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

Map2k4  -  mitogen-activated protein kinase kinase 4

Mus musculus

Synonyms: C-JUN N-terminal kinase kinase 1, Dual specificity mitogen-activated protein kinase kinase 4, JNK kinase 1, JNK-activating kinase 1, JNKK 1, ...
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 Map2k4

  • In this study, we elucidate key mechanisms of MKK4-mediated metastasis suppression [1].
  • Our finding that MKK4 and MKK6 both suppress metastasis points to the p38 pathway as an important regulatory pathway for metastatic colonization in ovarian cancer [1].
  • Surprisingly, however, aging SEK1-deficient chimeric mice frequently develop lymphadenopathy and polyclonal B and T cell expansions [2].
  • Dominant-negative SEK1 can block JNK activation by LPS, but not by Salmonella [3].
  • Ectopic expression of MKK4 in these cells, when injected into female SCID mice, suppressed the number of overt metastatic implants by nearly 90% [4].

Psychiatry related information on Map2k4

  • We also observed that nuclear inclusion-positive neurones from brains with Huntington's disease expressed SEK1 [5].

High impact information on Map2k4

  • JNP is thought to be required for the anti-apoptotic function of c-Jun during hepatogenesis, as mice lacking the JNK kinase SEK1 exhibit liver defects similar to those seen in Jun-/- fetuses [6].
  • Here we investigate the role of Sek1 in development and apoptosis by deleting sek1 in embryonic stem (ES) cells by homologous recombination [7].
  • These data indicate that SEK1 mediates survival signals in T-cell development [7].
  • An inactive SEK1 mutant blocks SAPK activation by extracellular stimuli without interfering with the MAPK pathway [8].
  • Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1 [9].

Biological context of Map2k4


Anatomical context of Map2k4

  • In contrast, only the activated form of SEK1 associated with JSAP1 in cotransfected COS-7 cells [15].
  • These normal apoptotic responses without SAPK/JNK activation were also observed in fibroblasts derived from sek1(-/-) mkk7(-/-) ES cells [12].
  • Studies of SEK1(-/-) embryonic stem cells demonstrated defects in stimulated SAPK phosphorylation but not in the phosphorylation of p38 kinase [14].
  • However, hepatogenesis and liver formation were severely impaired in the mutant embryos and E11.5 and E12.5 sek1(-/- )embryos had greatly reduced numbers of parenchymal hepatocytes [16].
  • These results indicate that in response to the aggregation of FcepsilonRI on mast cells, phosphatidylinositol 3-kinase activation is involved in the stimulation of the MEKK1, JNKK, JNK pathway [17].

Associations of Map2k4 with chemical compounds

  • Suppression of metastatic colonization by the context-dependent activation of the c-Jun NH2-terminal kinase kinases JNKK1/MKK4 and MKK7 [18].
  • The Sek1 mutation did not alter the induction of apoptosis in response to etoposide, cisplatinum, Adriamycin, and gamma-irradiation [19].
  • MKK4 was phosphorylated only in response to sorbitol, and neither of the stimuli caused phosphorylation of MKK3 or 6 [20].
  • Phosphatidylinositol 3 kinase, protein kinase A, protein kinase C, MAPK kinase 4, KIT, PIM1, and transforming growth factor-beta receptor 1, were significantly downregulated by genistein [21].
  • The strongest expression of the sek1 was found in the CA3 region of hippocampus, the region being highly vulnerable to exitotoxicity-induced apoptosis in kainate-treated animal models [22].

Regulatory relationships of Map2k4


Other interactions of Map2k4

  • The defective liver formation in sek1(-/-) embryos was not protected by additionaltnfr1 mutation, which rescues the embryonic lethality of mice lacking NF-kappaB signaling components [25].
  • SEK1(-/-) peripheral T cells showed decreased proliferation and IL-2 production after CD28 costimulation and PMA/Ca2+ ionophore activation [10].
  • In vivo studies show that both JNKK1/MKK4 and MKK7 suppress the formation of overt metastases by inhibiting the ability of disseminated cells to colonize the lung (secondary site) [18].
  • Mice lacking the stress-signaling kinase SEK1 die from embryonic day 10.5 (E10.5) to E12 [25].
  • Stimulation of stress-activated protein kinase/c-Jun N-terminal kinase by hepatocyte growth factor was attenuated in sek1(-/-) livers [25].

Analytical, diagnostic and therapeutic context of Map2k4

  • Our working hypothesis is that stress, vaccination, and PY may synergistically induce activation of MKK4 and JNK in the brain, leading to over-activation of these kinases and neurological injuries [26].
  • To gain insight into the role of SEK1 during embryonic development and in adult life, we examined the temporal and spatial patterns of sek1 expression in mice by using in situ hybridization and immunohistochemical study [22].
  • Furthermore, strawberry extract also blocked TPA-induced phosphorylation of extracellular signal-regulated kinases (ERKs) and UVB-induced phosphorylation of ERKs and JNK kinase in JB6 P+ mouse epidermal cell culture [27].
  • Whereas the metastatic ability of the AT6.1-MKK4/SEK1 cells was significantly reduced as compared with that of transfection controls, the growth rate of the primary tumors was not affected; the average tumor volume at day 29 after injection was approximately 2 cm [28].


