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Molecular and Cellular Biology, May 2008, p. 3162-3176, Vol. 28, No. 10
0270-7306/08/$08.00+0     doi:10.1128/MCB.01734-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Signaling through ShcA Is Required for Transforming Growth Factor β- and Neu/ErbB-2-Induced Breast Cancer Cell Motility and Invasion{triangledown} ,{dagger}

Jason J. Northey,1 Juliann Chmielecki,2 Elaine Ngan,1 Caterina Russo,2 Matthew G. Annis,2 William J. Muller,1,2 and Peter M. Siegel1,2,3*

Departments of Biochemistry,1 Medicine,2 Anatomy and Cell Biology, McGill University, Montréal, Québec, Canada3

Received 20 September 2007/ Returned for modification 5 November 2007/ Accepted 25 February 2008

Cooperation between the Neu/ErbB-2 and transforming growth factor β (TGF-β) signaling pathways enhances the invasive and metastatic capabilities of breast cancer cells; however, the underlying mechanisms mediating this synergy have yet to be fully explained. We demonstrate that TGF-β induces the migration and invasion of mammary tumor explants expressing an activated Neu/ErbB-2 receptor, which requires signaling from autophosphorylation sites located in the C terminus. A systematic analysis of mammary tumor explants expressing Neu/ErbB-2 add-back receptors that couple to distinct signaling molecules has mapped the synergistic effect of TGF-β-induced motility and invasion to signals emanating from tyrosine residues 1226/1227 and 1253 of Neu/ErbB-2. Given that the ShcA adaptor protein is known to interact with Neu/ErbB-2 through these residues, we investigated the importance of this signaling molecule in TGF-β-induced cell motility and invasion. The reduction of ShcA expression rendered cells expressing activated Neu/ErbB-2, or add-back receptors signaling specifically through tyrosines 1226/1227 or 1253, unresponsive to TGF-β-induced motility and invasion. In addition, a dominant-negative form of ShcA, lacking its three known tyrosine phosphorylation sites, completely abrogates the TGF-β-induced migration and invasion of breast cancer cells expressing activated Neu/ErbB-2. Our results implicate signaling through the ShcA adaptor as a key component in the synergistic interaction between these pathways.

* Corresponding author. Mailing address: 740 Penfield Avenue, Room 2201, Montréal, Québec, Canada H3A 1A4. Phone: (514) 398-4259. Fax: (514) 398-4020. E-mail: peter.siegel{at}mcgill.ca

{triangledown} Published ahead of print on 10 March 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, May 2008, p. 3162-3176, Vol. 28, No. 10
0270-7306/08/$08.00+0     doi:10.1128/MCB.01734-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Alam, S. M., Rajendran, M., Ouyang, S., Veeramani, S., Zhang, L., Lin, M.-F. (2009). A novel role of Shc adaptor proteins in steroid hormone-regulated cancers. Endocr Relat Cancer 16: 1-16 [Abstract] [Full Text]  


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