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

Nature Cell Biology volume 4, pages 632638 (2002) | Download Citation

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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.

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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.

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Author notes

    • Margaret C. Frame

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

Affiliations

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

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The authors declare no competing financial interests.

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Correspondence to Margaret C. Frame.

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DOI

https://doi.org/10.1038/ncb829

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