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Gene Review

MAP3K4  -  mitogen-activated protein kinase kinase...

Homo sapiens

Synonyms: KIAA0213, MAP three kinase 1, MAPK/ERK kinase kinase 4, MAPKKK4, MEK kinase 4, ...
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Disease relevance of MAP3K4

  • Unlike most mouse models of NTDs, MEKK4 mutant embryos display genetically co-segregated exencephaly and spina bifida, recapitulating the phenotypes observed in human patients [1].
  • However, a clear differential toxicity pattern was observed in favor of animals treated with Adcox-2 MTK when compared with controls [2].
  • A series of deletion mutants within the 5' flanking region of the hMT-IIA gene was constructed and fused to the structural sequences of the Herpes simplex thymidine kinase (TK) gene to generate hMTK chimeric genes [3].

High impact information on MAP3K4


Biological context of MAP3K4


Anatomical context of MAP3K4


Associations of MAP3K4 with chemical compounds


Physical interactions of MAP3K4

  • GADD45 proteins bind a site in MTK1 near the inhibitory domain and relieve autoinhibition [15].
  • Mutants of full-length MTK1 were isolated that can interact with MKK6 in the absence of the activator GADD45 proteins [15].
  • Additional studies demonstrate that the SH2 (Src homology 2)-domain-containing tyrosine phosphatase SHP2 co-immunoprecipitates with MEKK4 in an IFNgamma-dependent manner and co-localizes with MEKK4 after IFNgamma stimulation in the perinuclear region in HaCaT cells [10].
  • Furthermore, Ccd1 physically interacted with MEKK4 in their physiological concentrations and prevented MEKK4 from binding to Axin [16].

Enzymatic interactions of MAP3K4


Regulatory relationships of MAP3K4

  • CIN85 was also shown to regulate the activation of MEKK4 by GADD45 proteins and promote multi-ubiquitination of MEKK4 [18].

Other interactions of MAP3K4

  • We report the identification of a human MAPK kinase kinase, MAPKKK4, via sequence similarity with other MAPKKKs [11].
  • When truncated MAPKKK4 (DeltaMAPKKK4) was overexpressed in HEK293 cells, it was constitutively active and induced the activation of endogenous p38alpha, c-Jun N-terminal kinase (JNK)1/2 and extracellular signal-regulated kinase (ERK)2 in vivo [11].
  • A human homolog of the yeast Ssk2/Ssk22 MAP kinase kinase kinases, MTK1, mediates stress-induced activation of the p38 and JNK pathways [17].
  • In the autoinhibited conformation, the MTK1 kinase domain cannot interact with its substrate, MKK6 [15].
  • The MKKKs, MEKK3 and MEKK4, are upstream regulators of p38 in many cells [19].

Analytical, diagnostic and therapeutic context of MAP3K4



  1. Loss of mitogen-activated protein kinase kinase kinase 4 (MEKK4) results in enhanced apoptosis and defective neural tube development. Chi, H., Sarkisian, M.R., Rakic, P., Flavell, R.A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  2. Strategies to accomplish targeted expression of transgenes in ovarian cancer for molecular therapeutic applications. Casado, E., Gomez-Navarro, J., Yamamoto, M., Adachi, Y., Coolidge, C.J., Arafat, W.O., Barker, S.D., Wang, M.H., Mahasreshti, P.J., Hemminki, A., Gonzalez-Baron, M., Barnes, M.N., Pustilnik, T.B., Siegal, G.P., Alvarez, R.D., Curiel, D.T. Clin. Cancer Res. (2001) [Pubmed]
  3. Nucleotide sequence requirements for transient expression of human metallothionein-IIA-thymidine kinase fusion genes. Karin, M., Holtgreve, H. DNA (1984) [Pubmed]
  4. MEKK4 sequesters RIP2 to dictate NOD2 signal specificity. Clark, N.M., Marinis, J.M., Cobb, B.A., Abbott, D.W. Curr. Biol. (2008) [Pubmed]
  5. A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Takekawa, M., Saito, H. Cell (1998) [Pubmed]
  6. MEKK4 Signaling Regulates Filamin Expression and Neuronal Migration. Sarkisian, M.R., Bartley, C.M., Chi, H., Nakamura, F., Hashimoto-Torii, K., Torii, M., Flavell, R.A., Rakic, P. Neuron (2006) [Pubmed]
  7. GADD45beta/GADD45gamma and MEKK4 comprise a genetic pathway mediating STAT4-independent IFNgamma production in T cells. Chi, H., Lu, B., Takekawa, M., Davis, R.J., Flavell, R.A. EMBO J. (2004) [Pubmed]
  8. Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway. Gerwins, P., Blank, J.L., Johnson, G.L. J. Biol. Chem. (1997) [Pubmed]
  9. Ablation of MEKK4 kinase activity causes neurulation and skeletal patterning defects in the mouse embryo. Abell, A.N., Rivera-Perez, J.A., Cuevas, B.D., Uhlik, M.T., Sather, S., Johnson, N.L., Minton, S.K., Lauder, J.M., Winter-Vann, A.M., Nakamura, K., Magnuson, T., Vaillancourt, R.R., Heasley, L.E., Johnson, G.L. Mol. Cell. Biol. (2005) [Pubmed]
  10. Interferon-gamma-dependent tyrosine phosphorylation of MEKK4 via Pyk2 is regulated by annexin II and SHP2 in keratinocytes. Halfter, U.M., Derbyshire, Z.E., Vaillancourt, R.R. Biochem. J. (2005) [Pubmed]
  11. 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]
  12. Angiotensin II stimulated transcription of cyclooxygenase II is regulated by a novel kinase cascade involving Pyk2, MEKK4 and annexin II. Derbyshire, Z.E., Halfter, U.M., Heimark, R.L., Sy, T.H., Vaillancourt, R.R. Mol. Cell. Biochem. (2005) [Pubmed]
  13. Cell surface c-kit receptors in human leukemia cell lines and pediatric leukemia: selective preservation of c-kit expression on megakaryoblastic cell lines during adaptation to in vitro culture. Morita, S., Tsuchiya, S., Fujie, H., Itano, M., Ohashi, Y., Minegishi, M., Imaizumi, M., Endo, M., Takano, N., Konno, T. Leukemia (1996) [Pubmed]
  14. Signal transduction pathways regulated by arsenate and arsenite. Porter, A.C., Fanger, G.R., Vaillancourt, R.R. Oncogene (1999) [Pubmed]
  15. Regulation of MTK1/MEKK4 kinase activity by its N-terminal autoinhibitory domain and GADD45 binding. Mita, H., Tsutsui, J., Takekawa, M., Witten, E.A., Saito, H. Mol. Cell. Biol. (2002) [Pubmed]
  16. The DIX domain protein coiled-coil-DIX1 inhibits c-Jun N-terminal kinase activation by Axin and dishevelled through distinct mechanisms. Wong, C.K., Luo, W., Deng, Y., Zou, H., Ye, Z., Lin, S.C. J. Biol. Chem. (2004) [Pubmed]
  17. A human homolog of the yeast Ssk2/Ssk22 MAP kinase kinase kinases, MTK1, mediates stress-induced activation of the p38 and JNK pathways. Takekawa, M., Posas, F., Saito, H. EMBO J. (1997) [Pubmed]
  18. CIN85 regulates the ability of MEKK4 to activate the p38 MAP kinase pathway. Aissouni, Y., Zapart, G., Iovanna, J.L., Dikic, I., Soubeyran, P. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  19. MEKK3-mediated signaling to p38 kinase and TonE in hypertonically stressed kidney cells. Padda, R., Wamsley-Davis, A., Gustin, M.C., Ross, R., Yu, C., Sheikh-Hamad, D. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
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