The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

MAP2K6  -  mitogen-activated protein kinase kinase 6

Homo sapiens

Synonyms: Dual specificity mitogen-activated protein kinase kinase 6, MAP kinase kinase 6, MAPK/ERK kinase 6, MAPKK 6, MAPKK6, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of MAP2K6

  • However, upon transient ischemia followed by reperfusion, the MKK6 TG mouse hearts exhibited significantly better functional recovery and less injury than NTG mouse hearts [1].
  • In contrast, SB203580, a p38 MAPK-specific inhibitor, prevented MKK6-induced apoptosis in hepatoma cell lines [2].
  • Rules generated using only ICAM1, MAP2K6 and KDR were comparably robust, with a single representative rule producing an accuracy of 90% when used by itself on the validation set, suggesting a crucial role for these genes in nodal metastasis [3].
  • Immunohistochemistry demonstrated that MKK3 and MKK6 are expressed in RA and osteoarthritis (OA) synovium [4].
  • CONCLUSIONS: These data demonstrate that different repertoires of downstream signaling proteins, particularly those of the MEK6-p38 MAPK-CK2 pathway and the PI3K pathway, are correlated with phenotypic manifestations of a cell culture model of OSE at progressive stages in the development of ovarian cancer [5].

Psychiatry related information on MAP2K6

  • Immunoblot analysis demonstrated a significant increase of MKK6 level in Alzheimer's disease compared with age-matched controls [6].

High impact information on MAP2K6

  • Conversely, inactivation of SWI-SNF enzymatic subunits abrogated MKK6-dependent induction of muscle gene expression [7].
  • Dominant-negative MKK3 or MKK6 inhibited syncytial activation of p38, p53S46P, and apoptosis [8].
  • We further reported that SMCs cotransfected with active forms of MEK1 and MKK6 secreted a nondialyzable, heat-labile protein factor(s) which induced de-differentiation of surrounding normal SMCs [9].
  • Accordingly, a constitutively activated MKK6, a p38 activator, activated TGF-alpha shedding in the absence of exogenous stimuli [10].
  • Activation of the novel stress-activated protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6); comparison of its substrate specificity with that of other SAP kinases [11].

Biological context of MAP2K6


Anatomical context of MAP2K6


Associations of MAP2K6 with chemical compounds


Physical interactions of MAP2K6

  • Mutants of full-length MTK1 were isolated that can interact with MKK6 in the absence of the activator GADD45 proteins [22].
  • We also found that the preferential activation of p38alpha by MKK6 correlated with more efficient binding of MKK6 to p38alpha than to p38gamma [23].

Enzymatic interactions of MAP2K6


Regulatory relationships of MAP2K6

  • Co-transfection with SAPKK3 induced SAPK3 activity and greatly enhanced activation in response to osmotic shock [25].
  • SAPKK-4 and SAPKK-5 were also eluted from Mono S at higher NaC1 concentrations than SAPKK-3 and these enzymes activated SAP kinase-1 but not SAP kinase-2 [26].
  • Protein kinase R (PKR) interacts with and activates mitogen-activated protein kinase kinase 6 (MKK6) in response to double-stranded RNA stimulation [20].
  • In contrast, a constitutively active MKK6 mutant activated both p38 MAPK isoforms to similar extents [23].
  • Moreover, stimulation of the endogenous stress pathways by adenovirus-mediated delivery of recombinant MAPK kinase 6 also activates VDR and sensitizes MCF-7 cells to vitamin D(3)-dependent growth inhibition [27].

Other interactions of MAP2K6


Analytical, diagnostic and therapeutic context of MAP2K6

  • The surgically resected livers of 20 HCC patients were divided histologically into tumorous (T) and nontumorous (NT) lesions. p38 MAPK activity was analyzed using in vitro kinase assay and MKK6 activity was measured using Western blot analysis [2].
  • Some were novel candidates, while others are involved in well-characterized mechanisms that could be relevant to cisplatin resistance, such as RECQL for DNA repair and MAP2K6 in the MAP pathway; all the genes were further validated by Real-time PCR [30].
  • The mitogen-activated protein (MAP) kinase p38 and its upstream activator MAP kinase kinase 6 are involved in the activation of signal transducer and activator of transcription by hyperosmolarity [31].


