Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

EphA Receptors Form a Complex with Caspase-8 to Induce Apoptotic Cell Death

  • Lee, Haeryung (Department of Biological Science, Sookmyung Women's University) ;
  • Park, Sunjung (Department of Biological Science, Sookmyung Women's University) ;
  • Kang, Young-Sook (College of Pharmacy and Research Institute of Pharmaceutical Science, Sookmyung Women's University) ;
  • Park, Soochul (Department of Biological Science, Sookmyung Women's University)
  • Received : 2014.10.17
  • Accepted : 2014.11.26
  • Published : 2015.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

EphA7 has been implicated in the regulation of apoptotic cell death in neural epithelial cells. In this report, we provide evidence that EphA7 interacts with caspase-8 to induce apoptotic cell signaling. First, a pull-down assay using biotinylated ephrinA5-Fc showed that EphA7 co-precipitated with wild type caspase-8 or catalytically inactive caspase-8 mutant. Second, co-transfection of EphA7 with caspase-8 significantly increased the number of cleaved caspase-3 positive apoptotic cells under an experimental condition where transfection of EphA7 or caspase-8 alone did not affect cell viability or apoptosis. EphA4 also had a causative role in inducing apoptotic cell death with caspase-8, whereas EphA8 did not. Third, caspase-8 catalytic activity was essential for the apoptotic signaling cascade, whereas tyrosine kinase activity of the EphA4 receptor was not. Interestingly, we found that kinase-inactive EphA4 was well co-localized at the plasma membrane with catalytically inactive caspase-8, suggesting that an interaction between these mutant proteins was more stable. Finally, we observed that the extracellular region of the EphA7 receptor was critical for interacting with caspase-8, whereas the cytoplasmic region of EphA7 was not. Therefore, we propose that Eph receptors physically associate with a transmembrane protein to form an apoptotic signaling complex and that this unidentified receptor-like protein acts as a biochemical linker between the Eph receptor and caspase-8.

Keywords

References

  1. Ashkenazi, A., and Herbst, R.S. (2008). To kill a tumor cell: the potential of proapoptotic receptor agonists. J. Clin. Invest. 118, 1979-1990. https://doi.org/10.1172/JCI34359
  2. Boatright, K.M., and Salvesen, G.S. (2003). Mechanisms of caspase activation. Curr. Opin. Cell Biol. 15, 725-731. https://doi.org/10.1016/j.ceb.2003.10.009
  3. Chang, D.W., Xing, Z., Capacio, V.L., Peter, M.E., and Yang, X. (2003). Interdimer processing mechanism of procaspase-8 activation. EMBO J. 22, 4132-4142. https://doi.org/10.1093/emboj/cdg414
  4. Depaepe, V., Suarez-Gonzalez, N., Dufour, A., Passante, L., Gorski, J.A., Jones, K.R.,Ledent, C., and Vanderhaeghen, P. (2005). Ephrin signalling controls brain size by regulating apoptosis of neural progenitors. Nature 435, 1244-1250. https://doi.org/10.1038/nature03651
  5. Gu, C., Shim, S., Shin, J., Kim, J., Park, J., Han, K., and Park, S. (2005). The EphA8 receptor induces sustained MAP kinase activation to promote neurite outgrowth in neuronal cells. Oncogene 24, 4243-4256. https://doi.org/10.1038/sj.onc.1208584
  6. Holmberg, J., Clarke, D.L., and Frisen, J. (2000). Regulation of repulsion versus adhesion by different splice forms of an Eph receptor. Nature 408, 203-206. https://doi.org/10.1038/35041577
  7. Hsu, H., Huang, J., Shu, H.B., Baichwal, V., and Goeddel, D.V. (1996a). TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity 4, 387-396. https://doi.org/10.1016/S1074-7613(00)80252-6
  8. Hsu, H., Shu, H.B., Pan, M.G., and Goeddel, D.V. (1996b). TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 84, 299-308. https://doi.org/10.1016/S0092-8674(00)80984-8
  9. Johnson, C.E., and Kornbluth, S. (2008). Caspase cleavage is not for everyone. Cell 134, 720-721. https://doi.org/10.1016/j.cell.2008.08.019
  10. Kang, T.B., Ben-Moshe, T., Varfolomeev, E.E., Pewzner-Jung, Y., Yogev, N., Jurewicz, A., Waisman, A., Brenner, O., Haffner, R., Gustafsson, E., et al. (2004). Caspase-8 serves both apoptotic and nonapoptotic roles. J. Immunol. 173, 2976-2984. https://doi.org/10.4049/jimmunol.173.5.2976
  11. Kim, Y., Park, E., Noh, H., and Park, S. (2013). Expression of EphA8-Fc in transgenic mouse embryos induces apoptosis of neural epithelial cells during brain development. Dev. Neurobiol. 73, 702-712. https://doi.org/10.1002/dneu.22092
  12. Kischkel, F.C., Hellbardt, S., Behrmann, I., Germer, M., Pawlita, M., Krammer, P.H., and Peter, M.E. (1995). Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J. 14, 5579-5588.
  13. Kuan, C.Y., Roth, K.A., Flavell, R.A., and Rakic, P. (2000). Mechanisms of programmed cell death in the developing brain. Trends Neurosci. 23, 291-297. https://doi.org/10.1016/S0166-2236(00)01581-2
  14. Kumar, S. (2007). Caspase function in programmed cell death. Cell Death Differ. 14, 32-43. https://doi.org/10.1038/sj.cdd.4402060
  15. Lee, H., Park, E., Kim, Y., and Park, S. (2013). EphrinA5-EphA7 complex induces apoptotic cell death via TNFR1. Mol. Cells 35, 450-455. https://doi.org/10.1007/s10059-013-0072-3
  16. Nicholson, D.W. (1999). Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ. 6, 1028-1042. https://doi.org/10.1038/sj.cdd.4400598
  17. Park, S. (2013). Brain-region specific apoptosis triggered by Eph/ephrin signaling. Exp. Neurobiol. 22, 143-148. https://doi.org/10.5607/en.2013.22.3.143
  18. Park, E., Kim, Y., Noh, H., Lee, H., Yoo, S., and Park, S. (2013). EphA/ephrin-A signaling is critically involved in region-specific apoptosis during early brain development. Cell Death Differ. 20, 169-180. https://doi.org/10.1038/cdd.2012.121
  19. Peter, M.E., and Krammer, P.H. (2003). The CD95(APO-1/Fas) DISC and beyond. Cells Death Differ. 10, 26-35. https://doi.org/10.1038/sj.cdd.4401186
  20. Pop, C., and Salvesen, G.S. (2009). Human caspases: activation, specificity, and regulation. J. Biol. Chem. 284, 21777-21781. https://doi.org/10.1074/jbc.R800084200
  21. Schneider-Brachert, W., Tchikov, V., Neumeyer, J., Jakob, M., Winoto-Morbach, S., Held-Feindt, J., Heinrich, M., Merkel, O., Ehrenschwender, M., Adam, D., et al. (2004). Compartmentalization of TNF receptor 1 signaling: internalized TNF receptosomes as death signaling vesicles. Immunity 21, 415-428.
  22. Shin, J., Gu, C., Park, E., and Park, S. (2007). Identification of phosphotyrosine binding domain-containing proteins as novel downstream targets of the EphA8 signaling function. Mol. Cell. Biol. 27, 8113-8126. https://doi.org/10.1128/MCB.00794-07
  23. Wang, Z.B., Liu, Y.Q., and Cui, Y.F. (2005). Pathways to caspase activation. Cell Biol. Int. 29, 489-496. https://doi.org/10.1016/j.cellbi.2005.04.001
  24. Zhang, J., Cado, D., Chen, A., Kabra, N.H., and Winoto, A. (1998). Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature 392, 296-300. https://doi.org/10.1038/32681

Cited by

  1. MicroRNA-296-5p Promotes Invasiveness through Downregulation of Nerve Growth Factor Receptor and Caspase-8 vol.40, pp.4, 2017, https://doi.org/10.14348/molcells.2017.2270
  2. The Role of Apoptotic Signaling in Axon Guidance vol.6, pp.4, 2018, https://doi.org/10.3390/jdb6040024
  3. Dying to communicate: apoptotic functions of Eph/Ephrin proteins vol.23, pp.5-6, 2018, https://doi.org/10.1007/s10495-018-1458-7
  4. Long noncoding RNA RP11-838N2.4 enhances the cytotoxic effects of temozolomide by inhibiting the functions of miR-10a in glioblastoma cell lines vol.7, pp.28, 2015, https://doi.org/10.18632/oncotarget.9699
  5. Ligand-dependent EphA7 signaling inhibits prostate tumor growth and progression vol.8, pp.10, 2015, https://doi.org/10.1038/cddis.2017.507
  6. Inhibition of EphA/Ephrin-A signaling using genetic and pharmacologic approaches improves recovery following traumatic brain injury in mice vol.33, pp.10, 2019, https://doi.org/10.1080/02699052.2019.1641622
  7. Zfp422 promotes skeletal muscle differentiation by regulating EphA7 to induce appropriate myoblast apoptosis vol.27, pp.5, 2015, https://doi.org/10.1038/s41418-019-0448-9
  8. EphB3 interacts with initiator caspases and FHL-2 to activate dependence receptor cell death in oligodendrocytes after brain injury vol.2, pp.2, 2015, https://doi.org/10.1093/braincomms/fcaa175
  9. Approaches to Manipulate Ephrin-A:EphA Forward Signaling Pathway vol.13, pp.7, 2015, https://doi.org/10.3390/ph13070140
  10. Long‐distance regressive signaling in neural development and disease vol.10, pp.2, 2021, https://doi.org/10.1002/wdev.382