A Comprehensive, Multi-Scale Dynamical Model of ErbB Receptor Signal Transduction in Human Mammary Epithelial Cells

Authors

Tomáš Helikar, University of Nebraska-LincolnFollow
Naomi Kochi, University of Nebraska Medical Center
Bryan Kowal, University of Nebraska at OmahaFollow
Manjari Dimri, George Washington University School of Medicine
Mayumi Naramura, University of Nebraska Medical Center
Srikumar M. Raja, University of Nebraska Medical Center-Eppley Cancer Center
Vimla Band, University of Nebraska Medical Center
Hamid Band, University of Nebraska Medical Center
Jim A. Rogers, University of Nebraska at OmahaFollow

Document Type

Article

Date of this Version

2013

Citation

Helikar T, Kochi N, Kowal B, Dimri M, Naramura M, et al. (2013) A Comprehensive, Multi-Scale Dynamical Model of ErbB Receptor Signal Transduction in Human Mammary Epithelial Cells. PLoS ONE 8(4): e61757. doi:10.1371/journal.pone.0061757

Comments

Copyright 2013 Helikar et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License.

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.