  1. The p38 kinases MKK4 and MKK6 suppress metastatic colonization in human ovarian carcinoma. Hickson, J.A., Huo, D., Vander Griend, D.J., Lin, A., Rinker-Schaeffer, C.W., Yamada, S.D. Cancer Res. (2006) [Pubmed]
  2. SEK1/MKK4 is required for maintenance of a normal peripheral lymphoid compartment but not for lymphocyte development. Swat, W., Fujikawa, K., Ganiatsas, S., Yang, D., Xavier, R.J., Harris, N.L., Davidson, L., Ferrini, R., Davis, R.J., Labow, M.A., Flavell, R.A., Zon, L.I., Alt, F.W. Immunity (1998) [Pubmed]
  3. Distinct mechanisms target stress and extracellular signal-activated kinase 1 and Jun N-terminal kinase during infection of macrophages with Salmonella. Procyk, K.J., Rippo, M.R., Testi, R., Hoffmann, F., Parker, P.J., Baccarini, M. J. Immunol. (1999) [Pubmed]
  4. Mitogen-activated protein kinase kinase 4 (MKK4) acts as a metastasis suppressor gene in human ovarian carcinoma. Yamada, S.D., Hickson, J.A., Hrobowski, Y., Vander Griend, D.J., Benson, D., Montag, A., Karrison, T., Huo, D., Rutgers, J., Adams, S., Rinker-Schaeffer, C.W. Cancer Res. (2002) [Pubmed]
  5. Triggering of neuronal cell death by accumulation of activated SEK1 on nuclear polyglutamine aggregations in PML bodies. Yasuda, S., Inoue, K., Hirabayashi, M., Higashiyama, H., Yamamoto, Y., Fuyuhiro, H., Komure, O., Tanaka, F., Sobue, G., Tsuchiya, K., Hamada, K., Sasaki, H., Takeda, K., Ichijo, H., Kakizuka, A. Genes Cells (1999) [Pubmed]
  6. Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Behrens, A., Sibilia, M., Wagner, E.F. Nat. Genet. (1999) [Pubmed]
  7. Stress-signalling kinase Sek1 protects thymocytes from apoptosis mediated by CD95 and CD3. Nishina, H., Fischer, K.D., Radvanyi, L., Shahinian, A., Hakem, R., Rubie, E.A., Bernstein, A., Mak, T.W., Woodgett, J.R., Penninger, J.M. Nature (1997) [Pubmed]
  8. Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun. Sánchez, I., Hughes, R.T., Mayer, B.J., Yee, K., Woodgett, J.R., Avruch, J., Kyriakis, J.M., Zon, L.I. Nature (1994) [Pubmed]
  9. Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1. Yan, M., Dai, T., Deak, J.C., Kyriakis, J.M., Zon, L.I., Woodgett, J.R., Templeton, D.J. Nature (1994) [Pubmed]
  10. Impaired CD28-mediated interleukin 2 production and proliferation in stress kinase SAPK/ERK1 kinase (SEK1)/mitogen-activated protein kinase kinase 4 (MKK4)-deficient T lymphocytes. Nishina, H., Bachmann, M., Oliveira-dos-Santos, A.J., Kozieradzki, I., Fischer, K.D., Odermatt, B., Wakeham, A., Shahinian, A., Takimoto, H., Bernstein, A., Mak, T.W., Woodgett, J.R., Ohashi, P.S., Penninger, J.M. J. Exp. Med. (1997) [Pubmed]
  11. Different properties of SEK1 and MKK7 in dual phosphorylation of stress-induced activated protein kinase SAPK/JNK in embryonic stem cells. Kishimoto, H., Nakagawa, K., Watanabe, T., Kitagawa, D., Momose, H., Seo, J., Nishitai, G., Shimizu, N., Ohata, S., Tanemura, S., Asaka, S., Goto, T., Fukushi, H., Yoshida, H., Suzuki, A., Sasaki, T., Wada, T., Penninger, J.M., Nishina, H., Katada, T. J. Biol. Chem. (2003) [Pubmed]
  12. Stress induces mitochondria-mediated apoptosis independent of SAPK/JNK activation in embryonic stem cells. Nishitai, G., Shimizu, N., Negishi, T., Kishimoto, H., Nakagawa, K., Kitagawa, D., Watanabe, T., Momose, H., Ohata, S., Tanemura, S., Asaka, S., Kubota, J., Saito, R., Yoshida, H., Mak, T.W., Wada, T., Penninger, J.M., Azuma, N., Nishina, H., Katada, T. J. Biol. Chem. (2004) [Pubmed]
  13. c-Jun N-terminal kinase phosphorylates peroxisome proliferator-activated receptor-gamma1 and negatively regulates its transcriptional activity. Camp, H.S., Tafuri, S.R., Leff, T. Endocrinology (1999) [Pubmed]