  1. Overexpression of mitogen-activated protein kinase kinase 6 in the heart improves functional recovery from ischemia in vitro and protects against myocardial infarction in vivo. Martindale, J.J., Wall, J.A., Martinez-Longoria, D.M., Aryal, P., Rockman, H.A., Guo, Y., Bolli, R., Glembotski, C.C. J. Biol. Chem. (2005) [Pubmed]
  2. Involvement of the p38 mitogen-activated protein kinase cascade in hepatocellular carcinoma. Iyoda, K., Sasaki, Y., Horimoto, M., Toyama, T., Yakushijin, T., Sakakibara, M., Takehara, T., Fujimoto, J., Hori, M., Wands, J.R., Hayashi, N. Cancer (2003) [Pubmed]
  3. The use of genetic programming in the analysis of quantitative gene expression profiles for identification of nodal status in bladder cancer. Mitra, A.P., Almal, A.A., George, B., Fry, D.W., Lenehan, P.F., Pagliarulo, V., Cote, R.J., Datar, R.H., Worzel, W.P. BMC Cancer (2006) [Pubmed]
  4. Expression and activation of mitogen-activated protein kinase kinases-3 and -6 in rheumatoid arthritis. Chabaud-Riou, M., Firestein, G.S. Am. J. Pathol. (2004) [Pubmed]
  5. Profiling of protein kinases in the neoplastic transformation of human ovarian surface epithelium. Wong, A.S., Kim, S.O., Leung, P.C., Auersperg, N., Pelech, S.L. Gynecol. Oncol. (2001) [Pubmed]
  6. Activation of MKK6, an upstream activator of p38, in Alzheimer's disease. Zhu, X., Rottkamp, C.A., Hartzler, A., Sun, Z., Takeda, A., Boux, H., Shimohama, S., Perry, G., Smith, M.A. J. Neurochem. (2001) [Pubmed]
  7. p38 pathway targets SWI-SNF chromatin-remodeling complex to muscle-specific loci. Simone, C., Forcales, S.V., Hill, D.A., Imbalzano, A.N., Latella, L., Puri, P.L. Nat. Genet. (2004) [Pubmed]
  8. Essential role of p53 phosphorylation by p38 MAPK in apoptosis induction by the HIV-1 envelope. Perfettini, J.L., Castedo, M., Nardacci, R., Ciccosanti, F., Boya, P., Roumier, T., Larochette, N., Piacentini, M., Kroemer, G. J. Exp. Med. (2005) [Pubmed]
  9. Changes in the balance of phosphoinositide 3-kinase/protein kinase B (Akt) and the mitogen-activated protein kinases (ERK/p38MAPK) determine a phenotype of visceral and vascular smooth muscle cells. Hayashi, K., Takahashi, M., Kimura, K., Nishida, W., Saga, H., Sobue, K. J. Cell Biol. (1999) [Pubmed]
  10. Ectodomain shedding of TGF-alpha and other transmembrane proteins is induced by receptor tyrosine kinase activation and MAP kinase signaling cascades. Fan, H., Derynck, R. EMBO J. (1999) [Pubmed]
  11. Activation of the novel stress-activated protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6); comparison of its substrate specificity with that of other SAP kinases. Goedert, M., Cuenda, A., Craxton, M., Jakes, R., Cohen, P. EMBO J. (1997) [Pubmed]
  12. c-Abl-induced apoptosis, but not cell cycle arrest, requires mitogen-activated protein kinase kinase 6 activation. Cong, F., Goff, S.P. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  13. Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Wang, W., Chen, J.X., Liao, R., Deng, Q., Zhou, J.J., Huang, S., Sun, P. Mol. Cell. Biol. (2002) [Pubmed]
  14. Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in stress- and cytokine-stimulated monocytes and epithelial cells. Cuenda, A., Alonso, G., Morrice, N., Jones, M., Meier, R., Cohen, P., Nebreda, A.R. EMBO J. (1996) [Pubmed]
  15. MEK6 regulates human involucrin gene expression via a p38alpha - and p38delta -dependent mechanism. Dashti, S.R., Efimova, T., Eckert, R.L. J. Biol. Chem. (2001) [Pubmed]
  16. Activation of p38 has opposing effects on the proliferation and migration of endothelial cells. McMullen, M.E., Bryant, P.W., Glembotski, C.C., Vincent, P.A., Pumiglia, K.M. J. Biol. Chem. (2005) [Pubmed]
  17. Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade. Stein, B., Brady, H., Yang, M.X., Young, D.B., Barbosa, M.S. J. Biol. Chem. (1996) [Pubmed]
  18. The stress inducer arsenite activates mitogen-activated protein kinases extracellular signal-regulated kinases 1 and 2 via a MAPK kinase 6/p38-dependent pathway. Ludwig, S., Hoffmeyer, A., Goebeler, M., Kilian, K., Häfner, H., Neufeld, B., Han, J., Rapp, U.R. J. Biol. Chem. (1998) [Pubmed]
  19. 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]
  20. Protein kinase R (PKR) interacts with and activates mitogen-activated protein kinase kinase 6 (MKK6) in response to double-stranded RNA stimulation. Silva, A.M., Whitmore, M., Xu, Z., Jiang, Z., Li, X., Williams, B.R. J. Biol. Chem. (2004) [Pubmed]
  21. Rac1-MKK3-p38-MAPKAPK2 pathway promotes urokinase plasminogen activator mRNA stability in invasive breast cancer cells. Han, Q., Leng, J., Bian, D., Mahanivong, C., Carpenter, K.A., Pan, Z.K., Han, J., Huang, S. J. Biol. Chem. (2002) [Pubmed]
  22. 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]
  23. Differential activation of p38 mitogen-activated protein kinase isoforms depending on signal strength. Alonso, G., Ambrosino, C., Jones, M., Nebreda, A.R. J. Biol. Chem. (2000) [Pubmed]
  24. 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]
  25. Activation of stress-activated protein kinase-3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6); comparison of the specificities of SAPK3 and SAPK2 (RK/p38). Cuenda, A., Cohen, P., Buée-Scherrer, V., Goedert, M. EMBO J. (1997) [Pubmed]
  26. Cellular stresses and cytokines activate multiple mitogen-activated-protein kinase kinase homologues in PC12 and KB cells. Meier, R., Rouse, J., Cuenda, A., Nebreda, A.R., Cohen, P. Eur. J. Biochem. (1996) [Pubmed]
  27. The p38 and JNK pathways cooperate to trans-activate vitamin D receptor via c-Jun/AP-1 and sensitize human breast cancer cells to vitamin D(3)-induced growth inhibition. Qi, X., Pramanik, R., Wang, J., Schultz, R.M., Maitra, R.K., Han, J., DeLuca, H.F., Chen, G. J. Biol. Chem. (2002) [Pubmed]
  28. Activation of p21-activated kinase 6 by MAP kinase kinase 6 and p38 MAP kinase. Kaur, R., Liu, X., Gjoerup, O., Zhang, A., Yuan, X., Balk, S.P., Schneider, M.C., Lu, M.L. J. Biol. Chem. (2005) [Pubmed]
  29. A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. Moriguchi, T., Kuroyanagi, N., Yamaguchi, K., Gotoh, Y., Irie, K., Kano, T., Shirakabe, K., Muro, Y., Shibuya, H., Matsumoto, K., Nishida, E., Hagiwara, M. J. Biol. Chem. (1996) [Pubmed]
  30. Identification of genes associated with cisplatin resistance in human oral squamous cell carcinoma cell line. Zhang, P., Zhang, Z., Zhou, X., Qiu, W., Chen, F., Chen, W. BMC Cancer (2006) [Pubmed]
  31. The mitogen-activated protein (MAP) kinase p38 and its upstream activator MAP kinase kinase 6 are involved in the activation of signal transducer and activator of transcription by hyperosmolarity. Bode, J.G., Gatsios, P., Ludwig, S., Rapp, U.R., Häussinger, D., Heinrich, P.C., Graeve, L. J. Biol. Chem. (1999) [Pubmed]
WikiGenes - Universities