Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway

Nature Cell Biology volume 3, pages 527–530 (2001)Cite this article

Abstract

Interactions between Eph receptor tyrosine kinases (RTKs) and membrane-anchored ephrin ligands critically regulate axon pathfinding and development of the cardiovascular system, as well as migration of neural cells. Similar to other RTKs, ligand-activated Eph kinases recruit multiple signalling and adaptor proteins, several of which are involved in growth regulation1,2. However, in contrast to other RTKs, activation of Eph receptors fails to promote cell proliferation3,4 or to transform rodent fibroblasts5, indicating that Eph kinases may initiate signalling pathways that are distinct from those transmitted by other RTKs. Here we show that stimulation of endogenous EphA kinases with ephrin-A1 potently inhibits the Ras/MAPK cascade in a range of cell types, and attenuates activation of mitogen-activated protein kinase (MAPK) by receptors for platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF). In prostatic epithelial cells and endothelial cells, but not fibroblasts, treatment with ephrin-A1 inhibits cell proliferation. Our results identify EphA kinases as negative regulators of the Ras/MAPK pathway that exert anti-mitogenic functions in a cell-type-specific manner.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Ephrin-A1–Fc stimulation inhibits p42MAPK and p44MAPK and suppresses proliferation of pRNS-1-1 cells.
Figure 2: Activated EphA kinases target Ras.
Figure 3: Ephrin-A1–Fc treatment reduces MAPK activity and inhibits proliferation of primary human prostatic cancer cells.

Similar content being viewed by others

References

  1. Bruckner, K. & Klein, R. Curr. Opin. Neurobiol. 8, 375–382 (1998).

    Article  CAS  Google Scholar 

  2. Wilkinson, D. G. Int. Rev. Cytol. 196, 177–244 (2000).

    Article  CAS  Google Scholar 

  3. Bruce, V., Olivieri, G., Eickelberg, O. & Miescher, G. C. Brain Res. 821, 169–176 (1999).

    Article  CAS  Google Scholar 

  4. Brambilla, R. et al. EMBO J. 14, 3116–3126 (1995).

    Article  CAS  Google Scholar 

  5. Lhotak, V. & Pawson, T. Mol. Cell. Biol. 13, 7071–7079 (1993).

    Article  CAS  Google Scholar 

  6. Gale, N. W. et al. Neuron 17, 9–19 (1996).

    Article  CAS  Google Scholar 

  7. Marshall, C. J. Cell 80, 179–185 (1995).

    Article  CAS  Google Scholar 

  8. Peehl, D. M., Wong, S. T., Sellers, R. G., Jin, S. & Rhim, J. S. Carcinogenesis 18, 1643–1650 (1997).

    Article  CAS  Google Scholar 

  9. Keyse, S. M. Curr. Opin. Cell Biol. 12, 186–192 (2000).

    Article  CAS  Google Scholar 

  10. Brondello, J. M., Pouyssegur, J. & McKenzie, F. R. Science 286, 2514–2517 (1999).

    Article  CAS  Google Scholar 

  11. Posern, G., Weber, C. K., Rapp, U. R. & Feller, S. M. J. Biol. Chem. 273, 24297–24300 (1998).

    Article  CAS  Google Scholar 

  12. Walker-Daniels, J. et al. Prostate 41, 275–280 (1999).

    Article  CAS  Google Scholar 

  13. Holland, S. J. et al. EMBO J. 16, 3877–3888 (1997).

    Article  CAS  Google Scholar 

  14. Hock, B. et al. Oncogene 17, 255–260 (1998).

    Article  CAS  Google Scholar 

  15. Zisch, A. H. et al. Oncogene 19, 177–187 (2000).

    Article  CAS  Google Scholar 

  16. Anderson, D. et al. Science 250, 979–982 (1990).

    Article  CAS  Google Scholar 

  17. Stein, E., Huynh-Do, U., Lane, A. A., Cerretti, D. P. & Daniel, T. O. J. Biol. Chem. 273, 1303–1308 (1998).

    Article  CAS  Google Scholar 

  18. Schlessinger, J. Cell 103, 211–225 (2000).

    Article  CAS  Google Scholar 

  19. Lindberg, R. A. & Hunter, T. Mol. Cell. Biol. 10, 6316–6324 (1990).

    Article  CAS  Google Scholar 

  20. Gale, N. W. & Yancopoulos, G. D. Cell Tissue Res. 290, 227–241 (1997).

    Article  CAS  Google Scholar 

  21. Miao, H., Burnett, E., Kinch, M. S., Simon, E. & Wang, B. Nature Cell Biol. 2, 62–69 (2000).

    Article  CAS  Google Scholar 

  22. Klemke, R. L. et al. 137, 481–492 (1997).

  23. Lee, M. S. et al. Oncogene 8, 387–393 (1993).

    CAS  Google Scholar 

  24. Peehl, D. M. in Culture of Epithelial Cells (ed. Freshney, R. I.) 159–180 (Wiley-Liss, New York,1992).

    Google Scholar 

Download references

Acknowledgements

B.W. is supported by an award from CaP CURE and by grants from Department of the Army, the National Institutes of Health, and the American Heart Association. D.M.P. is supported by an award from CaP CURE.

Author information

Authors and Affiliations

  1. Rammelkamp Center for Research, MetroHealth Campus, Case Western Reserve University School of Medicine, 2500 MetroHealth Drive, Cleveland, 44109, Ohio, USA

    Hui Miao, Bih-Rong Wei, Qing Li, Terry Alexandrou, Jeffrey R. Schelling, John R. Sedor, Elisabeth Burnett & Bingcheng Wang

  2. Ireland Cancer Center and Department of Pharmacology, Case Western Reserve University School of Medicine, 2500 MetroHealth Drive, Cleveland, 44109, Ohio, USA

    Hui Miao, Bih-Rong Wei & Bingcheng Wang

  3. Department of Urology, Stanford University, Stanford, 94305, California, USA

    Donna M. Peehl

  4. Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, 20814, Maryland, USA

    Johng S. Rhim

Authors
  1. Hui Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bih-Rong Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Donna M. Peehl
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Terry Alexandrou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jeffrey R. Schelling
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Johng S. Rhim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John R. Sedor
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Elisabeth Burnett
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bingcheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bingcheng Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Miao, H., Wei, BR., Peehl, D. et al. Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway. Nat Cell Biol 3, 527–530 (2001). https://doi.org/10.1038/35074604

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35074604

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing