The Impact Of The Regulatory Design On The Response Of Epidermal Growth Factor Receptor-Mediated Signal Transduction Towards Oncogenic Mutations

The Impact Of The Regulatory Design On The Response Of Epidermal Growth Factor Receptor-Mediated Signal Transduction Towards Oncogenic Mutations

Authors:

Jana Wolf, Serge Dronov, Frank Tobin, Igor Goryanin

Field:

Scientific Computing and Mathematical Modelling

Document Content:

This study investigates how the design of regulatory mechanisms influences the response of epidermal growth factor receptor (EGFR)-mediated signal transduction to oncogenic mutations. Utilizing a detailed pathway model, the research compares two distinct regulatory modes: negative feedback via ERKPP to SOS, and feed-forward deactivation via transiently activated Ras-GAP proteins. The findings reveal that receptor overexpression leads to qualitatively different outcomes depending on the regulatory structure. Specifically, in the system with transiently activated Ras-GAP, receptor overexpression can result in an attenuation of ERK activation, an effect that has been observed experimentally. The model incorporating transiently activated Ras-GAP demonstrates greater robustness against receptor overexpression and Ras mutations, capable of compensating for these oncogenic perturbations, especially when regulation is strong. In contrast, negative feedback mechanisms were found to be less effective in protecting the system against Ras mutations. A general sensitivity analysis indicated that negative feedback confers higher robustness to variations in single reactions, highlighting the limitations of such analyses for predicting the impact of specific oncogenic mutations.

Table of Contents:

• Keywords
• Correspondence
• Present address
• Database
• Abbreviations
• Regulations and mutations in EGFR signalling
• Stimulation of wild-type cells
• Effect of receptor overexpression and Ras mutations
• Results
• The model
• Effect of the regulatory strength
• Sensitivity towards activating mutations
• Experimental procedures
• Mathematical model
• Simulation of oncogenic perturbations
• References
• Supplementary material