Copine-III interacts with ErbB2 and promotes tumor cell migration

C. Heinrich, C. Keller, A. Boulay, M. Vecchi, M. Bianchi, R. Sack, S. Lienhard, S. Duss, J. Hofsteenge, N. E. Hynes

Research output: Contribution to journalArticlepeer-review

Abstract

ErbB2 amplification and overexpression in breast cancer correlates with aggressive disease and poor prognosis. To find novel ErbB2-interacting proteins, we used stable isotope labeling of amino acids in cell culture followed by peptide affinity pull-downs and identified specific binders using relative quantification by mass spectrometry. Copine-III, a member of a Ca 2-dependent phospholipid-binding protein family, was identified as binding to phosphorylated Tyr1248 of ErbB2. In breast cancer cells, Copine-III requires Ca 2 for binding to the plasma membrane, where it interacts with ErbB2 upon receptor stimulation, an interaction that is dependent on receptor activity. Copine-III also binds receptor of activated C kinase 1 and colocalizes with phosphorylated focal adhesion kinase at the leading edge of migrating cells. Importantly, knockdown of Copine-III in T47D breast cancer cells causes a decrease in Src kinase activation and ErbB2-dependent wound healing. Our data suggest that Copine-III is a novel player in the regulation of ErbB2-dependent cancer cell motility. In primary breast tumors, high CPNE3 RNA levels significantly correlate with ERBB2 amplification. Moreover, in an in situ tissue microarray analysis, we detected differential protein expression of Copine-III in normal versus breast, prostate and ovarian tumors, suggesting a more general role for Copine-III in carcinogenesis.

Original languageEnglish
Pages (from-to)1598-1610
Number of pages13
JournalOncogene
Volume29
Issue number11
DOIs
Publication statusPublished - Mar 2010

Keywords

  • Cell migration
  • Copine-III
  • ErbB2
  • FRET acceptor photobleaching
  • HRG
  • Quantitative mass spectrometry

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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