Wolf-Yadlin, A. et al. Effects of HER2 overexpression on cell signaling networks governing proliferation and migration. Mol. Syst. Biol. 2, 54

Biological Engineering Division, MIT, Cambridge, MA, USA.
Molecular Systems Biology (Impact Factor: 10.87). 02/2006; 2(1):54. DOI: 10.1038/msb4100094
Source: PubMed


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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    • "For example, we have shown that mitotic exit requires dephosphorylation of the endocytic protein, dynII, at S764 [17,47]. In large-scale mass spectrometry-based proteomic studies SNX9 has been reported to be phosphorylated on six residues [50–56]. The SNX9 phospho-sites S176 and Y177 lie in the LC domain and are in close proximity to the second LC CHC binding site, suggesting that phosphorylation at these sites could regulate clathrin binding. "
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    • "HER2 overexpression increases tumour cell proliferation, invasiveness and predicts poor prognosis. Wolf-Yadlin and other scientists [48,49,58-61] have used phosphoproteomics and MS to investigate the role of phosphorylation in the effects of HER2 overexpression on EGF- and HRG-mediated signalling of erbB receptors. They identified specific combinations of phosphorylation sites that correlate with cell proliferation and migration and that potentially represent targets for therapeutic intervention. "
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