Phosphoproteomics-based Modeling Defines the Regulatory Mechanism Underlying Aberrant EGFR Signaling

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2010 Nov 19

PMID 21085658

Citations 9

Authors

Shinya Tasaki

Masao Nagasaki

Hiroko Kozuka-Hata

Kentaro Semba

Noriko Gotoh

Seisuke Hattori

Jun-Ichiro Inoue

Tadashi Yamamoto

Satoru Miyano

Sumio Sugano

Masaaki Oyama

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Mathematical Modeling and Inference of Epidermal Growth Factor-Induced Mitogen-Activated Protein Kinase Cell Signaling Pathways.

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8-Br-cGMP suppresses tumor progression through EGFR/PLC γ1 pathway in epithelial ovarian cancer.

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Analytical reduction of combinatorial complexity arising from multiple protein modification sites.

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Functional aspects of the EGF-induced MAP kinase cascade: a complex self-organizing system approach.

Kosmidis E, Moschou V, Ziogas G, Boukovinas I, Albani M, Laskaris N PLoS One. 2014; 9(11):e111612.

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PKIS: computational identification of protein kinases for experimentally discovered protein phosphorylation sites.

Zou L, Wang M, Shen Y, Liao J, Li A, Wang M BMC Bioinformatics. 2013; 14:247.

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