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Gene Review

MAP2K7  -  mitogen-activated protein kinase kinase 7

Homo sapiens

Synonyms: Dual specificity mitogen-activated protein kinase kinase 7, JNK kinase 2, JNK-activating kinase 2, JNKK 2, JNKK2, ...
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Disease relevance of MAP2K7


High impact information on MAP2K7

  • This stimuli-dependent interaction of c-FLIP(L) with MKK7 might selectively suppress the prolonged phase of JNK activation [4].
  • However, FcepsilonRI-induced activation of the tumor necrosis factor-alpha (TNF-alpha) gene promoter is not affected by expression of kinase-inactive MKK7 [5].
  • Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase [6].
  • No scaffold protein was required for the MEKK2-JNKK2-JNK1 tripartite-complex formation [7].
  • In addition, the results demonstrate that Lyn activates SAPK by an MKK7-dependent, SEK1-independent mechanism [8].

Biological context of MAP2K7

  • We generated inducible cell lines from the human embryonal kidney carcinoma cell line, HEK293, by stable transfection with a constitutively active mutant of MKK7, MKK7(3E), fused to green fluorescent protein (GFP), under the control of an ecdysone-inducible promoter [9].
  • These data implicate active MKK7 in the negative regulation of cell proliferation and provide evidence for a new role for this kinase in the regulation of a distinct, hitherto unrecognized set of genes [9].
  • Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7 [10].
  • Furthermore, hJNKK2 alpha activated the JNK-dependent signal transduction pathway in vivo by induction of c-Jun- and ATF2-mediated gene transcription [11].
  • MKK7 is ubiquitously expressed in all adult and embryonic organs but displays high expression in epithelial tissues at later stages of fetal development [12].

Anatomical context of MAP2K7


Associations of MAP2K7 with chemical compounds


Physical interactions of MAP2K7

  • IL-1beta-induced AP-1 binding activity and AP-1-driven gene expression were strictly MKK-7 dependent [20].
  • Furthermore, MKK-4 coprecipitated with MKK-7 and vice versa, indicating that the 3 kinases form a stable complex in FLS [21].

Enzymatic interactions of MAP2K7


Co-localisations of MAP2K7

  • A third JNK pool is colocalized with MKK7 in the nucleus, and specific activities of both increase during neuritogenesis, nuclear JNK activity increasing 10-fold, whereas c-Jun expression and activity decrease [22].

Regulatory relationships of MAP2K7


Other interactions of MAP2K7

  • Although the regulation of JNKK1 activities and that of JNKK2 activities could be very similar, the two kinases may play somewhat different regulatory roles in a cell-type-dependent manner [25].
  • However, in contrast with Thr-183 and Tyr-185, the phosphorylation of Thr-404 and Ser-407 is not increased in response to other agonists that activate MKK7 and SAPK1/JNK, suggesting that phosphorylation of these residues is catalysed by another protein kinase, such as CK2, which also phosphorylates Thr-404 and Ser-407 in vitro [10].
  • Transient transfection assays demonstrated that JNKK2 potentiated the stimulation of c-Jun transcriptional activity by MEKK1 [26].
  • Finally, MMP-3 production only required MKK-7, and there was no effect of MKK-4 deficiency [20].
  • In confirmatory experiments performed in vivo, DLK both associated with and activated MKK7 [16].
  • These data provide a basis for Gadd45beta-mediated blockade of MKK7, and ultimately, TNFalpha-induced PCD [27].

Analytical, diagnostic and therapeutic context of MAP2K7

  • The mRNA for MKK7 is widely expressed in humans and mice and encodes a 47-kDa protein (419 amino acids), as determined by immunoblotting endogenous MKK7 with an antibody raised against its N terminus [28].
  • Here we report the molecular cloning of a new member of the mammalian MAP kinase kinase group (MKK7) that functions as an activator of JNK [6].
  • Phosphospecific antibodies and immunohistochemistry were used to evaluate the activation state of synovial MKK-4 and MKK-7 [21].
  • METHODS: Ad19- and mock-infected HCFs were solubilized at various time points after infection, and cell lysates were subjected to SDS-PAGE followed by immunoblot analysis with a panel of antibodies against components of the MKK7/JNK/c-Jun pathway or immunoprecipitated for JNK assay [29].


  1. Cardiac hypertrophy induced by mitogen-activated protein kinase kinase 7, a specific activator for c-Jun NH2-terminal kinase in ventricular muscle cells. Wang, Y., Su, B., Sah, V.P., Brown, J.H., Han, J., Chien, K.R. J. Biol. Chem. (1998) [Pubmed]
  2. Identification of a novel synthetic thiazolidin compound capable of inducing c-Jun NH2-terminal kinase-dependent apoptosis in human colon cancer cells. Teraishi, F., Wu, S., Zhang, L., Guo, W., Davis, J.J., Dong, F., Fang, B. Cancer Res. (2005) [Pubmed]
  3. c-Jun NH2-terminal kinase activation leads to a FADD-dependent but Fas ligand-independent cell death in Jurkat T cells. Chen, Y., Lai, M.Z. J. Biol. Chem. (2001) [Pubmed]
  4. An antiapoptotic protein, c-FLIP(L), directly binds to MKK7 and inhibits the JNK pathway. Nakajima, A., Komazawa-Sakon, S., Takekawa, M., Sasazuki, T., Yeh, W.C., Yagita, H., Okumura, K., Nakano, H. EMBO J. (2006) [Pubmed]
  5. Role of MEKK2-MEK5 in the regulation of TNF-alpha gene expression and MEKK2-MKK7 in the activation of c-Jun N-terminal kinase in mast cells. Chayama, K., Papst, P.J., Garrington, T.P., Pratt, J.C., Ishizuka, T., Webb, S., Ganiatsas, S., Zon, L.I., Sun, W., Johnson, G.L., Gelfand, E.W. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  6. Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase. Tournier, C., Whitmarsh, A.J., Cavanagh, J., Barrett, T., Davis, R.J. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  7. Synergistic interaction of MEK kinase 2, c-Jun N-terminal kinase (JNK) kinase 2, and JNK1 results in efficient and specific JNK1 activation. Cheng, J., Yang, J., Xia, Y., Karin, M., Su, B. Mol. Cell. Biol. (2000) [Pubmed]
  8. Role for Lyn tyrosine kinase as a regulator of stress-activated protein kinase activity in response to DNA damage. Yoshida, K., Weichselbaum, R., Kharbanda, S., Kufe, D. Mol. Cell. Biol. (2000) [Pubmed]
  9. Inducible expression of a constitutively active mutant of mitogen-activated protein kinase kinase 7 specifically activates c-JUN NH2-terminal protein kinase, alters expression of at least nine genes, and inhibits cell proliferation. Wolter, S., Mushinski, J.F., Saboori, A.M., Resch, K., Kracht, M. J. Biol. Chem. (2002) [Pubmed]
  10. Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7. Fleming, Y., Armstrong, C.G., Morrice, N., Paterson, A., Goedert, M., Cohen, P. Biochem. J. (2000) [Pubmed]
  11. Molecular cloning and characterization of a human protein kinase that specifically activates c-Jun N-terminal kinase. Yang, J., New, L., Jiang, Y., Han, J., Su, B. Gene (1998) [Pubmed]
  12. Activation of stress-activated protein kinases/c-Jun N-terminal protein kinases (SAPKs/JNKs) by a novel mitogen-activated protein kinase kinase. Yao, Z., Diener, K., Wang, X.S., Zukowski, M., Matsumoto, G., Zhou, G., Mo, R., Sasaki, T., Nishina, H., Hui, C.C., Tan, T.H., Woodgett, J.P., Penninger, J.M. J. Biol. Chem. (1997) [Pubmed]
  13. The JNKK2-JNK1 fusion protein acts as a constitutively active c-Jun kinase that stimulates c-Jun transcription activity. Zheng, C., Xiang, J., Hunter, T., Lin, A. J. Biol. Chem. (1999) [Pubmed]
