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

Mapk8  -  mitogen-activated protein kinase 8

Mus musculus

Synonyms: AI849689, JNK, JNK1, Jnk1, MAP kinase 8, ...
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 Mapk8


Psychiatry related information on Mapk8

  • The stress kinase c-jun N-terminal kinase (JNK) was recently shown to be involved in the pathophysiology of major inflammatory conditions, including Alzheimer's disease, stroke, obesity, and type II diabetes [7].
  • Thus, lack of insulin brain stimulation induces JNK hyperphosphorylation followed by hyperphosphorylation of tau and neurofilament, and ultrastructural cellular damage, that over time may induce decrease in cognition and learning disabilities [8].

High impact information on Mapk8

  • Critically, identity of a JNK substrate that promotes TNFalpha-induced apoptosis has been outstanding [9].
  • The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover [9].
  • Sustained JNK activation in NF-kappaB-deficient cells was suggested to depend on reactive oxygen species (ROS), but how ROS affect JNK activation was unclear [10].
  • This correlated with enhanced reactive oxygen species (ROS) production, increased JNK activation, and hepatocyte death, giving rise to augmented compensatory proliferation of surviving hepatocytes [11].
  • Brief oral administration of an antioxidant around the time of DEN exposure blocked prolonged JNK activation and compensatory proliferation and prevented excessive DEN-induced carcinogenesis in Ikkbeta(Deltahep) mice [11].

Chemical compound and disease context of Mapk8


Biological context of Mapk8


Anatomical context of Mapk8

  • Bam32 links the B cell receptor to ERK and JNK and mediates B cell proliferation but not survival [21].
  • These results show that signaling pathways for SAPK activation are developmentally regulated in T cells [17].
  • In particular, c-Jun N-terminal kinase (JNK) is highly activated in RA fibroblast-like synoviocytes and synovium [22].
  • RESULTS: Sustained activation of JNK was observed in cultured mouse hepatocytes and in vivo in the liver after APAP treatment [1].
  • Here we investigated the functional importance of JNK signaling in regulating differentiated cellular growth in the post-mitotic myocardium [23].

Associations of Mapk8 with chemical compounds


Physical interactions of Mapk8

  • Enhancement of LPS-inducible COX-2 expression and C/EBP DNA binding by C2 was abrogated in dominant-negative mutant of JNK1 [JNK1(-)] cells [30].
  • Amelioration of colon damage was associated with a significant reduction of the activation of JNK and reduction of the DNA binding of AP-1 [31].
  • Components of the JNK signaling pathway interact with the JIP1 scaffold protein [32].
  • Like other members of the JIP family of scaffold proteins, JIP4 binds JNK and also the light chain of the microtubule motor protein kinesin-1 [33].
  • Thrombin induces nitric-oxide synthase via Galpha12/13-coupled protein kinase C-dependent I-kappaBalpha phosphorylation and JNK-mediated I-kappaBalpha degradation [34].

Enzymatic interactions of Mapk8

  • Western blot analyses showed significantly increased levels of TNF-alpha (1.8-fold) and phosphorylated-SAPK/JNK1/2 (1.5-fold) in transgenic hearts [35].
  • The co-precipitated complex by the anti-phospho-JNK antibody was capable of phosphorylating intrinsic or extrinsic p53 on Ser-15 [36].
  • One consequence of obesity is that JNK phosphorylates the adapter protein insulin receptor substrate 1 (IRS-1) on Ser 307 and inhibits signaling by the insulin receptor [37].
  • JNK catalyzed phosphorylation of c-Jun was also detected in the acini [38].
  • These results suggest that JIP1 plays a pivotal role in regulating the maintenance of phosphorylated JNK and neuronal survival in postischemic brain, but is not essential for JNK activation and early development [39].

Regulatory relationships of Mapk8

  • Our findings define a MEKK-regulated JNK pathway activated by FcepsilonRI that regulates TNF-alpha production in mast cells [40].
  • Inhibition of either DCA-induced ERK1/2 or DCA-induced JNK1/2 signaling enhanced the apoptotic response of hepatocytes [27].
  • Consequently, expression and activation of c-Jun, which depends on JNK activity, were impaired in Jnk1 null cells but enhanced in Jnk2 null cells [41].
  • The lack of correlation with AP-1 activity and MMP expression was probably because non-FLS cells in the joint may express more JNK-1 than do FLS [42].
  • To study the role of JNK in tonicity-stimulated COX-2 expression, IMCD-3 cell lines stably transfected with dominant-negative mutants of three JNKs (JNK-1, -2, and -3) were used [43].
  • Taken together, data from our study reveal a novel underlying mechanism in H(2)O(2)-induced nonapoptotic cell death: JNK1 promotes a sustained PARP-1 activation via nuclear translocation, protein-protein interaction and PARP-1 phosphorylation [44].
  • Knockdown of JNK1 enhanced insulin signaling in vitro [45].
  • Gadd45beta ablation did not affect hepatotoxic JNK signaling after a TNFR-mediated immune challenge, suggesting specificity in the inducible hepatic program for JNK restraint activated during distinct TNFR-mediated challenges [46].

Other interactions of Mapk8

  • Although JNK1 and JNK2 were shown to differentially regulate fibroblast proliferation, the underlying mechanistic basis remains unclear [16].
  • In addition to underscoring the importance of JNK1-mediated hepatocyte death and compensatory proliferation, these results strongly suggest that the control of tissue renewal through the IKK and JNK pathways plays a key role in liver carcinogenesis [47].
  • Whereas hepatocyte-specific deletion of IKKbeta augmented DEN-induced hepatocyte death and cytokine-driven compensatory proliferation, disruption of JNK1 abrogated this response [47].
  • MNNG was found to induce the activation of JNK/SAPK and p38 mitogen-activated protein kinases (MAPKs) [48].
  • The phosphatidylinositol 3-kinase inhibitor wortmannin specifically blocked the UV-stimulated activation of JNK1 but did not affect UV-driven activation of extracellular regulated kinase 2 (ERK2) [26].

