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Gene Review

MAP2K5  -  mitogen-activated protein kinase kinase 5

Homo sapiens

Synonyms: Dual specificity mitogen-activated protein kinase kinase 5, HsT17454, MAP kinase kinase 5, MAPK/ERK kinase 5, MAPKK 5, ...
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Disease relevance of MAP2K5


High impact information on MAP2K5

  • Taken together, these results strongly suggest that in some cell types the MEK5/BMK1 MAP kinase signaling pathway regulates serum-induced early gene expression through the transcription factor MEF2C [4].
  • MEK5 is the only MAP2K to express a PB1 domain, and we have shown that it heterodimerizes with the PB1 domain of MEKK2 [5].
  • They further show that the activating phosphorylation of ERK5 by MEK5 results in the dissociation of the binding between the N- and C-terminal halves and thus inhibits nuclear export of ERK5, causing its nuclear import [6].
  • Here we demonstrate that the aPKCs interact in an EGF-inducible manner with MEK5 and that this interaction is required and sufficient for the activation of MEK5 in response to EGF [7].
  • [Ru(CO)(3)Cl(2)](2) activated PPARdelta transcriptional activity via the MEK5/ERK5 signaling pathway [8].

Chemical compound and disease context of MAP2K5


Biological context of MAP2K5


Anatomical context of MAP2K5

  • Much less information is available about the MEK5-ERK5 module and its role in renal epithelial cell proliferation and differentiation [11].
  • Both MEK5 and ERK5 are expressed in many adult tissue and are abundant in heart and skeletal muscle [12].
  • Thus, we conclude that the MEK5/ERK5 MAP kinase cascade is critical for early steps of muscle cell differentiation [13].
  • MEK5 and ERK5 are localized in the nuclei of resting as well as stimulated cells, while MEKK2 translocates from the cytosol to the nucleus upon stimulation [14].
  • The 23 amino acids encoded by the 5' exon in the larger alpha isoform are similar to a sequence found in certain proteins believed to associate with the actin cytoskeleton; this alternatively spliced modular domain may lead to the differential subcellular localization of MEK5 alpha [15].

Physical interactions of MAP2K5

  • Through utilization of a yeast two-hybrid screen, we have identified MEKK3 as a molecule that physically interacts with MEK5 [16].

Regulatory relationships of MAP2K5


Other interactions of MAP2K5

  • MEK5 is the upstream BMK1 kinase and exists as naturally occurring splice variants, MEK5alpha and MEK5beta [18].
  • MEK5 overexpression is associated with metastatic prostate cancer, and stimulates proliferation, MMP-9 expression and invasion [1].
  • This interaction appears to take place in mammalian cells as evidenced by the fact that cellular MEK5 and MEKK3 co-immunoprecipitate [16].
  • Although MEK5 is known to mediate BDNF stimulation of ERK5 in central nervous system neurons, other upstream signaling components have not been identified [19].
  • MEKK3 regulates MKK3 and MKK5/6/7 [20].

Analytical, diagnostic and therapeutic context of MAP2K5

  • The MEK5 cDNA was isolated by degenerate PCR and encodes a 444-amino acid protein, which has approximately 40% identity to known MEKs [12].
  • RT-PCR result also demonstrated that MEK5 mRNA was significantly induced by Stat3-C in TERT cells [2].
  • RESULTS: Of the 1186 genes detected through microarray analysis, MEK5 was increased 22-fold in APO- cells [21].


