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.

An anti-HER2 antibody conjugated with monomethyl auristatin E is highly effective in HER2-positive human gastric cancer

“…5,6 HER2 belongs to human epidermal growth factor receptor (EGFR, HER) family, which includes 4 closely related members, HER1 (EGFR and ErbB1), HER2 (ErbB2), HER3 (ErbB3), and HER4(ErbB4). [7][8][9] HER2 can dimerize with other HER members to play a key role in cell signaling transduction. 9 Gastric cancers at advanced stages express higher levels of HER2 compared to cancers at early stages.…”

A Kinase Inhibitor Screen Reveals Protein Kinase C-dependent Endocytic Recycling of ErbB2 in Breast Cancer Cells

“…Other studies showed that PKC-␦ (61, 62), protein kinase A (61-64), Rho kinase (65), and LIM kinase (66), as well as lipid kinase diacylglyecerol kinase ␦ and phospholipase D modulate EGFR endocytosis (64, 67, 68, 68 -70). Finally, c-Src has been shown to promote EGFR endocytosis likely into a recycling compartment (71)(72)(73)(74). A previous study showed that PMA treatment of ErbB2-transfected fibroblasts induced the juxtamembrane threonine-686 phosphorylation of ErbB2, as well as ErbB2 internalization and intra-cytoplasmic accumulation, but no further characterization of intracellular compartments was carried out (75).…”

Development of Nanotoxicology: Implications for Drug Delivery and Medical Devices

“…With knowledge on the energetics and mechanisms of endocytic pathways emerging, reliable computational models can be developed [86]. However, we must first acquire improved characterization of NPs as the quality of the data input will determine the quality of results that can be extracted from these models.…”