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Gene Review

MAP2K4  -  mitogen-activated protein kinase kinase 4

Homo sapiens

Synonyms: Dual specificity mitogen-activated protein kinase kinase 4, JNK-activating kinase 1, JNKK, JNKK1, MAP kinase kinase 4, ...
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Disease relevance of MAP2K4


Psychiatry related information on MAP2K4


High impact information on MAP2K4

  • JNKK activated the JNKs but did not activate the ERKs and was unresponsive to Raf-1 in transfected HeLa cells [6].
  • Mutations in this region interfere with the ability of JNKK1 to respond to TNF but do not affect its activation by physical stressors [7].
  • 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 [8].
  • Arsenic trioxide inhibits nuclear receptor function via SEK1/JNK-mediated RXRalpha phosphorylation [9].
  • We provide a novel scenario of the proapoptotic role of IkappaB kinase beta (IKKbeta)-NF-kappaB, which can act as the activator of the JNK pathway through the induction of GADD45alpha for triggering MKK4/JNK activation, in response to the stimulation of arsenite, a cancer therapeutic reagent [10].

Chemical compound and disease context of MAP2K4


Biological context of MAP2K4

  • The MKK4 protein has been implicated in activation of JNK1 and p38 MAPK on phosphorylation by conserved kinase pathways [2].
  • In addition, in a panel of 45 pancreatic carcinomas prescreened for loss of heterozygosity, one somatic missense mutation of MKK4 is observed and confirmed in the primary tumor (2%) [2].
  • Finally, activated Akt inhibited SEK1-mediated apoptosis, and this effect of Akt was prevented by overexpression of SEK(S78A) [14].
  • This docking site conforms to the consensus sequence for known D-sites in other MKKs and contains the first of the two cleavage sites for anthrax lethal factor protease that have been found in the N terminus of MKK4 [15].
  • Staurosporine inhibited GST-MKK4 with an IC50 of 70 nM [16].

Anatomical context of MAP2K4

  • The exception is breast cancer, where genetic inactivation in 3 of 22 (15%) cell lines had suggested that the mutational involvement of MAP2K4 might be accentuated in this tumor type [1].
  • Here, we report that two human tumor cell lines, derived from pancreatic carcinoma and lung carcinoma, harbor homozygous deletions that eliminate coding portions of the MKK4 locus at 17p, located approximately 10 cM centromeric of p53 [3].
  • Furthermore, LY294002 induced apoptosis of MKK4-null but not wild-type mouse embryo fibroblasts [4].
  • SEK-AL, a dominant-negative mutant of SEK1, was transfected into HL-60 cells (HL-60/SEK-AL) to assess the role of JNK/SAPK activity in apoptosis [17].
  • Expression of a dominant negative mutant of Ras blocked the anisomycin-induced activation of SAPK and SEK1, but did not affect markedly the arsenite-induced or heat shock-induced activation in PC12 cells [18].

Associations of MAP2K4 with chemical compounds


Physical interactions of MAP2K4

  • A docking site in MKK4 mediates high affinity binding to JNK MAPKs and competes with similar docking sites in JNK substrates [15].
  • It binds the upstream kinases ASK1 and MKK4 and couples stimulation of the angiotensin II receptor AT1aR to activation of a cytoplasmic pool of JNK3 [22].
  • Furthermore, MKK-4 coprecipitated with MKK-7 and vice versa, indicating that the 3 kinases form a stable complex in FLS [23].

Enzymatic interactions of MAP2K4

  • Transiently expressed SEK1 isolated from palytoxin-treated cells can phosphorylate and activate JNK, which, in turn, can phosphorylate c-Jun [24].

Regulatory relationships of MAP2K4

  • In contrast SEK can activate SAPK when present in substoichiometric amounts, but this activation is slow, consistent with the rate-limiting step in activation being the dissociation of an inactive SEK:SAPK complex [25].
  • Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation [14].
  • Consistent with these observations, immunoprecipitated MEKK2 directly activated recombinant MKK4 in vitro but failed to activate MKK3 [26].
  • In contrast, MKK4-activated JNK3 alpha 1 had no increase in Vmax compared to nonactivated levels and had no phosphorylation on the basis of mass spectrometry [27].
  • Cotransfection of dominant-negative JNK kinase inhibits phosphorylation of kinase-negative MLK2 by anisomycin-activated JNK [28].

Other interactions of MAP2K4

  • 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 [29].
  • The inhibitory action of insulin on SEK1 or JNK1 activation was prevented by the phosphatidylinositol 3-kinase inhibitor LY294002 [14].
  • Ser/Thr protein phosphatase 5 inactivates hypoxia-induced activation of an apoptosis signal-regulating kinase 1/MKK-4/JNK signaling cascade [30].
  • Impaired activity of these stress kinases by PED correlated with inhibition of stress-induced Cdc-42, MKK4, and MKK6 activation [31].
  • Co-expressed MAP kinase kinase (MKK)-1, MKK-4, MKK-3 and MKK-6 were activated in vivo by DeltaMAPKKK4 [32].

Analytical, diagnostic and therapeutic context of MAP2K4


  1. Mutation rate of MAP2K4/MKK4 in breast carcinoma. Su, G.H., Song, J.J., Repasky, E.A., Schutte, M., Kern, S.E. Hum. Mutat. (2002) [Pubmed]
  2. Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene. Su, G.H., Hilgers, W., Shekher, M.C., Tang, D.J., Yeo, C.J., Hruban, R.H., Kern, S.E. Cancer Res. (1998) [Pubmed]
  3. Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor. Teng, D.H., Perry, W.L., Hogan, J.K., Baumgard, M., Bell, R., Berry, S., Davis, T., Frank, D., Frye, C., Hattier, T., Hu, R., Jammulapati, S., Janecki, T., Leavitt, A., Mitchell, J.T., Pero, R., Sexton, D., Schroeder, M., Su, P.H., Swedlund, B., Kyriakis, J.M., Avruch, J., Bartel, P., Wong, A.K., Tavtigian, S.V. Cancer Res. (1997) [Pubmed]
  4. Evidence that phosphatidylinositol 3-kinase- and mitogen-activated protein kinase kinase-4/c-Jun NH2-terminal kinase-dependent Pathways cooperate to maintain lung cancer cell survival. Lee, H.Y., Srinivas, H., Xia, D., Lu, Y., Superty, R., LaPushin, R., Gomez-Manzano, C., Gal, A.M., Walsh, G.L., Force, T., Ueki, K., Mills, G.B., Kurie, J.M. J. Biol. Chem. (2003) [Pubmed]
  5. JKK1, an upstream activator of JNK/SAPK, is activated in Alzheimer's disease. Zhu, X., Ogawa, O., Wang, Y., Perry, G., Smith, M.A. J. Neurochem. (2003) [Pubmed]
  6. Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. Lin, A., Minden, A., Martinetto, H., Claret, F.X., Lange-Carter, C., Mercurio, F., Johnson, G.L., Karin, M. Science (1995) [Pubmed]
  7. JNKK1 organizes a MAP kinase module through specific and sequential interactions with upstream and downstream components mediated by its amino-terminal extension. Xia, Y., Wu, Z., Su, B., Murray, B., Karin, M. Genes Dev. (1998) [Pubmed]
  8. 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]
  9. Arsenic trioxide inhibits nuclear receptor function via SEK1/JNK-mediated RXRalpha phosphorylation. Mann, K.K., Padovani, A.M., Guo, Q., Colosimo, A.L., Lee, H.Y., Kurie, J.M., Miller, W.H. J. Clin. Invest. (2005) [Pubmed]
  10. IKK{beta} programs to turn on the GADD45{alpha}-MKK4-JNK apoptotic cascade specifically via p50 NF-{kappa}B in arsenite response. Song, L., Li, J., Zhang, D., Liu, Z.G., Ye, J., Zhan, Q., Shen, H.M., Whiteman, M., Huang, C. J. Cell Biol. (2006) [Pubmed]
  11. Loss of expression of receptor tyrosine kinase family genes PTK7 and SEK in metastatic melanoma. Easty, D.J., Mitchell, P.J., Patel, K., Flørenes, V.A., Spritz, R.A., Bennett, D.C. Int. J. Cancer (1997) [Pubmed]
  12. Blockage of NF-kappaB induces serine 15 phosphorylation of mutant p53 by JNK kinase in prostate cancer cells. Zerbini, L.F., Wang, Y., Correa, R.G., Cho, J.Y., Libermann, T.A. Cell Cycle (2005) [Pubmed]
  13. Specific amino acid deficiency alters the expression of genes in human melanoma and other tumor cell lines. Meadows, G.G., Zhang, H., Ge, X. J. Nutr. (2001) [Pubmed]
  14. Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation. Park, H.S., Kim, M.S., Huh, S.H., Park, J., Chung, J., Kang, S.S., Choi, E.J. J. Biol. Chem. (2002) [Pubmed]
  15. A docking site in MKK4 mediates high affinity binding to JNK MAPKs and competes with similar docking sites in JNK substrates. Ho, D.T., Bardwell, A.J., Abdollahi, M., Bardwell, L. J. Biol. Chem. (2003) [Pubmed]
