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

Shinya Tasaki, Masao Nagasaki, Hiroko Kozuka-Hata, Kentaro Senba, 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

    Fingerprint

    Epidermal Growth Factor Receptor
    mutation
    Mutation
    Cell signaling
    Epidermal Growth Factor
    Tyrosine
    tyrosine
    epidermal growth factor receptors
    Chemical activation
    cells
    kinetics
    Degradation
    Kinetics
    degradation
    methodology
    Proteins
    proteins

    ASJC Scopus subject areas

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

    Cite this

    Tasaki, S., Nagasaki, M., Kozuka-Hata, H., Senba, K., Gotoh, N., Hattori, 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

    Phosphoproteomics-Based modeling defines the regulatory mechanism underlying aberrant EGFR signaling. / Tasaki, Shinya; Nagasaki, Masao; Kozuka-Hata, Hiroko; Senba, Kentaro; Gotoh, Noriko; Hattori, Seisuke; Inoue, Jun ichiro; Yamamoto, Tadashi; Miyano, Satoru; Sugano, Sumio; Oyama, Masaaki.

    In: PLoS One, Vol. 5, No. 11, e13926, 2010.

    Research output: Contribution to journalArticle

    Tasaki, S, Nagasaki, M, Kozuka-Hata, H, Senba, K, Gotoh, N, Hattori, S, Inoue, JI, Yamamoto, T, Miyano, S, Sugano, S & Oyama, M 2010, 'Phosphoproteomics-Based modeling defines the regulatory mechanism underlying aberrant EGFR signaling', PLoS One, vol. 5, no. 11, e13926. https://doi.org/10.1371/journal.pone.0013926
    Tasaki, Shinya ; Nagasaki, Masao ; Kozuka-Hata, Hiroko ; Senba, Kentaro ; Gotoh, Noriko ; Hattori, Seisuke ; Inoue, Jun ichiro ; Yamamoto, Tadashi ; Miyano, Satoru ; Sugano, Sumio ; Oyama, Masaaki. / Phosphoproteomics-Based modeling defines the regulatory mechanism underlying aberrant EGFR signaling. In: PLoS One. 2010 ; Vol. 5, No. 11.
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