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p140Cap dual regulation of E-cadherin/EGFR cross-talk and Ras signalling in tumour cell scatter and proliferation

Oncogene volume 29, pages 3677–3690 (2010)Cite this article

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Abstract

The adaptor protein p140Cap/SNIP is a novel Src-binding protein that regulates Src activation through C-terminal Src kinase (Csk). Here, by gain and loss of function approaches in breast and colon cancer cells, we report that p140Cap immobilizes E-cadherin at the cell membrane and inhibits EGFR and Erk1/2 signalling, blocking scatter and proliferation of cancer cells. p140Cap-dependent regulation of E-cadherin/EGFR cross-talk and cell motility is due to the inhibition of Src kinase. However, rescue of Src activity is not sufficient to restore Erk1/2 phosphorylation and proliferation. Indeed, p140Cap also impairs Erk1/2 phosphorylation by affecting Ras activity, downstream to the EGFR. In conclusion, p140Cap stabilizes adherens junctions and inhibits EGFR and Ras signalling through the dual control of both Src and Ras activities, thus affecting crucial cancer properties such as invasion and growth. Interestingly, p140Cap expression is lost in more aggressive human breast cancers, showing an inverse correlation with EGFR expression. Therefore, p140Cap mechanistically behaves as a tumour suppressor that inhibits signalling pathways leading to aggressive phenotypes.

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Acknowledgements

We thank PP Pandolfi (Boston, MA), A Sorkin (Denver, Co), J Stow (Brisbane, Australia), C Sasaki (Baltimore, Maryland) and K Nishida (Osaka, Japan) for reagent gifts. This work was supported by grants from the AIRC, AICR, EU FP7 Metafight program, MUR, Progetto Alfieri, Regione Piemonte (Oncoprot, Druidi, PiStem and BioTher), Regione Piemonte Sanità. MP Camacho Leal is supported by the AICR.

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  1. L Damiano and P Di Stefano: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Biotechnology Centre and Department of Genetics, Biology and Biochemistry, Torino, Italy

    L Damiano, P Di Stefano, M P Camacho Leal, S Cabodi, L Tordella, E Turco & P Defilippi

  2. Department of Experimental Medicine and Pathology, University ‘La Sapienza’, Roma, Italy

    M Barba & F Mainiero

  3. Department of Biomedical Sciences and Human Oncology, University of Torino, Torino, Italy

    A Sapino & I Castellano

  4. Edinburgh Cancer Research Centre Western General Hospital, Edinburgh, UK

    M Canel & M Frame

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  1. L Damiano
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Correspondence to P Defilippi.

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Damiano, L., Di Stefano, P., Camacho Leal, M. et al. p140Cap dual regulation of E-cadherin/EGFR cross-talk and Ras signalling in tumour cell scatter and proliferation. Oncogene 29, 3677–3690 (2010). https://doi.org/10.1038/onc.2010.128

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