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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Transient activation of the MAP kinase signaling pathway by the forward signaling of EphA4 in PC12 cells

  • Shin, Jong-Dae (The Institute of Natural Science, Sookmyung Women's University) ;
  • Gu, Chang-Kyu (The Institute of Natural Science, Sookmyung Women's University) ;
  • Kim, Ji-Eun (Department of Biological Science, Sookmyung Women's University) ;
  • Park, Soo-Chul (Department of Biological Science, Sookmyung Women's University)
  • Received : 2008.04.14
  • Accepted : 2008.05.27
  • Published : 2008.06.30
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Abstract

In the present study, we demonstrate that ephrin-A5 is able to induce a transient increase of MAP kinase activity in PC12 cells. However, the effects of ephrin-A5 on the MAP kinase signaling pathway are about three-fold less than that of EGF. In addition, we demonstrate that EphA4 is the only Eph member expressed in PC12 cells, and that tyrosine phosphorylation induced by ephrin-A5 treatment is consistent with the magnitude and longevity of MAP kinase activation. Experiments using the Ras dominant negative mutant N17Ras reveal that Ras plays a pivotal role in ephrin-A5-induced MAP kinase activation in PC12 cells. Importantly, we found that the EphA4 receptor is rapidly internalized by endocytosis upon engagement of ephrin-A5, leading to a subsequent reduction in the MAP kinase activation. Together, these data suggest a novel regulatory mechanism of differential Ras-MAP kinase signaling kineticsexhibited by the forward signaling of EphA4 in PC12 cells.

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References

  1. Himanen, J., Saha, N. and Nikolov, D. (2007) Cell-cell signaling via Eph receptors and ephrins. Curr. Opin. Cell Biol. 19, 534-542. https://doi.org/10.1016/j.ceb.2007.08.004
  2. Rlanagan, J. and Vanderhagen, P. (1998) The ephrins and Eph receptors in neural development. Annu. Rev. Neurosci. 21, 309-345. https://doi.org/10.1146/annurev.neuro.21.1.309
  3. Stein, E., Lane, A., Cerretti, D., Schoecklmann, H., Schroff, D., Van Etten, R. and Daniel, T. (1998) Eph receptors discriminate specific ligand oligomers to determine alternative signaling complexes, attachment, and assembly responses. Gene. & Dev. 12, 667-678. https://doi.org/10.1101/gad.12.5.667
  4. Egea, J. and Klein, R. (2007) Bidirectional Eph-ephrin signaling during axon guidance. Trends. Cell Biol. 17, 230-238. https://doi.org/10.1016/j.tcb.2007.03.004
  5. Halloran, M. and Wolman, M. (2006) Repulsion or adhesion: receptors make the call. Curr. Opin. Cell Biol. 18, 533-540. https://doi.org/10.1016/j.ceb.2006.08.010
  6. Kullander, K. and Klein, R. (2002) Mechanisms and functions of eph and ephrin signalling. Nat. Rev. Mol. Cell Biol. 3, 475-486. https://doi.org/10.1038/nrm856
  7. Pouyssegur, J. and Lenormand, P. (2003) Fidelity and spatio- temporal control in MAP kinase (ERKs) signalling. Eur. J. Biochem. 270, 3291-3299. https://doi.org/10.1046/j.1432-1033.2003.03707.x
  8. Kao, S., Jaiswal, R. K., Kolch, W. and Landreth, G. E. (2001) Identification of the mechanisms regulating the differential activation of the mapk cascade by epidermal growth factor and nerve growth factor in PC12 cells. J. Biol. Chem. 276, 18169-18177. https://doi.org/10.1074/jbc.M008870200
  9. Huff, K., End, D., and Guroff, G. (1981) Nerve growth factor- induced alteration in the response of PC12 pheochromocytoma cells to epidermal growth factor. J. Cell Biol. 88, 189-198. https://doi.org/10.1083/jcb.88.1.189
  10. Greene, L. A. and Tischler, A. S. (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc. Natl. Acad. Sci. U. S. A. 73, 2424-2428. https://doi.org/10.1073/pnas.73.7.2424
  11. Pratt, R. and Kinch, S. (2002) Activation of the EphA2 tyrosine kinase stimulates the MAP/ERK kinase signaling cascade. Oncogene 21, 7690-7699. https://doi.org/10.1038/sj.onc.1205758
  12. Vindis, C., Cerretti, D. P., Daniel, T.O. and Huynh-Do, U. (2003) EphB1 recruits c-Src and $p52^{Shc}$ to activate MAPK/ ERK and promote chemotaxis. J. Cell Biol. 162, 661-671. https://doi.org/10.1083/jcb.200302073
  13. Becker, E., Huynh-Do, U., Holland, S., Pawson, T., Daniel, T. and Skolnik, E. Y. (2000) Nck-interacting ste20 kinase couples Eph receptors to c-Jun N-terminal kinase and integrin activation. Mol. Cell Biol. 20, 1537-1545. https://doi.org/10.1128/MCB.20.5.1537-1545.2000
  14. Elowe, S., Holland, S. J., Kulkarni, S. and Pawson, T. (2001) Downregulation of the Ras-mitogen-activated protein kinase pathway by the EphB2 receptor tyrosine kinase is required for Ephrin-induced neurite retraction. Mol. Cell Biol. 21, 7429-7441. https://doi.org/10.1128/MCB.21.21.7429-7441.2001
  15. Tong, J., Elowe, S., Nash, P. and Pawson, T. (2003) Manipulation of EphB2 regulatory motifs and SH2 binding sites switches MAPK signaling and biological activity. J. Biol. Chem. 278, 6111-6119. https://doi.org/10.1074/jbc.M208972200
  16. 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
  17. Zimmer, M., Palmer. A., Köhler, J. and Klein, R. (2003) EphB-ephrinB bi-directional endocytosis terminates adhesion allowing contact mediated repulsion. Nat. Cell Biol. 5, 869-878. https://doi.org/10.1038/ncb1045
  18. Irie, F., Okuno, M., Pasquale, E. B. and Yamaguchi, Y. (2005) EphrinB-EphB signalling regulates clathrin-mediated endocytosis through tyrosine phosphorylation of synaptojanin 1. Nat. Cell Biol. 7, 501-509. https://doi.org/10.1038/ncb1252
  19. Vieira, P., Lamaze, C. and Schmid, K. L. (1996) Control of EGF receptor signaling by Clathrin-mediated endocytosis. Science 271, 2086-2089.
  20. Gu, C. and Park, S. (2001) The EphA8 receptor regulates integrin activity through p110gamma phosphatidylinositol-3 kinase in a tyrosine kinase activity-independent manner. Mol. Cell Biol. 21, 4579-4597. https://doi.org/10.1128/MCB.21.14.4579-4597.2001
  21. Choi, S. and Park, S. (1999) Phosphorylation at Tyr-838 in the kinase domain of EphA8 modulates Fyn binding to the Tyr-615 site by enhancing tyrosine kinase activity. Oncogene 18, 5413-5422. https://doi.org/10.1038/sj.onc.1202917
  22. Herrmann, C., Martin, G. A. and Wittinghofer, A. (1995) Quantitative analysis of the complex between p21ras and the Ras-binding domain of the human Raf-1 protein kinase. J. Biol. Chem. 270, 2901-2905. https://doi.org/10.1074/jbc.270.7.2901

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