  1. MEK5 overexpression is associated with metastatic prostate cancer, and stimulates proliferation, MMP-9 expression and invasion. Mehta, P.B., Jenkins, B.L., McCarthy, L., Thilak, L., Robson, C.N., Neal, D.E., Leung, H.Y. Oncogene (2003) [Pubmed]
  2. Stat3 upregulates MEK5 expression in human breast cancer cells. Song, H., Jin, X., Lin, J. Oncogene (2004) [Pubmed]
  3. Activation of the MEK5/ERK5 cascade is responsible for biliary dysgenesis in a rat model of Caroli's disease. Sato, Y., Harada, K., Kizawa, K., Sanzen, T., Furubo, S., Yasoshima, M., Ozaki, S., Ishibashi, M., Nakanuma, Y. Am. J. Pathol. (2005) [Pubmed]
  4. BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C. Kato, Y., Kravchenko, V.V., Tapping, R.I., Han, J., Ulevitch, R.J., Lee, J.D. EMBO J. (1997) [Pubmed]
  5. PB1 domain-dependent signaling complex is required for extracellular signal-regulated kinase 5 activation. Nakamura, K., Uhlik, M.T., Johnson, N.L., Hahn, K.M., Johnson, G.L. Mol. Cell. Biol. (2006) [Pubmed]
  6. Regulation of nuclear translocation of extracellular signal-regulated kinase 5 by active nuclear import and export mechanisms. Kondoh, K., Terasawa, K., Morimoto, H., Nishida, E. Mol. Cell. Biol. (2006) [Pubmed]
  7. MEK5, a new target of the atypical protein kinase C isoforms in mitogenic signaling. Diaz-Meco, M.T., Moscat, J. Mol. Cell. Biol. (2001) [Pubmed]
  8. ERK5 Activation Inhibits Inflammatory Responses via Peroxisome Proliferator-activated Receptor {delta} (PPAR{delta}) Stimulation. Woo, C.H., Massett, M.P., Shishido, T., Itoh, S., Ding, B., McClain, C., Che, W., Vulapalli, S.R., Yan, C., Abe, J. J. Biol. Chem. (2006) [Pubmed]
  9. c-myc Promoter-binding protein 1 (MBP-1) regulates prostate cancer cell growth by inhibiting MAPK pathway. Ghosh, A.K., Steele, R., Ray, R.B. J. Biol. Chem. (2005) [Pubmed]
  10. An analysis of the phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (ERK5) by mitogen-activated protein kinase kinase 5 (MKK5) in vitro. Mody, N., Campbell, D.G., Morrice, N., Peggie, M., Cohen, P. Biochem. J. (2003) [Pubmed]
  11. ERK1/2-driven and MKP-mediated inhibition of EGF-induced ERK5 signaling in human proximal tubular cells. Sarközi, R., Miller, B., Pollack, V., Feifel, E., Mayer, G., Sorokin, A., Schramek, H. J. Cell. Physiol. (2007) [Pubmed]
  12. Components of a new human protein kinase signal transduction pathway. Zhou, G., Bao, Z.Q., Dixon, J.E. J. Biol. Chem. (1995) [Pubmed]
  13. Extracellular signal regulated kinase 5 (ERK5) is required for the differentiation of muscle cells. Dinev, D., Jordan, B.W., Neufeld, B., Lee, J.D., Lindemann, D., Rapp, U.R., Ludwig, S. EMBO Rep. (2001) [Pubmed]
  14. MEK5 and ERK5 are localized in the nuclei of resting as well as stimulated cells, while MEKK2 translocates from the cytosol to the nucleus upon stimulation. Raviv, Z., Kalie, E., Seger, R. J. Cell. Sci. (2004) [Pubmed]
  15. Isolation of MEK5 and differential expression of alternatively spliced forms. English, J.M., Vanderbilt, C.A., Xu, S., Marcus, S., Cobb, M.H. J. Biol. Chem. (1995) [Pubmed]
  16. MEKK3 directly regulates MEK5 activity as part of the big mitogen-activated protein kinase 1 (BMK1) signaling pathway. Chao, T.H., Hayashi, M., Tapping, R.I., Kato, Y., Lee, J.D. J. Biol. Chem. (1999) [Pubmed]
  17. WNK1 activates ERK5 by an MEKK2/3-dependent mechanism. Xu, B.E., Stippec, S., Lenertz, L., Lee, B.H., Zhang, W., Lee, Y.K., Cobb, M.H. J. Biol. Chem. (2004) [Pubmed]
  18. 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]
  19. Brain-derived Neurotrophic Factor Activates ERK5 in Cortical Neurons via a Rap1-MEKK2 Signaling Cascade. Wang, Y., Su, B., Xia, Z. J. Biol. Chem. (2006) [Pubmed]
  20. Inhibition of mitogen-activated kinase kinase kinase 3 activity through phosphorylation by the serum- and glucocorticoid-induced kinase 1. Chun, J., Kwon, T., Kim, D.J., Park, I., Chung, G., Lee, E.J., Hong, S.K., Chang, S.I., Kim, H.Y., Kang, S.S. J. Biochem. (2003) [Pubmed]
  21. 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]
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