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

Biological Engineering Division, MIT, Cambridge, MA, USA.
Molecular Systems Biology (Impact Factor: 14.1). 02/2006; 2:54. DOI: 10.1038/msb4100094
Source: PubMed

ABSTRACT 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.

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Available from: Alejandro Wolf-Yadlin, Aug 04, 2015
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    • "activated proteins or phosphorylated sequences into subclasses to reflect the kinetics of their recruitment in the cascade (Zhang et al., 2005; Schmelzle et al., 2006; Wolf-Yadlin et al., 2006) or their correlation with the activation level of the governing RTK (Petti et al., 2005; Huang et al., 2007). Alternatively, Bayesian network modeling was used to analyze several datasets that target the same RTK, but obtained in different conditions on different cell types, and to suggest probable logical organizations of proteins repeatedly identified in several studies (Bose et al., 2006; Guha et al., 2008). "
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    • "However, the way HER2 over-expression deregulates these multiple signaling pathways is still poorly understood [19] [39]. Within this background, PTPs (protein tyrosine phosphatases) and DSPs (dual-specificity phosphatases) might play a role, since members of these families are signaling molecules in RTK (receptor tyrosine kinase) pathways. "
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    • "Kumar et al. [41] applied partial least-squares regression modeling to ascertain principal components, representing quantitatively weighted combinations of signals, most strongly correlated with (or against) the phenotypic cell behaviors (proliferation, migration) measured concomitantly with the tyrosine phosphopeptide sites assessed by mass spectrometry in the previously-described study by Wolf-Yadlin et al. [29]. From the 62 phosphosites on 45 proteins quantified across six conditions (two cell types: parental and HER2-overexpressing human mammary epithelial cells; three ligand treatments: EGF, HRG, and autocrine stimulation), this analysis constructed a model comprising two principal components containing 9 phosphosites on 6 key proteins. "
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