  16. Development of a non-radioactive, 384-well format assay to detect inhibitors of the mitogen-activated protein kinase kinase 4. Togame, H., Fuchikami, K., Sagara, A., Inbe, H., Ziegelbauer, K. Assay and drug development technologies. (2005) [Pubmed]
  17. Role of c-Jun N-terminal kinase/p38 stress signaling in 1-beta-D-arabinofuranosylcytosine-induced apoptosis. Stadheim, T.A., Saluta, G.R., Kucera, G.L. Biochem. Pharmacol. (2000) [Pubmed]
  18. Ras-dependent and Ras-independent activation pathways for the stress-activated-protein-kinase cascade. Kawasaki, H., Moriguchi, T., Matsuda, S., Li, H.Z., Nakamura, S., Shimohama, S., Kimura, J., Gotoh, Y., Nishida, E. Eur. J. Biochem. (1996) [Pubmed]
  19. Synergistic activation of SAPK1/JNK1 by two MAP kinase kinases in vitro. Lawler, S., Fleming, Y., Goedert, M., Cohen, P. Curr. Biol. (1998) [Pubmed]
  20. DNA binding of activator protein-1 is increased in human mesangial cells cultured in high glucose concentrations. Wilmer, W.A., Cosio, F.G. Kidney Int. (1998) [Pubmed]
  21. Nitric oxide modulates the c-Jun N-terminal kinase/stress-activated protein kinase activity through activating c-Jun N-terminal kinase kinase. Kim, H., Shim, J., Han, P.L., Choi, E.J. Biochemistry (1997) [Pubmed]
  22. Dynamic interaction between the dual specificity phosphatase MKP7 and the JNK3 scaffold protein beta-arrestin 2. Willoughby, E.A., Collins, M.K. J. Biol. Chem. (2005) [Pubmed]
  23. 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]
  24. Regulation of a c-Jun amino-terminal kinase/stress-activated protein kinase cascade by a sodium-dependent signal transduction pathway. Kuroki, D.W., Minden, A., Sánchez, I., Wattenberg, E.V. J. Biol. Chem. (1997) [Pubmed]
  25. Concentration-dependent positive and negative regulation of a MAP kinase by a MAP kinase kinase. Kieran, M.W., Katz, S., Vail, B., Zon, L.I., Mayer, B.J. Oncogene (1999) [Pubmed]
  26. Characterization of the mitogen-activated protein kinase kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK3/p38 pathways regulated by MEK kinases 2 and 3. MEK kinase 3 activates MKK3 but does not cause activation of p38 kinase in vivo. Deacon, K., Blank, J.L. J. Biol. Chem. (1997) [Pubmed]
  27. Activation of JNK3 alpha 1 requires both MKK4 and MKK7: kinetic characterization of in vitro phosphorylated JNK3 alpha 1. Lisnock, J., Griffin, P., Calaycay, J., Frantz, B., Parsons, J., O'Keefe, S.J., LoGrasso, P. Biochemistry (2000) [Pubmed]
  28. Activated JNK phosphorylates the c-terminal domain of MLK2 that is required for MLK2-induced apoptosis. Phelan, D.R., Price, G., Liu, Y.F., Dorow, D.S. J. Biol. Chem. (2001) [Pubmed]
  29. 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]
  30. Ser/Thr protein phosphatase 5 inactivates hypoxia-induced activation of an apoptosis signal-regulating kinase 1/MKK-4/JNK signaling cascade. Zhou, G., Golden, T., Aragon, I.V., Honkanen, R.E. J. Biol. Chem. (2004) [Pubmed]
  31. Multiple members of the mitogen-activated protein kinase family are necessary for PED/PEA-15 anti-apoptotic function. Condorelli, G., Trencia, A., Vigliotta, G., Perfetti, A., Goglia, U., Cassese, A., Musti, A.M., Miele, C., Santopietro, S., Formisano, P., Beguinot, F. J. Biol. Chem. (2002) [Pubmed]
  32. Human mitogen-activated protein kinase kinase kinase mediates the stress-induced activation of mitogen-activated protein kinase cascades. Chan-Hui, P.Y., Weaver, R. Biochem. J. (1998) [Pubmed]
  33. Regulation of JNK by MKK-7 in fibroblast-like synoviocytes. Inoue, T., Hammaker, D., Boyle, D.L., Firestein, G.S. Arthritis Rheum. (2006) [Pubmed]
  34. Ligation of major histocompatability complex (MHC) class I molecules on human T cells induces cell death through PI-3 kinase-induced c-Jun NH2-terminal kinase activity: a novel apoptotic pathway distinct from Fas-induced apoptosis. Skov, S., Klausen, P., Claesson, M.H. J. Cell Biol. (1997) [Pubmed]
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