1. ¹Department of Medical Sciences, McMaster University, Hamilton, Ontario, Canada
2. ²Sunnybrook and Women's College Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada M4N 3M5
3. ³Department of Biology, McMaster University, Hamilton, Ontario, Canada
4. ⁴Molecular Oncology Group, Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3A 1A1
5. ⁵Molecular Oncology Group, Department of Medicine, McGill University, Montreal, Quebec, Canada H3A 1A1
6. ⁶UCSF Comprehensive Cancer Center, UCSF Cancer Research Institute, San Francisco, CA 94115, USA
7. ⁷Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada

Correspondence: WJ Muller, Molecular Oncology Group, McGill University Health Center, Rm H5-21, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1; E-mail: william.muller@mcgill.ca

Received 27 January 2005; Revised 18 May 2005; Accepted 3 June 2005; Published online 19 September 2005.

Abstract

c-Src associates with and is activated by the ErbB-2 receptor tyrosine kinase, but is unable to bind the EGFR. Although c-Src has been found to interact directly and specifically with the ErbB-2 receptor, the significance of this interaction is unclear. Using both chimeric receptor and site-directed mutagenesis approaches, the region of interaction of c-Src on ErbB-2 was identified. Significantly, EGFR could be converted into a receptor capable of binding c-Src by replacement of a catalytic domain of ErbB-2. We further demonstrated that MDCK cells that express mutant EGFR that are competent in c-Src recruitment lose epithelial polarity in organoid cultures, whereas cells overexpressing the wild-type EGFR retain a polarized phenotype. ErbB-2-dependent activation of c-Src results in disruption of epithelial cell–cell contacts leading to cell dispersal that correlates with the re-localization of phospho-MAPK to focal adhesions. Taken together, these observations suggest that recruitment of c-Src to these closely related EGFR family members plays a critical role in modulating cell polarity.