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Gene Review

MAPK8  -  mitogen-activated protein kinase 8

Homo sapiens

Synonyms: JNK, JNK-46, JNK1, JNK1A2, JNK21B1/2, ...
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Disease relevance of MAPK8


Psychiatry related information on MAPK8

  • Understanding the connection between AbetaPP phosphorylation and the JNK signaling pathway, which mediates cell response to stress may have important implications in understanding the pathogenesis of Alzheimer's disease [6].

High impact information on MAPK8


Chemical compound and disease context of MAPK8


Biological context of MAPK8


Anatomical context of MAPK8


Associations of MAPK8 with chemical compounds


Physical interactions of MAPK8

  • A docking site in MKK4 mediates high affinity binding to JNK MAPKs and competes with similar docking sites in JNK substrates [30].
  • We showed previously that MEKK1 binds directly to JNK/SAPK [31].
  • However, the corresponding region of JNK bound by this JIP-1-based peptide was unknown [32].
  • JNK inhibition with SP600125 also blocked binding of Sp1 to the DR5/TRAIL-R2 promoter [33].
  • In addition, ectopic expression of the JNK-binding domain of IB2 decreases IL-1beta-induced pancreatic beta-cell death [34].

Enzymatic interactions of MAPK8

  • We find that the JNKs are the predominant Elk-1 activation domain kinases in extracts of UV-irradiated cells and that immunopurified JNK1/2 phosphorylate Elk-1 on the same major sites recognized by ERK1/2, that potentiate its transcriptional activity [35].
  • Immunoblotting analysis indicated that JNK1 was phosphorylated by JNKK2 in the fusion protein on both Thr(183) and Tyr(185) residues [36].
  • Amyloid beta protein precursor is phosphorylated by JNK-1 independent of, yet facilitated by, JNK-interacting protein (JIP)-1 [6].
  • ASK1 phosphorylates c-Jun N-terminal kinase (JNK) and elicits an apoptotic response [37].
  • Furthermore, K8 was also phosphorylated on Ser-73 by JNK in vitro, yielding similar phosphopeptide maps as the in vivo phosphorylated material [38].

Co-localisations of MAPK8

  • A third JNK pool is colocalized with MKK7 in the nucleus, and specific activities of both increase during neuritogenesis, nuclear JNK activity increasing 10-fold, whereas c-Jun expression and activity decrease [39].

Regulatory relationships of MAPK8


Other interactions of MAPK8

  • These results indicate that HPK1 is a novel functional activator of the JNK/SAPK signaling pathway [40].
  • The protein kinase activity of these JNK isoforms was measured using the transcription factors ATF2, Elk-1 and members of the Jun family as substrates [16].
  • Glucocorticoid receptor-JNK interaction mediates inhibition of the JNK pathway by glucocorticoids [18].
  • Incubation of HUVEC with PD98059, which inhibits flow-mediated ERK1/2 activation, prevented flow from inhibiting cytokine activation of JNK [46].
  • We also investigated the role of NIK in JNK activation by TNF [47].