Analytical, diagnostic and therapeutic context of Mapk8


  1. c-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity. Gunawan, B.K., Liu, Z.X., Han, D., Hanawa, N., Gaarde, W.A., Kaplowitz, N. Gastroenterology (2006) [Pubmed]
  2. JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease. Hunot, S., Vila, M., Teismann, P., Davis, R.J., Hirsch, E.C., Przedborski, S., Rakic, P., Flavell, R.A. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  3. A critical role of neural-specific JNK3 for ischemic apoptosis. Kuan, C.Y., Whitmarsh, A.J., Yang, D.D., Liao, G., Schloemer, A.J., Dong, C., Bao, J., Banasiak, K.J., Haddad, G.G., Flavell, R.A., Davis, R.J., Rakic, P. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  4. Distinct gene expression profiles and reduced JNK signaling in retinitis pigmentosa caused by RP1 mutations. Liu, J., Huang, Q., Higdon, J., Liu, W., Xie, T., Yamashita, T., Cheon, K., Cheng, C., Zuo, J. Hum. Mol. Genet. (2005) [Pubmed]
  5. Deficiency of c-Jun-NH(2)-terminal kinase-1 in mice enhances skin tumor development by 12-O-tetradecanoylphorbol-13-acetate. She, Q.B., Chen, N., Bode, A.M., Flavell, R.A., Dong, Z. Cancer Res. (2002) [Pubmed]
  6. cJun NH2-terminal kinase 1 (JNK1): roles in metabolic regulation of insulin resistance. Sabio, G., Davis, R.J. Trends Biochem. Sci. (2010) [Pubmed]
  7. C-jun N-terminal kinase mediates tumor necrosis factor-alpha suppression of differentiation in myoblasts. Strle, K., Broussard, S.R., McCusker, R.H., Shen, W.H., LeCleir, J.M., Johnson, R.W., Freund, G.G., Dantzer, R., Kelley, K.W. Endocrinology (2006) [Pubmed]
  8. The effect of insulin deficiency on tau and neurofilament in the insulin knockout mouse. Schechter, R., Beju, D., Miller, K.E. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  9. The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover. Chang, L., Kamata, H., Solinas, G., Luo, J.L., Maeda, S., Venuprasad, K., Liu, Y.C., Karin, M. Cell (2006) [Pubmed]
  10. Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Kamata, H., Honda, S., Maeda, S., Chang, L., Hirata, H., Karin, M. Cell (2005) [Pubmed]
  11. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Maeda, S., Kamata, H., Luo, J.L., Leffert, H., Karin, M. Cell (2005) [Pubmed]
  12. G alpha 13 signals via p115RhoGEF cascades regulating JNK1 and primitive endoderm formation. Lee, Y.N., Malbon, C.C., Wang, H.Y. J. Biol. Chem. (2004) [Pubmed]
  13. JNK activation by tetrahydrobiopterin: implication for Parkinson's disease. Choi, H.J., Lee, S.Y., Cho, Y., Hwang, O. J. Neurosci. Res. (2004) [Pubmed]
  14. Map kinase c-JUN N-terminal kinase mediates PMMA induction of osteoclasts. Yamanaka, Y., Abu-Amer, Y., Faccio, R., Clohisy, J.C. J. Orthop. Res. (2006) [Pubmed]
  15. Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance. Tuncman, G., Hirosumi, J., Solinas, G., Chang, L., Karin, M., Hotamisligil, G.S. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  16. Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation. Sabapathy, K., Hochedlinger, K., Nam, S.Y., Bauer, A., Karin, M., Wagner, E.F. Mol. Cell (2004) [Pubmed]
  17. 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]
  18. A reinvestigation of the multisite phosphorylation of the transcription factor c-Jun. Morton, S., Davis, R.J., McLaren, A., Cohen, P. EMBO J. (2003) [Pubmed]
  19. Fas-induced proteolytic activation and intracellular redistribution of the stress-signaling kinase MEKK1. Deak, J.C., Cross, J.V., Lewis, M., Qian, Y., Parrott, L.A., Distelhorst, C.W., Templeton, D.J. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  20. MEK kinase 1 is critically required for c-Jun N-terminal kinase activation by proinflammatory stimuli and growth factor-induced cell migration. Xia, Y., Makris, C., Su, B., Li, E., Yang, J., Nemerow, G.R., Karin, M. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  21. Bam32 links the B cell receptor to ERK and JNK and mediates B cell proliferation but not survival. Han, A., Saijo, K., Mecklenbräuker, I., Tarakhovsky, A., Nussenzweig, M.C. Immunity (2003) [Pubmed]
  22. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. Han, Z., Boyle, D.L., Chang, L., Bennett, B., Karin, M., Yang, L., Manning, A.M., Firestein, G.S. J. Clin. Invest. (2001) [Pubmed]
  23. c-Jun N-terminal kinases (JNK) antagonize cardiac growth through cross-talk with calcineurin-NFAT signaling. Liang, Q., Bueno, O.F., Wilkins, B.J., Kuan, C.Y., Xia, Y., Molkentin, J.D. EMBO J. (2003) [Pubmed]
  24. A novel mitogen-activated protein kinase phosphatase is an important negative regulator of lipopolysaccharide-mediated c-Jun N-terminal kinase activation in mouse macrophage cell lines. Matsuguchi, T., Musikacharoen, T., Johnson, T.R., Kraft, A.S., Yoshikai, Y. Mol. Cell. Biol. (2001) [Pubmed]
  25. Glucose utilization is essential for hypoxia-inducible factor 1 alpha-dependent phosphorylation of c-Jun. Laderoute, K.R., Calaoagan, J.M., Knapp, M., Johnson, R.S. Mol. Cell. Biol. (2004) [Pubmed]
  26. Activation of c-Jun N-terminal kinase 1 by UV irradiation is inhibited by wortmannin without affecting c-iun expression. Fritz, G., Kaina, B. Mol. Cell. Biol. (1999) [Pubmed]
  27. Bile acid regulation of C/EBPbeta, CREB, and c-Jun function, via the extracellular signal-regulated kinase and c-Jun NH2-terminal kinase pathways, modulates the apoptotic response of hepatocytes. Qiao, L., Han, S.I., Fang, Y., Park, J.S., Gupta, S., Gilfor, D., Amorino, G., Valerie, K., Sealy, L., Engelhardt, J.F., Grant, S., Hylemon, P.B., Dent, P. Mol. Cell. Biol. (2003) [Pubmed]
  28. JNK1 Is required for the induction of Mkp1 expression in macrophages during proliferation and lipopolysaccharide-dependent activation. Sánchez-Tilló, E., Comalada, M., Xaus, J., Farrera, C., Valledor, A.F., Caelles, C., Lloberas, J., Celada, A. J. Biol. Chem. (2007) [Pubmed]
  29. Differential transmission of MEKK1 morphogenetic signals by JNK1 and JNK2. Takatori, A., Geh, E., Chen, L., Zhang, L., Meller, J., Xia, Y. Development (2008) [Pubmed]
  30. Potentiation of lipopolysaccharide-inducible cyclooxygenase 2 expression by C2-ceramide via c-Jun N-terminal kinase-mediated activation of CCAAT/enhancer binding protein beta in macrophages. Cho, Y.H., Lee, C.H., Kim, S.G. Mol. Pharmacol. (2003) [Pubmed]
  31. Activator protein-1 signalling pathway and apoptosis are modulated by poly(ADP-ribose) polymerase-1 in experimental colitis. Zingarelli, B., Hake, P.W., Burroughs, T.J., Piraino, G., O'connor, M., Denenberg, A. Immunology (2004) [Pubmed]
  32. Requirement of the JIP1 scaffold protein for stress-induced JNK activation. Whitmarsh, A.J., Kuan, C.Y., Kennedy, N.J., Kelkar, N., Haydar, T.F., Mordes, J.P., Appel, M., Rossini, A.A., Jones, S.N., Flavell, R.A., Rakic, P., Davis, R.J. Genes Dev. (2001) [Pubmed]
  33. Role of the JIP4 scaffold protein in the regulation of mitogen-activated protein kinase signaling pathways. Kelkar, N., Standen, C.L., Davis, R.J. Mol. Cell. Biol. (2005) [Pubmed]
  34. Thrombin induces nitric-oxide synthase via Galpha12/13-coupled protein kinase C-dependent I-kappaBalpha phosphorylation and JNK-mediated I-kappaBalpha degradation. Kang, K.W., Choi, S.Y., Cho, M.K., Lee, C.H., Kim, S.G. J. Biol. Chem. (2003) [Pubmed]
  35. Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice mimics ischemic preconditioning through SAPK/JNK1/2 activation. Martire, A., Fernandez, B., Buehler, A., Strohm, C., Schaper, J., Zimmermann, R., Kolattukudy, P.E., Schaper, W. Cardiovasc. Res. (2003) [Pubmed]
  36. Low levels of glutathione peroxidase 1 activity in selenium-deficient mouse liver affect c-Jun N-terminal kinase activation and p53 phosphorylation on Ser-15 in pro-oxidant-induced aponecrosis. Cheng, W.H., Zheng, X., Quimby, F.R., Roneker, C.A., Lei, X.G. Biochem. J. (2003) [Pubmed]