  14. T lymphocyte activation signals for interleukin-2 production involve activation of MKK6-p38 and MKK7-SAPK/JNK signaling pathways sensitive to cyclosporin A. Matsuda, S., Moriguchi, T., Koyasu, S., Nishida, E. J. Biol. Chem. (1998) [Pubmed]
  15. The MKK7 gene encodes a group of c-Jun NH2-terminal kinase kinases. Tournier, C., Whitmarsh, A.J., Cavanagh, J., Barrett, T., Davis, R.J. Mol. Cell. Biol. (1999) [Pubmed]
  16. The mixed lineage kinase DLK utilizes MKK7 and not MKK4 as substrate. Merritt, S.E., Mata, M., Nihalani, D., Zhu, C., Hu, X., Holzman, L.B. J. Biol. Chem. (1999) [Pubmed]
  17. Differential gene regulation by specific gain-of-function JNK1 proteins expressed in Swiss 3T3 fibroblasts. Han, S.Y., Kim, S.H., Heasley, L.E. J. Biol. Chem. (2002) [Pubmed]
  18. Synergistic activation of SAPK1/JNK1 by two MAP kinase kinases in vitro. Lawler, S., Fleming, Y., Goedert, M., Cohen, P. Curr. Biol. (1998) [Pubmed]
  19. Activation of c-Jun NH2-terminal kinase is required for gemcitabine's cytotoxic effect in human lung cancer H1299 cells. Teraishi, F., Zhang, L., Guo, W., Dong, F., Davis, J.J., Lin, A., Fang, B. FEBS Lett. (2005) [Pubmed]
  20. Regulation of JNK by MKK-7 in fibroblast-like synoviocytes. Inoue, T., Hammaker, D., Boyle, D.L., Firestein, G.S. Arthritis Rheum. (2006) [Pubmed]
  21. Expression of the MAPK kinases MKK-4 and MKK-7 in rheumatoid arthritis and their role as key regulators of JNK. Sundarrajan, M., Boyle, D.L., Chabaud-Riou, M., Hammaker, D., Firestein, G.S. Arthritis Rheum. (2003) [Pubmed]
  22. Dual roles for c-Jun N-terminal kinase in developmental and stress responses in cerebellar granule neurons. Coffey, E.T., Hongisto, V., Dickens, M., Davis, R.J., Courtney, M.J. J. Neurosci. (2000) [Pubmed]
  23. Cloning and expression of human mitogen-activated protein kinase kinase 7gamma1. Michael, L., Swantek, J., Robinson, M.J. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  24. Negative regulation of JNK signaling by the tumor suppressor CYLD. Reiley, W., Zhang, M., Sun, S.C. J. Biol. Chem. (2004) [Pubmed]
  25. Molecular cloning and characterization of human JNKK2, a novel Jun NH2-terminal kinase-specific kinase. Wu, Z., Wu, J., Jacinto, E., Karin, M. Mol. Cell. Biol. (1997) [Pubmed]
  26. Identification of c-Jun NH2-terminal protein kinase (JNK)-activating kinase 2 as an activator of JNK but not p38. Lu, X., Nemoto, S., Lin, A. J. Biol. Chem. (1997) [Pubmed]
  27. Insights into the structural basis of the GADD45beta-mediated inactivation of the JNK kinase, MKK7/JNKK2. Papa, S., Monti, S.M., Vitale, R.M., Bubici, C., Jayawardena, S., Alvarez, K., De Smaele, E., Dathan, N., Pedone, C., Ruvo, M., Franzoso, G. J. Biol. Chem. (2007) [Pubmed]
  28. Human mitogen-activated protein kinase kinase 7 (MKK7) is a highly conserved c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activated by environmental stresses and physiological stimuli. Foltz, I.N., Gerl, R.E., Wieler, J.S., Luckach, M., Salmon, R.A., Schrader, J.W. J. Biol. Chem. (1998) [Pubmed]
  29. JNK regulates MCP-1 expression in adenovirus type 19-infected human corneal fibroblasts. Xiao, J., Chodosh, J. Invest. Ophthalmol. Vis. Sci. (2005) [Pubmed]
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