Analytical, diagnostic and therapeutic context of MAPK8


  1. Cyclooxygenase-2 inhibitor (SC-236) suppresses activator protein-1 through c-Jun NH2-terminal kinase. Wong, B.C., Jiang, X.H., Lin, M.C., Tu, S.P., Cui, J.T., Jiang, S.H., Wong, W.M., Yuen, M.F., Lam, S.K., Kung, H.F. Gastroenterology (2004) [Pubmed]
  2. Epstein-Barr virus latent membrane protein-1 triggers AP-1 activity via the c-Jun N-terminal kinase cascade. Kieser, A., Kilger, E., Gires, O., Ueffing, M., Kolch, W., Hammerschmidt, W. EMBO J. (1997) [Pubmed]
  3. A splicing variant of a death domain protein that is regulated by a mitogen-activated kinase is a substrate for c-Jun N-terminal kinase in the human central nervous system. Zhang, Y., Zhou, L., Miller, C.A. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  4. Sustained activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase pathways by hepatitis B virus X protein mediates apoptosis via induction of Fas/FasL and tumor necrosis factor (TNF) receptor 1/TNF-alpha expression. Wang, W.H., Grégori, G., Hullinger, R.L., Andrisani, O.M. Mol. Cell. Biol. (2004) [Pubmed]
  5. Activation of extracellular signal-regulated kinase and c-Jun-NH(2)-terminal kinase but not p38 mitogen-activated protein kinases is required for RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells. Yu, W., Liao, Q.Y., Hantash, F.M., Sanders, B.G., Kline, K. Cancer Res. (2001) [Pubmed]
  6. Amyloid beta protein precursor is phosphorylated by JNK-1 independent of, yet facilitated by, JNK-interacting protein (JIP)-1. Scheinfeld, M.H., Ghersi, E., Davies, P., D'Adamio, L. J. Biol. Chem. (2003) [Pubmed]
  7. The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes. Waeber, G., Delplanque, J., Bonny, C., Mooser, V., Steinmann, M., Widmann, C., Maillard, A., Miklossy, J., Dina, C., Hani, E.H., Vionnet, N., Nicod, P., Boutin, P., Froguel, P. Nat. Genet. (2000) [Pubmed]
  8. Signal transduction by the JNK group of MAP kinases. Davis, R.J. Cell (2000) [Pubmed]
  9. A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Takekawa, M., Saito, H. Cell (1998) [Pubmed]
  10. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Liu, Z.G., Hsu, H., Goeddel, D.V., Karin, M. Cell (1996) [Pubmed]
  11. Jun kinase modulates tumor necrosis factor-dependent apoptosis in liver cells. Liedtke, C., Plümpe, J., Kubicka, S., Bradham, C.A., Manns, M.P., Brenner, D.A., Trautwein, C. Hepatology (2002) [Pubmed]
  12. Diallyl trisulfide-induced apoptosis in human prostate cancer cells involves c-Jun N-terminal kinase and extracellular-signal regulated kinase-mediated phosphorylation of Bcl-2. Xiao, D., Choi, S., Johnson, D.E., Vogel, V.G., Johnson, C.S., Trump, D.L., Lee, Y.J., Singh, S.V. Oncogene (2004) [Pubmed]
  13. Quercetin inhibits Shc- and phosphatidylinositol 3-kinase-mediated c-Jun N-terminal kinase activation by angiotensin II in cultured rat aortic smooth muscle cells. Yoshizumi, M., Tsuchiya, K., Kirima, K., Kyaw, M., Suzaki, Y., Tamaki, T. Mol. Pharmacol. (2001) [Pubmed]
  14. Extracellular signal-regulated protein kinase, but not c-Jun N-terminal kinase, is activated by type II gonadotropin-releasing hormone involved in the inhibition of ovarian cancer cell proliferation. Kim, K.Y., Choi, K.C., Park, S.H., Auersperg, N., Leung, P.C. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  15. Activation of SAPK/JNK by TNF receptor 1 through a noncytotoxic TRAF2-dependent pathway. Natoli, G., Costanzo, A., Ianni, A., Templeton, D.J., Woodgett, J.R., Balsano, C., Levrero, M. Science (1997) [Pubmed]
  16. Selective interaction of JNK protein kinase isoforms with transcription factors. Gupta, S., Barrett, T., Whitmarsh, A.J., Cavanagh, J., Sluss, H.K., Dérijard, B., Davis, R.J. EMBO J. (1996) [Pubmed]
  17. Dissociation of Akt1 from its negative regulator JIP1 is mediated through the ASK1-MEK-JNK signal transduction pathway during metabolic oxidative stress: a negative feedback loop. Song, J.J., Lee, Y.J. J. Cell Biol. (2005) [Pubmed]
  18. Glucocorticoid receptor-JNK interaction mediates inhibition of the JNK pathway by glucocorticoids. Bruna, A., Nicolàs, M., Muñoz, A., Kyriakis, J.M., Caelles, C. EMBO J. (2003) [Pubmed]
  19. A direct interaction between JNK1 and CrkII is critical for Rac1-induced JNK activation. Girardin, S.E., Yaniv, M. EMBO J. (2001) [Pubmed]
  20. Activation of the c-Jun N-terminal kinase pathway by a novel protein kinase related to human germinal center kinase. Diener, K., Wang, X.S., Chen, C., Meyer, C.F., Keesler, G., Zukowski, M., Tan, T.H., Yao, Z. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  21. Interaction of hematopoietic progenitor kinase 1 with adapter proteins Crk and CrkL leads to synergistic activation of c-Jun N-terminal kinase. Ling, P., Yao, Z., Meyer, C.F., Wang, X.S., Oehrl, W., Feller, S.M., Tan, T.H. Mol. Cell. Biol. (1999) [Pubmed]
  22. Cytokine-specific activation of distinct mitogen-activated protein kinase subtype cascades in human neutrophils stimulated by granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor-alpha. Suzuki, K., Hino, M., Hato, F., Tatsumi, N., Kitagawa, S. Blood (1999) [Pubmed]
  23. Signal transduction pathways involved in soluble fractalkine-induced monocytic cell adhesion. Cambien, B., Pomeranz, M., Schmid-Antomarchi, H., Millet, M.A., Breittmayer, V., Rossi, B., Schmid-Alliana, A. Blood (2001) [Pubmed]
  24. Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is required for lipopolysaccharide stimulation of tumor necrosis factor alpha (TNF-alpha) translation: glucocorticoids inhibit TNF-alpha translation by blocking JNK/SAPK. Swantek, J.L., Cobb, M.H., Geppert, T.D. Mol. Cell. Biol. (1997) [Pubmed]
  25. Inhibition of c-Jun-N-terminal-kinase sensitizes tumor cells to CD95-induced apoptosis and induces G2/M cell cycle arrest. Kuntzen, C., Sonuc, N., De Toni, E.N., Opelz, C., Mucha, S.R., Gerbes, A.L., Eichhorst, S.T. Cancer Res. (2005) [Pubmed]
  26. Role of the JNK pathway in NMDA-mediated excitotoxicity of cortical neurons. Centeno, C., Repici, M., Chatton, J.Y., Riederer, B.M., Bonny, C., Nicod, P., Price, M., Clarke, P.G., Papa, S., Franzoso, G., Borsello, T. Cell Death Differ. (2007) [Pubmed]
  27. TAK1 mediates the ceramide signaling to stress-activated protein kinase/c-Jun N-terminal kinase. Shirakabe, K., Yamaguchi, K., Shibuya, H., Irie, K., Matsuda, S., Moriguchi, T., Gotoh, Y., Matsumoto, K., Nishida, E. J. Biol. Chem. (1997) [Pubmed]
  28. Dissection of a signaling pathway by which pathogen-associated molecular patterns recruit the JNK and p38 MAPKs and trigger cytokine release. Zhong, J., Kyriakis, J.M. J. Biol. Chem. (2007) [Pubmed]
  29. The beta1 integrin activates JNK independent of CagA, and JNK activation is required for Helicobacter pylori CagA+-induced motility of gastric cancer cells. Snider, J.L., Allison, C., Bellaire, B.H., Ferrero, R.L., Cardelli, J.A. J. Biol. Chem. (2008) [Pubmed]
  30. 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]
  31. MEKK1 binds raf-1 and the ERK2 cascade components. Karandikar, M., Xu, S., Cobb, M.H. J. Biol. Chem. (2000) [Pubmed]
  32. Reverse two-hybrid screening identifies residues of JNK required for interaction with the kinase interaction motif of JNK-interacting protein-1. Barr, R.K., Hopkins, R.M., Watt, P.M., Bogoyevitch, M.A. J. Biol. Chem. (2004) [Pubmed]
  33. Bile acids up-regulate death receptor 5/TRAIL-receptor 2 expression via a c-Jun N-terminal kinase-dependent pathway involving Sp1. Higuchi, H., Grambihler, A., Canbay, A., Bronk, S.F., Gores, G.J. J. Biol. Chem. (2004) [Pubmed]
  34. cDNA cloning and mapping of a novel islet-brain/JNK-interacting protein. Negri, S., Oberson, A., Steinmann, M., Sauser, C., Nicod, P., Waeber, G., Schorderet, D.F., Bonny, C. Genomics (2000) [Pubmed]
  35. Induction of c-fos expression through JNK-mediated TCF/Elk-1 phosphorylation. Cavigelli, M., Dolfi, F., Claret, F.X., Karin, M. EMBO J. (1995) [Pubmed]
  36. The JNKK2-JNK1 fusion protein acts as a constitutively active c-Jun kinase that stimulates c-Jun transcription activity. Zheng, C., Xiang, J., Hunter, T., Lin, A. J. Biol. Chem. (1999) [Pubmed]
  37. C-terminus of heat shock protein 70--interacting protein facilitates degradation of apoptosis signal-regulating kinase 1 and inhibits apoptosis signal-regulating kinase 1--dependent apoptosis. Hwang, J.R., Zhang, C., Patterson, C. Cell Stress Chaperones (2005) [Pubmed]
  38. The intermediate filament protein keratin 8 is a novel cytoplasmic substrate for c-Jun N-terminal kinase. He, T., Stepulak, A., Holmström, T.H., Omary, M.B., Eriksson, J.E. J. Biol. Chem. (2002) [Pubmed]
  39. Dual roles for c-Jun N-terminal kinase in developmental and stress responses in cerebellar granule neurons. Coffey, E.T., Hongisto, V., Dickens, M., Davis, R.J., Courtney, M.J. J. Neurosci. (2000) [Pubmed]
  40. Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade. Hu, M.C., Qiu, W.R., Wang, X., Meyer, C.F., Tan, T.H. Genes Dev. (1996) [Pubmed]
  41. A novel method to identify protein kinase substrates: eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta. Knebel, A., Morrice, N., Cohen, P. EMBO J. (2001) [Pubmed]
  42. TNF receptor-associated factor-2 is involved in both IL-1 beta and TNF-alpha signaling cascades leading to NF-kappa B activation and IL-8 expression in human intestinal epithelial cells. Jobin, C., Holt, L., Bradham, C.A., Streetz, K., Brenner, D.A., Sartor, R.B. J. Immunol. (1999) [Pubmed]
  43. Microtubule-interfering agents activate c-Jun N-terminal kinase/stress-activated protein kinase through both Ras and apoptosis signal-regulating kinase pathways. Wang, T.H., Wang, H.S., Ichijo, H., Giannakakou, P., Foster, J.S., Fojo, T., Wimalasena, J. J. Biol. Chem. (1998) [Pubmed]
  44. Cdc42 induces activation loop phosphorylation and membrane targeting of mixed lineage kinase 3. Du, Y., Böck, B.C., Schachter, K.A., Chao, M., Gallo, K.A. J. Biol. Chem. (2005) [Pubmed]
  45. Activation of JNK-dependent pathway is required for HIV viral protein R-induced apoptosis in human monocytic cells: involvement of antiapoptotic BCL2 and c-IAP1 genes. Mishra, S., Mishra, J.P., Kumar, A. J. Biol. Chem. (2007) [Pubmed]
  46. Fluid shear stress inhibits TNF-alpha activation of JNK but not ERK1/2 or p38 in human umbilical vein endothelial cells: Inhibitory crosstalk among MAPK family members. Surapisitchat, J., Hoefen, R.J., Pi, X., Yoshizumi, M., Yan, C., Berk, B.C. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  47. Tumor necrosis factor (TNF)-mediated kinase cascades: bifurcation of nuclear factor-kappaB and c-jun N-terminal kinase (JNK/SAPK) pathways at TNF receptor-associated factor 2. Song, H.Y., Régnier, C.H., Kirschning, C.J., Goeddel, D.V., Rothe, M. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  48. CD22 cross-linking generates B-cell antigen receptor-independent signals that activate the JNK/SAPK signaling cascade. Tuscano, J.M., Riva, A., Toscano, S.N., Tedder, T.F., Kehrl, J.H. Blood (1999) [Pubmed]
  49. Gamma-synuclein promotes cancer cell survival and inhibits stress- and chemotherapy drug-induced apoptosis by modulating MAPK pathways. Pan, Z.Z., Bruening, W., Giasson, B.I., Lee, V.M., Godwin, A.K. J. Biol. Chem. (2002) [Pubmed]
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