  37. An essential role of the JIP1 scaffold protein for JNK activation in adipose tissue. Jaeschke, A., Czech, M.P., Davis, R.J. Genes Dev. (2004) [Pubmed]
  38. Organization of mammary epithelial cells into 3D acinar structures requires glucocorticoid and JNK signaling. Murtagh, J., McArdle, E., Gilligan, E., Thornton, L., Furlong, F., Martin, F. J. Cell Biol. (2004) [Pubmed]
  39. Repression of phospho-JNK and infarct volume in ischemic brain of JIP1-deficient mice. Im, J.Y., Lee, K.W., Kim, M.H., Lee, S.H., Ha, H.Y., Cho, I.H., Kim, D., Yu, M.S., Kim, J.B., Lee, J.K., Kim, Y.J., Youn, B.W., Yang, S.D., Shin, H.S., Han, P.L. J. Neurosci. Res. (2003) [Pubmed]
  40. Mast cell tumor necrosis factor alpha production is regulated by MEK kinases. Ishizuka, T., Terada, N., Gerwins, P., Hamelmann, E., Oshiba, A., Fanger, G.R., Johnson, G.L., Gelfand, E.W. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  41. c-Jun N-terminal protein kinase 1 (JNK1), but not JNK2, is essential for tumor necrosis factor alpha-induced c-Jun kinase activation and apoptosis. Liu, J., Minemoto, Y., Lin, A. Mol. Cell. Biol. (2004) [Pubmed]
  42. Joint damage and inflammation in c-Jun N-terminal kinase 2 knockout mice with passive murine collagen-induced arthritis. Han, Z., Chang, L., Yamanishi, Y., Karin, M., Firestein, G.S. Arthritis Rheum. (2002) [Pubmed]
  43. MAPK mediation of hypertonicity-stimulated cyclooxygenase-2 expression in renal medullary collecting duct cells. Yang, T., Huang, Y., Heasley, L.E., Berl, T., Schnermann, J.B., Briggs, J.P. J. Biol. Chem. (2000) [Pubmed]
  44. c-Jun N-terminal kinase mediates hydrogen peroxide-induced cell death via sustained poly(ADP-ribose) polymerase-1 activation. Zhang, S., Lin, Y., Kim, Y.S., Hande, M.P., Liu, Z.G., Shen, H.M. Cell Death Differ. (2007) [Pubmed]
  45. Liver-specific knockdown of JNK1 up-regulates proliferator-activated receptor gamma coactivator 1 beta and increases plasma triglyceride despite reduced glucose and insulin levels in diet-induced obese mice. Yang, R., Wilcox, D.M., Haasch, D.L., Jung, P.M., Nguyen, P.T., Voorbach, M.J., Doktor, S., Brodjian, S., Bush, E.N., Lin, E., Jacobson, P.B., Collins, C.A., Landschulz, K.T., Trevillyan, J.M., Rondinone, C.M., Surowy, T.K. J. Biol. Chem. (2007) [Pubmed]
  46. Gadd45beta promotes hepatocyte survival during liver regeneration in mice by modulating JNK signaling. Papa, S., Zazzeroni, F., Fu, Y.X., Bubici, C., Alvarez, K., Dean, K., Christiansen, P.A., Anders, R.A., Franzoso, G. J. Clin. Invest. (2008) [Pubmed]
  47. Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Sakurai, T., Maeda, S., Chang, L., Karin, M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  48. The cJun N-terminal kinase (JNK) signaling pathway mediates induction of urokinase-type plasminogen activator (uPA) by the alkylating agent MNNG. Parra, M., Lluís, F., Miralles, F., Caelles, C., Muñoz-Cánoves, P. Blood (2000) [Pubmed]
  49. Hepatic ischemic preconditioning in mice is associated with activation of NF-kappaB, p38 kinase, and cell cycle entry. Teoh, N., Dela Pena, A., Farrell, G. Hepatology (2002) [Pubmed]
  50. Neuroprotection against focal ischemic brain injury by inhibition of c-Jun N-terminal kinase and attenuation of the mitochondrial apoptosis-signaling pathway. Gao, Y., Signore, A.P., Yin, W., Cao, G., Yin, X.M., Sun, F., Luo, Y., Graham, S.H., Chen, J. J. Cereb. Blood Flow Metab. (2005) [Pubmed]
  51. Experimental dry eye stimulates production of inflammatory cytokines and MMP-9 and activates MAPK signaling pathways on the ocular surface. Luo, L., Li, D.Q., Doshi, A., Farley, W., Corrales, R.M., Pflugfelder, S.C. Invest. Ophthalmol. Vis. Sci. (2004) [Pubmed]
WikiGenes - Universities