx via NMDA receptors and contributes to ischemic tolerance in the hippocampal CA1 region of rats. Wang, R.M., Yang, F., Zhang, Y.X. Life Sci. (2006) [Pubmed]
  23. Redox-dependent MAP kinase signaling by Ang II in vascular smooth muscle cells: role of receptor tyrosine kinase transactivation. Touyz, R.M., Cruzado, M., Tabet, F., Yao, G., Salomon, S., Schiffrin, E.L. Can. J. Physiol. Pharmacol. (2003) [Pubmed]
  24. Molecular cloning of mouse ERK5/BMK1 splice variants and characterization of ERK5 functional domains. Yan, C., Luo, H., Lee, J.D., Abe , J., Berk, B.C. J. Biol. Chem. (2001) [Pubmed]
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