HER2 carboxyl-terminal fragments regulate cell migration and cortactin phosphorylation

Jesús García-Castillo, Kim Pedersen, Pier Davide Angelini, Joan Josep Bech-Serra, Núria Colomé, Matthew Paul Cunningham, Joseph Lluis Parra-Palau, Francesc Canals, José Baselga, Joaquín Arribas

Research output: Contribution to journalArticleResearchpeer-review

24 Citations (Scopus)

Abstract

A group of breast cancer patients with a higher probability of developing metastasis expresses a series of carboxyl-terminal fragments (CTFs) of the tyrosine kinase receptor HER2. One of these fragments, 611-CTF, is a hyperactive form of HER2 that constitutively establishes homodimers maintained by disulfide bonds, making it an excellent model to study overactivation of HER2 during tumor progression and metastasis. Here we show that expression of 611-CTF increases cell motility in a variety of assays. Since cell motility is frequently regulated by phosphorylation/dephosphorylation, we looked for phosphoproteins mediating the effect of 611-CTF using two alternative proteomic approaches, stable isotope labeling with amino acids in cell culture and difference gel electrophoresis, and found that the latter is particularly well suited to detect changes in multiphosphorylated proteins. The difference gel electrophoresis screening identified cortactin, a cytoskeleton-binding protein involved in the regulation of cell migration, as a phosphoprotein probably regulated by 611-CTF. This result was validated by characterizing cortactin in cells expressing this HER2 fragment. Finally, we showed that the knockdown of cortactin impairs 611-CTF-induced cell migration. These results suggest that cortactin is a target of 611-CTF involved in the regulation of cell migration and, thus, in the metastatic behavior of breast tumors expressing this CTF. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.
Original languageEnglish
Pages (from-to)25302-25313
JournalJournal of Biological Chemistry
Volume284
Issue number37
DOIs
Publication statusPublished - 11 Sep 2009

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