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PMID: 18332126 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Signaling through ShcA is required for transforming growth factor beta- and Neu/ErbB-2-induced breast cancer cell motility and invasion.

Molecular and cellular biology ·Vol. 28 ·No. 10 ·2008-05-00 ·Pages 3162-76

Northey JJ, Chmielecki J, Ngan E, Russo C, Annis MG, Muller WJ, Siegel PM

Abstract

Cooperation between the Neu/ErbB-2 and transforming growth factor beta (TGF-beta) 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-beta 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-beta-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-beta-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-beta-induced motility and invasion. In addition, a dominant-negative form of ShcA, lacking its three known tyrosine phosphorylation sites, completely abrogates the TGF-beta-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.

MeSH Terms
Adaptor Proteins, Signal Transducing/antagonists & inhibitors,genetics,metabolism Animals Cell Movement/drug effects Female Focal Adhesions Gene Expression Lung Neoplasms/secondary Mammary Neoplasms, Experimental/genetics,metabolism,pathology,physiopathology Mice Mice, Nude Neoplasm Invasiveness Phosphotyrosine/metabolism Point Mutation RNA, Small Interfering/genetics Receptor, ErbB-2/chemistry,genetics,metabolism Shc Signaling Adaptor Proteins Signal Transduction Src Homology 2 Domain-Containing, Transforming Protein 1 Transfection Transforming Growth Factor beta/pharmacology
Chemicals
Adaptor Proteins, Signal Transducing RNA, Small Interfering Shc Signaling Adaptor Proteins Shc1 protein, mouse Src Homology 2 Domain-Containing, Transforming Protein 1 Transforming Growth Factor beta Phosphotyrosine Erbb2 protein, mouse Receptor, ErbB-2
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Northey Jason J
Departments of Biochemistry, Anatomy and Cell Biology, McGill University, Montréal, Québec, Canada.
Chmielecki Juliann
Ngan Elaine
Russo Caterina
Annis Matthew G
Muller William J
Siegel Peter M
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
1098-5549
DOI
10.1128/MCB.01734-07
Published
2008-05-00
Epub
2008-00-10
Pages
3162-76
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC2423163
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.01734-07 PMC Full Text View journal details
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