All tags cancer c-Jun N-terminal kinase (JNK) MAPK signalling

c-Jun N-terminal kinase (JNK) MAPK signalling

Activation of JNK1/2 MAPK occurs following osmotic stress, UV irradiation, cytokine withdrawal, mitogenic signaling and MTA treatment.

The JNK MAPK proteins are encoded by three genes, MAPK8 encodes JNK1 protein, MAPK9 encodes JNK2 and MAPK10 encodes JNK3, which are also alternatively spliced and give rise to at least 10 different isoforms [Gupta et al.,1996].

Activation of JNK1/2 MAPKs occurs through the mixed-lineage kinases, which phosphorylate and activate the upstream MAPKKs such as MAPKK4 and MAPKK7, which in turn co-operatively phosphorylate and activate the JNK1/2 MAPKs. Activation of JNK1/2 MAPK can also occur through the MAPKKKs including, the MEK kinases (MEKKs), transforming growth factor β (TGF β)– activated kinase 1 (TAK1) and apoptosis inducing kinase 1 (ASK1) [Gallo and Johnson, 2002].

Each JNK MAPK isoform can phosphorylate c-Jun, JunB, JunD and ATF2 which forms part of the AP-1 (activator protein-1) transcription factor complex [Davis, 2000]. The AP-1 transcription factor complex targets a range of genes involved in cell cycle progression, cell survival and apoptosis [Wagner and Nebreda, 2009].

The origin of JNK

JNK was originally identified as having a role in apoptosis following the withdrawal of growth factors from PC12 pheochromocytoma cells [Xia et al., 1995]. Over-expression of the upstream JNK MAPK activator, MEKK1, results in sustained JNK activation and upregulation of the death receptor ligand FasL [Faris et al., 1998].

Gene disruption studies in mice have shown that JNK contributes to cell death initiation. In vivo JNK3 is required for cell death in hippocampal neurons following excitotoxic stress, whereas, JNK1 and JNK2 are required for thymocyte apoptosis following engagement of the T-cell receptor [Sabapathy et al., 1999; Yang et al., 1997]. JNK1/2 MAPK activation alone can stimulate cytochrome C release and apoptosis through the intrinsic cell death pathway; however, Bax and Bak are essential to JNK1/2 MAPK mediated apoptosis [Lei and Davis, 2003].

References

  • Gupta, S., T. Barrett, et al. (1996). "Selective interaction of JNK protein kinase isoforms with transcription factors." Embo J 15(11): 2760-70.
  • Davis, R. J. (2000). "Signal transduction by the JNK group of MAP kinases." Cell 103(2): 239-52.
  • Gallo, K. A. and G. L. Johnson (2002). "Mixed-lineage kinase control of JNK and p38 MAPK pathways." Nat Rev Mol Cell Biol 3(9): 663-72.
  • Wagner, E. F. and A. R. Nebreda (2009). "Signal integration by JNK and p38 MAPK pathways in cancer development." Nat Rev Cancer 9(8): 537-49.
  • Xia, Z., M. Dickens, et al. (1995). "Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis." Science 270(5240): 1326-31.
  • Faris, M., N. Kokot, et al. (1998). "The c-Jun N-terminal kinase cascade plays a role in stress-induced apoptosis in Jurkat cells by up-regulating Fas ligand expression." J Immunol 160(1): 134-44.
  • Sabapathy, K., Y. Hu, et al. (1999). "JNK2 is required for efficient T-cell activation and apoptosis but not for normal lymphocyte development." Curr Biol 9(3): 116-25.
  • Yang, D. D., C. Y. Kuan, et al. (1997). "Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene." Nature 389(6653): 865-70.
  • Lei, K. and R. J. Davis (2003). "JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis." Proc Natl Acad Sci USA 100(5): 2432-7.
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