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.
Highlights
epidermal growth factor (EGF) receptor (ErbB1) and other members of the ErbB family of receptor tyrosine kinases (RTKs) play essential physiological roles in development and maintenance of epithelial tissues by generating cell proliferation, survival, differentiation and migration signals in response to specific ligands and via the stimulation of several signaling pathways including PI3K/Akt, MAPK, Src, as well as STAT pathways [1,2]
The hMEC model The hMEC model for EGFR signaling networks in a human mammary epithelial cell was created by manually collecting information on local biochemical interactions from the primary literature
We present a new and most comprehensive computational model of ErbB receptor signaling in a human mammary epithelial cell, use simulations to make a specific prediction on the biological behavior of a hMEC under experimental conditions that model the overexpression of EGFR and Src as seen in human cancers, and use laboratory experiments to fully verify the prediction
Summary
EGF receptor (ErbB1) and other members of the ErbB family of receptor tyrosine kinases (RTKs) play essential physiological roles in development and maintenance of epithelial tissues by generating cell proliferation, survival, differentiation and migration signals in response to specific ligands and via the stimulation of several signaling pathways including PI3K/Akt, MAPK, Src, as well as STAT pathways [1,2]. The level of intricacy of the ErbB signaling system is further multiplied by the fact that ErbB signaling pathways are closely intertwined with a number of other signaling pathways such as those downstream of integrins and GProtein-coupled Receptors [8]. Together, these complexities have hampered our basic understanding of ErbB receptor signaling and our ability to develop treatments for diseases, such as breast cancer, lung cancer, gliomas and others, associated with aberrant ErbB receptor signaling
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