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:

Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling

Nature Cell Biology volume 4, pages 632–638 (2002)Cite this article

Abstract

Although Src expression and activity are often elevated in colon cancer1,2,3, the precise consequences of overexpression of the non-catalytic Src homology (SH) domains, or enhanced catalytic activity, are unknown. We show that, in KM12C colon cancer cells, elevated Src activity causes the components of adherens junctions, including vinculin, to be redistributed to Src-induced integrin–adhesion complexes. Specifically, elevated Src activity blocks proper assembly of cell–cell contacts after cells are switched from media containing a low level of calcium to media containing a high level of calcium, and E-cadherin remains internalized. In contrast, although elevated expression of the non-catalytic domains of Src is sufficient to induce assembly of integrin–adhesion complexes, it does not induce disorganization of E-cadherin-associated intercellular contacts. Surprisingly, Src-induced disruption of E-cadherin localization requires specific integrin signalling, because E-cadherin redistribution is blocked by loss of cell-matrix interaction, or by inhibitory antibodies to αv or β1 integrin subunits. Furthermore, phosphorylation of the integrin-regulated focal adhesion kinase (FAK) on Src-specific sites is required for Src-induced de-regulation of E-cadherin, demonstrating interdependence between integrin-induced signals and cadherin-associated adhesion changes induced by Src.

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: Elevated expression of active Src induces peripheral adhesion complex formation and disturbs E-cadherin regulation.
Figure 2: The non-catalytic Src domains induce peripheral adhesion complexes but not disorganization of E-cadherin-associated cell–cell contacts.
Figure 3: Src-induced de-regulation of cell–cell contacts requires cell–substrate interaction and specific integrin function.
Figure 4: Interfering with FAK phosphorylation suppresses Src-induced E-cadherin de-regulation.

Similar content being viewed by others

References

  1. Talamonti, M. S., Roh, M. S., Curley, S. A. & Gallick, G. E. J. Clin. Invest. 91, 53–60 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Biscardi, J. S., Tice, D. A. & Parsons, S. J. Adv. Cancer Res. 76, 61–119 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Cartwright, C. A., Coad, C. A. & Egbert, B. M. J. J. Clin. Invest. 93, 509–515 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Irby, R. B. et al. Nature Genet. 21, 187–190 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Abram, C. L. & Courtneidge, S. A. Exp. Cell Res. 254, 1–13 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Kaplan, K. B., Swedlow, J. R., Morgan, D. O. & Varmus, H. E. Genes Dev. 9, 1505–1517 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Felsenfeld, D. P., Schwartzberg, P. L., Venegas, A., Tse, R. & Sheetz, M. P. Nature Cell Biol. 1, 200–206 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Owens, D. W. et al. Mol. Biol. Cell 11, 51–64 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Calautti, E. et al. J. Cell Biol. 156, 137–148 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fincham, V. J., Brunton, V. G. & Frame, M. C. Mol. Cell Biol. 20,6518–6536 (2000).

  11. Fincham, V. J. & Frame, M. C. EMBO J. 17, 81–92 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Klinghoffer, R. A., Sachsenmaier, C., Cooper, J. A. & Soriano, P. EMBO J. 18, 2459–2471 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Morikawa, K., Walker, S., Jessup, J. M. & Fidler, I. J. Cancer Res. 48, 1943–1948 (1988).

    CAS  PubMed  Google Scholar 

  14. Mao, W. et al. Oncogene 15, 3083–3090 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Lewis, J. M. & Schwartz, M. A. Mol. Biol. Cell 6, 151–160 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Calalb, M. B., Polte, T. R. & Hanks, S. K. Mol. Cell. Biol. 15, 954–963 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Schlaepfer, D. D. & Hunter, T. Mol. Cell. Biol. 16, 5623–5633 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Warren, S. L. & Nelson, W. J. Mol. Cell. Biol. 7, 1326–1337 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Behrens, J. et al. J. Cell. Biol. 120, 757–766 (1993).

    Article  CAS  PubMed  Google Scholar 

  20. Hamaguchi, M. et al. EMBO J. 12, 307–314 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Boyer, B., Roche, S., Denoyelle, M. & Thiery, J. P. EMBO J. 16, 5904–5913 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fujita, Y. et al. Nature Cell Biol. 4, 222–231 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Morgenstern, J. P. & Land, H. Nucleic Acids Res. 18, 3587–3596 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. McLean, G. W., Fincham, V. J. & Frame, M. C. J. Biol. Chem. 275, 23333–23339 (2000).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank J. Wyke and V. Fincham for help and comments, and P. McHardy and T. McGuire for help with figures. We are also grateful to I. Fidler for KM12C cells, P. Schwartzberg for CA10-Src251–GFP, T. Hunter and N. Carter for anti-Src N2-17 ascites fluid, D. Sheppard and J. Marshall for the antibodies to various integrin subunits. This work was funded by Cancer Research UK.

Author information

Author notes

  1. Margaret C. Frame

    Present address: The Beatson Oncology Centre, Western Infirmary, Glasgow, G11 6NT, UK

Authors and Affiliations

  1. The Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Bearsden, G61 1BD, Glasgow, UK

    Egle Avizienyte, Anne W. Wyke, Robert J. Jones, Gordon W. McLean, M. Andrew Westhoff, Valerie G. Brunton & Margaret C. Frame

  2. Institute of Biological and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK

    Robert J. Jones

Authors
  1. Egle Avizienyte
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anne W. Wyke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert J. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gordon W. McLean
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Andrew Westhoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Valerie G. Brunton
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Margaret C. Frame
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Margaret C. Frame.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Avizienyte, E., Wyke, A., Jones, R. et al. Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling. Nat Cell Biol 4, 632–638 (2002). https://doi.org/10.1038/ncb829

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb829

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