期刊
MOLECULAR SYSTEMS BIOLOGY
卷 2, 期 -, 页码 -出版社
WILEY
DOI: 10.1038/msb4100094
关键词
cell migration; cell proliferation; epidermal growth factor receptor; signal transduction; tyrosine phosphorylation
资金
- NCI NIH HHS [U54 CA112967, CA96504, CA112967, R01 CA096504] Funding Source: Medline
- NIGMS NIH HHS [P50 GM068762, P50-GM68762] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA096504] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P50GM068762] Funding Source: NIH RePORTER
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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