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

Mol Cell Biol. 2008 May;28(10):3162-76. doi: 10.1128/MCB.01734-07. Epub 2008 Mar 10.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Movement / drug effects
  • Female
  • Focal Adhesions
  • Gene Expression
  • Lung Neoplasms / secondary
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism*
  • Mammary Neoplasms, Experimental / pathology
  • Mammary Neoplasms, Experimental / physiopathology
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness
  • Phosphotyrosine / metabolism
  • Point Mutation
  • RNA, Small Interfering / genetics
  • Receptor, ErbB-2 / chemistry
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism*
  • Shc Signaling Adaptor Proteins
  • Signal Transduction
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Transfection
  • Transforming Growth Factor beta / pharmacology*

Substances

  • 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