scholarly journals Signaling through ShcA Is Required for Transforming Growth Factor β- and Neu/ErbB-2-Induced Breast Cancer Cell Motility and Invasion

2008 ◽  
Vol 28 (10) ◽  
pp. 3162-3176 ◽  
Author(s):  
Jason J. Northey ◽  
Juliann Chmielecki ◽  
Elaine Ngan ◽  
Caterina Russo ◽  
Matthew G. Annis ◽  
...  

ABSTRACT 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.

Cell ◽  
1987 ◽  
Vol 48 (3) ◽  
pp. 417-428 ◽  
Author(s):  
Cornelius Knabbe ◽  
Marc E. Lippman ◽  
Lalage M. Wakefield ◽  
Kathleen C. Flanders ◽  
Attan Kasid ◽  
...  

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