title: A comprehensive, multi-scale dynamical model of ErbB receptor signal transduction in human mammary epithelial cells.
abstract: The non-receptor tyrosine kinase Src and receptor tyrosine kinase epidermal growth factor receptor (EGFR/ErbB1) have been established as collaborators in cellular signaling and their combined dysregulation plays key roles in human cancers, including breast cancer. In part due to the complexity of the biochemical network associated with the regulation of these proteins as well as their cellular functions, the role of Src in EGFR regulation remains unclear. Herein we present a new comprehensive, multi-scale dynamical model of ErbB receptor signal transduction in human mammary epithelial cells. This model, constructed manually from published biochemical literature, consists of 245 nodes representing proteins and their post-translational modifications sites, and over 1,000 biochemical interactions. Using computer simulations of the model, we find it is able to reproduce a number of cellular phenomena. Furthermore, the model predicts that overexpression of Src results in increased endocytosis of EGFR in the absence/low amount of the epidermal growth factor (EGF). Our subsequent laboratory experiments also suggest increased internalization of EGFR upon Src overexpression under EGF-deprived conditions, further supporting this model-generated hypothesis.
authors: Department of Mathematics, University of Nebraska at Omaha, Omaha, Nebraska, USA.
authors: Tomáš
authors: T
authors: Helikar
authors: Naomi
authors: N
authors: Kochi
authors: Bryan
authors: B
authors: Kowal
authors: Manjari
authors: M
authors: Dimri
authors: Mayumi
authors: M
authors: Naramura
authors: Srikumar M
authors: SM
authors: Raja
authors: Vimla
authors: V
authors: Band
authors: Hamid
authors: H
authors: Band
authors: Jim A
authors: JA
authors: Rogers
mesh_terms: D001940:Breast / Q000378:metabolism*; D003198:Computer Simulation; D004705:Endocytosis / Q000502:physiology; D004815:Epidermal Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D066246:ErbB Receptors / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D008954:Models, Biological; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019061:src-Family Kinases
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