Abstract
TrkA, a receptor for nerve growth factor, plays a crucial role in neuronal cell growth and differentiation. However, overactivation of TrkA signaling leads to cell death in various cell types. TrkA-mediated cell death shows some similarities to DNA damage-induced cell death. In this study, we examined how TrkA-induced cell death is regulated upon DNA damage. Cytoplasmic expression of TrkA protein was differentially modulated during the camptothecin-induced DNA damage response in TrkA-expressing U2OS cells. TrkA-induced cell death was synergistically increased by DNA damage, but it was blocked in the presence of the JNK inhibitor SP600125. Overexpression of a 54-kDa JNK isoform (JNK1α2) aggravated TrkA-induced cell death and was associated with TrkA functional activation. These results suggest that TrkA shares a functional connection with other mediators in the DNA damage response via JNK signaling.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Barker, P.A., Lomen-Hoerth, C., Gensch, E.M., Meakin, S.O., Glass, D.J., and Shooter, E.M. (1993). Tissue-specific alternative splicing generates two isoforms of the trkA receptor. J. Biol. Chem. 268, 15150–15157.
Bogoyevitch, M.A. (2006). The isoform-specific functions of the c-Jun N-terminal Kinases (JNKs): differences revealed by gene targeting. Bioessays 28, 923–934.
Chou, T.T., Trojanowski, J.Q., and Lee, V.M. (2000). A novel apoptotic pathway induced by nerve growth factor-mediated TrkA activation in medulloblastoma. J. Biol. Chem. 275, 565–570.
Fleming, Y., Armstrong, C.G., Morrice, N., Paterson, A., Goedert, M., and Cohen, P. (2000). Synergistic activation of stressactivated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7. Biochem. J. 352, 145–154.
Hsiang, Y.H., and Liu, L.F. (1988). Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res. 48, 1722–1726.
Jullien, J., Guili, V., Reichardt, L.F., and Rudkin, B.B. (2002). Molecular kinetics of nerve growth factor receptor trafficking and activation. J. Biol. Chem. 277, 38700–38708.
Jung, E.J., and Kim, D.R. (2008). Apoptotic cell death in TrkAoverexpressing cells: kinetic regulation of ERK phosphorylation and caspase-7 activation. Mol. Cells 26, 12–17.
Jung, E.J., Kim, C.W., and Kim, D.R. (2008). Cytosolic accumulation of gammaH2AX is associated with tropomyosin-related kinase A-induced cell death in U2OS cells. Exp. Mol. Med. 40, 276–285.
Kaplan, D.R., and Miller, F.D. (2000). Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol. 10, 381–391.
Koo, M.S., Kwo, Y.G., Park, J.H., Choi, W.J., Billiar, T.R., and Kim, Y.M. (2002). Signaling and function of caspase and c-jun Nterminal kinase in cisplatin-induced apoptosis. Mol. Cells 13, 194–201.
Lavoie, J.F., Lesauteur, L., Kohn, J., Wong, J., Furtoss, O., Thiele, C.J., Miller, F.D., and Kaplan, D.R. (2005). TrkA induces apoptosis of neuroblastoma cells and does so via a p53-dependent mechanism. J. Biol. Chem. 280, 29199–29207.
Lee, S., Lee H.S., Baek, M., Lee, D.Y., Bang, Y.J., Cho, H.N., Lee, Y.S., Ha, J.H., Kim, H.Y., and Jeoung, D.I. (2002). MAPK signaling is involved in camptothecin-induced cell death. Mol. Cells 14, 348–354.
Lucarelli, E., Kaplan, D., and Thiele, C.J. (1997). Activation of trk-A but not trk-B signal transduction pathway inhibits growth of neuroblastoma cells. Eur. J. Cancer 33, 2068–2070.
Nakagawara, A. (2001). Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett. 169, 107–114.
Ohta, T., Watanabe, T., Katayama, Y., Kurihara, J., Yoshino, A., Nishimoto, H., and Kishimoto, H. (2006). TrkA expression is associated with an elevated level of apoptosis in classic medulloblastomas. Neuropathol. 26, 170–177.
Reichardt, L.F. (2006). Neurotrophin-regulated signalling pathways. Phil. Trans. R. Soc. B. 361, 1545–1564.
Saxena, S., Bucci, C., Weis, J., and Kruttgen, A. (2005a). The small GTPase Rab7 controls the endosomal trafficking and neuritogenic signaling of the nerve growth factor receptor TrkA. J. Neurosci. 25, 10930–10940.
Saxena, S., Howe, C.L., Cosgaya, J.M., Steiner, P., Hirling, H., Chan, J.R., Weis, J., and Kruttgen, A. (2005b). Differential endocytic sorting of p75NTR and TrkA in response to NGF: a role for late endosomes in TrkA trafficking. Mol. Cell. Neurosci. 28, 571–587.
Tacconelli, A., Farina, A.R., Cappabianca, L., Desantis, G., Tessitore, A., Vetuschi, A., Sferra, R., Rucci, N., Argenti, B., Screpanti, I., et al. (2004).TrkA alternative splicing: a regulated tumorpromoting switch in human neuroblastoma. Cancer Cell 6, 347–360.
Takamura, M., Matsuda, Y., Yamagiwa, S., Tamura, Y., Honda, Y., Suzuki, K., Ichida, T., and Aoyagi, Y. (2007). An inhibitor of c-Jun NH2-terminal kinase, SP600125, protects mice from Dgala-ctosamine/lipopolysaccharide-induced hepatic failure by modulating BH3-only proteins. Life Sci. 80, 1335–1344.
Tournier, C., Hess, P., Yang, D.D., Xu, J., Turner, T.K., Nimnual, A., Bar-Sagi, D.S., Jones, N., Flavell, R.A., and Davis, R.J. (2000). Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 288, 870–874.
Turner, N.A., Xia, F., Azhar, G., Zhang, X., Liu, L., and Wei, J.Y. (1998). Oxidative stress induces DNA fragmentation and caspase activation via the c-Jun NH2-terminal kinase pathway in H9c2 cardiac muscle cells. J. Mol. Cell Cardiol. 30, 1789–1801.
Ulrich, E., Duwel, A., Kauffmann-Zeh, A., Gilbert, C., Lyon, D., Rudkin, B., Evan, G., and Martin-Zanca, D. (1998). Specific TrkA survival signals interfere with different apoptotic pathways. Oncogene 16, 825–832.
Volosin, M., Song, W., Almeida, R.D., Kaplan, D.R., Hempstead, B.L., and Friedman, W.J. (2006). Interaction of survival and death signaling in basal forebrain neurons: roles of neurotrophins and proneurotrophins. J. Neurosci. 26, 7756–7766.
Waetzig, V., Loose, K., Haeusgen, W., and Herdegen, T. (2008). c-Jun N-terminal kinases mediate Fas-induced neurite regeneration in PC12 cells. Biochem. Pharmacol. 76, 1476–1484.
Widmann, C., Gibson, S., Jarpe, M.B., and Johnson, G.L. (1999). Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol. Rev. 79, 143–180.
Yamauchi, J., Chan, J.R., and Shooter, E.M. (2003). Neurotrophin 3 activation of TrkC induces Schwann cell migration through the c-Jun N-terminal kinase pathway. Proc. Natl. Acad. Sci. USA 100, 14421–14426.
Zhang, Y., Moheban, D.B., Conway, B.R., Bhattacharyya, A., and Segal, R.A. (2000). Cell surface Trk receptors mediate NGF-induced survival while internalized receptors regulate NGF-induced differentiation. J. Neurosci. 20, 5671–5678.
Zhang, Y., Wang, Y.G., Zhang, Q., Liu, X.J., Liu, X., Jiao, L., Zhu, W., Zhang, Z.H., Zhao, X.L., and He, C. (2009). Interaction of Mint2 with TrkA is involved in regulation of nerve growth factor-induced neurite outgrowth. J. Biol. Chem. 284, 12469–12479.
Zhou, J., Valletta, J.S., Grimes, M.L., and Mobley, W.C. (1995). Multiple levels for regulation of TrkA in PC12 cells by nerve growth factor. J. Neurochem. 65, 1146–1156.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Jung, E.J., Kim, D.R. Control of TrkA-induced cell death by JNK activation and differential expression of TrkA upon DNA damage. Mol Cells 30, 121–125 (2010). https://doi.org/10.1007/s10059-010-0096-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10059-010-0096-x