Phosphoproteomics-Based modeling defines the regulatory mechanism underlying aberrant EGFR signaling

Shinya Tasaki, Masao Nagasaki, Hiroko Kozuka-Hata, Kentaro Semba, Noriko Gotoh, Seisuke Hattori, Jun ichiro Inoue, Tadashi Yamamoto, Satoru Miyano, Sumio Sugano, Masaaki Oyama

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Article numbere13926
JournalPloS one
Volume5
Issue number11
DOIs
Publication statusPublished - 2010 Dec 9

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Tasaki, S., Nagasaki, M., Kozuka-Hata, H., Semba, K., Gotoh, N., Hattori, S., Inoue, J. I., Yamamoto, T., Miyano, S., Sugano, S., & Oyama, M. (2010). Phosphoproteomics-Based modeling defines the regulatory mechanism underlying aberrant EGFR signaling. PloS one, 5(11), [e13926]. https://doi.org/10.1371/journal.pone.0013926