Effects of HER2 overexpression on cell signaling networks governing proliferation and migration.

TitleEffects of HER2 overexpression on cell signaling networks governing proliferation and migration.
Publication TypeJournal Article
Year of Publication2006
AuthorsWolf-Yadlin, A, Kumar, N, Zhang, Y, Hautaniemi, S, Zaman, M, Kim, H-D, Grantcharova, V, Lauffenburger, DA, White, FM
JournalMol Syst Biol
Date Published2006
KeywordsAlgorithms, Breast, Cell Division, Cell Line, Cell Movement, Dimerization, Epidermal Growth Factor, Epithelial Cells, Female, Gene Expression, Genes, erbB-1, Genes, erbB-2, Humans, Least-Squares Analysis, Mass Spectrometry, Neuregulin-1, Phosphorylation, Phosphotyrosine, Protein Processing, Post-Translational, Receptor, Epidermal Growth Factor, Receptor, erbB-2, Recombinant Fusion Proteins, Signal Transduction

Although human epidermal growth factor receptor 2 (HER2) overexpression is implicated in tumor progression for a variety of cancer types, how it dysregulates signaling networks governing cell behavioral functions is poorly understood. To address this problem, we use quantitative mass spectrometry to analyze dynamic effects of HER2 overexpression on phosphotyrosine signaling in human mammary epithelial cells stimulated by epidermal growth factor (EGF) or heregulin (HRG). Data generated from this analysis reveal that EGF stimulation of HER2-overexpressing cells activates multiple signaling pathways to stimulate migration, whereas HRG stimulation of these cells results in amplification of a specific subset of the migration signaling network. Self-organizing map analysis of the phosphoproteomic data set permitted elucidation of network modules differentially regulated in HER2-overexpressing cells in comparison with parental cells for EGF and HRG treatment. Partial least-squares regression analysis of the same data set identified quantitative combinations of signals within the networks that strongly correlate with cell proliferation and migration measured under the same battery of conditions. Combining these modeling approaches enabled association of epidermal growth factor receptor family dimerization to activation of specific phosphorylation sites, which appear to most critically regulate proliferation and/or migration.

Alternate JournalMol. Syst. Biol.
PubMed ID17016520
PubMed Central IDPMC1682017
Grant ListCA112967 / CA / NCI NIH HHS / United States
CA96504 / CA / NCI NIH HHS / United States
P50-GM68762 / GM / NIGMS NIH HHS / United States