Effects of HER2 overexpression on cell signaling networks governing proliferation and migration.
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.
Wolf-Yadlin
Alejandro
A
Biological Engineering Division, MIT, Cambridge, MA, USA.
Kumar
Neil
N
Zhang
Yi
Y
Hautaniemi
Sampsa
S
Zaman
Muhammad
M
Kim
Hyung-Do
HD
Grantcharova
Viara
V
Lauffenburger
Douglas A
DA
White
Forest M
FM
D000465:Algorithms; D001940:Breast / Q000166:cytology*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D019281:Dimerization; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D005260:Female; D015870:Gene Expression; D018773:Genes, erbB-1; D018734:Genes, erbB-2; D006801:Humans; D016018:Least-Squares Analysis; D013058:Mass Spectrometry; D020890:Neuregulin-1 / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020890:Neuregulin-1; D019000:Phosphotyrosine; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins