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.
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Acknowledgements
This work was supported by grants from the US Army (DAMD) and CBCRA awarded to WJM. A CBCRA grant was awarded to MP. HK was supported by a studentship from the CIHR, and RC was supported by a Pre-doctoral scholarship from the US Army (DAMD). WJM is a recipient of a CRC chair in Molecular Oncology. MP is a CIHR senior scientist.
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Kim, H., Chan, R., Dankort, D. et al. The c-Src tyrosine kinase associates with the catalytic domain of ErbB-2: implications for ErbB-2 mediated signaling and transformation. Oncogene 24, 7599–7607 (2005). https://doi.org/10.1038/sj.onc.1208898
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DOI: https://doi.org/10.1038/sj.onc.1208898
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