  14. SEK1 deficiency reveals mitogen-activated protein kinase cascade crossregulation and leads to abnormal hepatogenesis. Ganiatsas, S., Kwee, L., Fujiwara, Y., Perkins, A., Ikeda, T., Labow, M.A., Zon, L.I. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  15. JSAP1, a novel jun N-terminal protein kinase (JNK)-binding protein that functions as a Scaffold factor in the JNK signaling pathway. Ito, M., Yoshioka, K., Akechi, M., Yamashita, S., Takamatsu, N., Sugiyama, K., Hibi, M., Nakabeppu, Y., Shiba, T., Yamamoto, K.I. Mol. Cell. Biol. (1999) [Pubmed]
  16. Defective liver formation and liver cell apoptosis in mice lacking the stress signaling kinase SEK1/MKK4. Nishina, H., Vaz, C., Billia, P., Nghiem, M., Sasaki, T., De la Pompa, J.L., Furlonger, K., Paige, C., Hui, C., Fischer, K.D., Kishimoto, H., Iwatsubo, T., Katada, T., Woodgett, J.R., Penninger, J.M. Development (1999) [Pubmed]
  17. Aggregation of the FcepsilonRI on mast cells stimulates c-Jun amino-terminal kinase activity. A response inhibited by wortmannin. Ishizuka, T., Oshiba, A., Sakata, N., Terada, N., Johnson, G.L., Gelfand, E.W. J. Biol. Chem. (1996) [Pubmed]
  18. Suppression of metastatic colonization by the context-dependent activation of the c-Jun NH2-terminal kinase kinases JNKK1/MKK4 and MKK7. Vander Griend, D.J., Kocherginsky, M., Hickson, J.A., Stadler, W.M., Lin, A., Rinker-Schaeffer, C.W. Cancer Res. (2005) [Pubmed]
  19. Impaired TCR-mediated apoptosis and Bcl-XL expression in T cells lacking the stress kinase activator SEK1/MKK4. Nishina, H., Radvanyi, L., Raju, K., Sasaki, T., Kozieradzki, I., Penninger, J.M. J. Immunol. (1998) [Pubmed]
  20. Stimulation of MAPK cascades by insulin and osmotic shock: lack of an involvement of p38 mitogen-activated protein kinase in glucose transport in 3T3-L1 adipocytes. Kayali, A.G., Austin, D.A., Webster, N.J. Diabetes (2000) [Pubmed]
  21. Synergistic antileukemia effect of genistein and chemotherapy in mouse xenograft model and potential mechanism through MAPK signaling. Shen, J., Tai, Y.C., Zhou, J., Stephen Wong, C.H., Cheang, P.T., Fred Wong, W.S., Xie, Z., Khan, M., Han, J.H., Chen, C.S. Exp. Hematol. (2007) [Pubmed]
  22. Dynamic expression of SEK1 suggests multiple roles of the gene during embryogenesis and in adult brain of mice. Lee, J.K., Hwang, W.S., Lee, Y.D., Han, P.L. Brain Res. Mol. Brain Res. (1999) [Pubmed]
  23. Vanadate induction of NF-kappaB involves IkappaB kinase beta and SAPK/ERK kinase 1 in macrophages. Chen, F., Demers, L.M., Vallyathan, V., Ding, M., Lu, Y., Castranova, V., Shi, X. J. Biol. Chem. (1999) [Pubmed]
  24. c-Abl activation regulates induction of the SEK1/stress-activated protein kinase pathway in the cellular response to 1-beta-D-arabinofuranosylcytosine. Kharbanda, S., Pandey, P., Ren, R., Mayer, B., Zon, L., Kufe, D. J. Biol. Chem. (1995) [Pubmed]
  25. SEK1/MKK4-mediated SAPK/JNK signaling participates in embryonic hepatoblast proliferation via a pathway different from NF-kappaB-induced anti-apoptosis. Watanabe, T., Nakagawa, K., Ohata, S., Kitagawa, D., Nishitai, G., Seo, J., Tanemura, S., Shimizu, N., Kishimoto, H., Wada, T., Aoki, J., Arai, H., Iwatsubo, T., Mochita, M., Watanabe, T., Satake, M., Ito, Y., Matsuyama, T., Mak, T.W., Penninger, J.M., Nishina, H., Katada, T. Dev. Biol. (2002) [Pubmed]
  26. Vaccination alone or in combination with pyridostigmine promotes and prolongs activation of stress-activated kinases induced by stress in the mouse brain. Wang, D., Perides, G., Liu, Y.F. J. Neurochem. (2005) [Pubmed]
  27. Inhibitory effect on activator protein-1, nuclear factor-kappaB, and cell transformation by extracts of strawberries (Fragaria x ananassa Duch.). Wang, S.Y., Feng, R., Lu, Y., Bowman, L., Ding, M. J. Agric. Food Chem. (2005) [Pubmed]
  28. Mitogen-activated protein kinase kinase 4/stress-activated protein/Erk kinase 1 (MKK4/SEK1), a prostate cancer metastasis suppressor gene encoded by human chromosome 17. Yoshida, B.A., Dubauskas, Z., Chekmareva, M.A., Christiano, T.R., Stadler, W.M., Rinker-Schaeffer, C.W. Cancer Res. (1999) [Pubmed]
WikiGenes - Universities