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Updated: Jun 6, 2026
Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Phosphoproteomics-based modeling defines the regulatory mechanism underlying aberrant EGFR signaling
Shinya Tasaki1, Masao Nagasaki, Hiroko Kozuka-Hata
1Medical Proteomics Laboratory, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Background:
Mutation of the epidermal growth factor receptor (EGFR) results in a discordant cell signaling, leading to the development of various diseases. However, the mechanism underlying the alteration of downstream signaling due to such mutation has not yet been completely understood at the system level. Here, we report a phosphoproteomics-based methodology for characterizing the regulatory mechanism underlying aberrant EGFR signaling using computational network modeling.
Methodology/Principal Findings:
Our phosphoproteomic analysis of the mutation at tyrosine 992 (Y992), one of the multifunctional docking sites of EGFR, revealed network-wide effects of the mutation on EGF signaling in a time-resolved manner. Computational modeling based on the temporal activation profiles enabled us to not only rediscover already-known protein interactions with Y992 and internalization property of mutated EGFR but also further gain model-driven insights into the effect of cellular content and the regulation of EGFR degradation. Our kinetic model also suggested critical reactions facilitating the reconstruction of the diverse effects of the mutation on phosphoproteome dynamics.
Conclusions/Significance:
Our integrative approach provided a mechanistic description of the disorders of mutated EGFR signaling networks, which could facilitate the development of a systematic strategy toward controlling disease-related cell signaling.
Insights
This study reveals how epidermal growth factor receptor (EGFR) mutations disrupt cell signaling using phosphoproteomics and network modeling. The findings offer insights into disease mechanisms and potential therapeutic strategies for EGFR-related disorders.
Area of Science:
- Cellular Biology
- Systems Biology
- Biochemistry
Background:
- Epidermal growth factor receptor (EGFR) mutations cause aberrant cell signaling, contributing to various diseases.
- The precise mechanisms of downstream signaling alterations in mutated EGFR remain incompletely understood at a systems level.
Purpose of the Study:
- To characterize the regulatory mechanisms of aberrant EGFR signaling using a phosphoproteomics-based methodology and computational network modeling.
- To elucidate the system-level effects of specific EGFR mutations on downstream signaling pathways.
Main Methods:
- Utilized phosphoproteomics to analyze the effects of EGFR mutations, specifically at tyrosine 992 (Y992), on EGF signaling over time.
- Developed computational network models based on temporal activation profiles to understand signaling dynamics.
- Integrated phosphoproteomic data with kinetic modeling to identify key regulatory reactions.
Main Results:
- Identified network-wide effects of the Y992 EGFR mutation on EGF signaling in a time-resolved manner.
- Computational modeling confirmed known interactions and EGFR internalization properties, while also revealing insights into cellular content effects and EGFR degradation regulation.
- The kinetic model highlighted critical reactions influencing phosphoproteome dynamics in response to the mutation.
Conclusions:
- The integrative approach provided a mechanistic understanding of signaling network disorders caused by mutated EGFR.
- This work facilitates the development of systematic strategies for controlling disease-related cell signaling pathways.
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