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Molecular & Cellular Proteomics 8:226-231, 2009.
© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Temporal Perturbation of Tyrosine Phosphoproteome Dynamics Reveals the System-wide Regulatory Networks ^*,S

Masaaki Oyama^,,¶, Hiroko Kozuka-Hata^,, Shinya Tasaki^,||, Kentaro Semba^**,, Seisuke Hattori^,¶¶, Sumio Sugano^||, Jun-ichiro Inoue^, and Tadashi Yamamoto

From the Medical Proteomics Laboratory, Department of Cancer Biology, and Division of Cellular Proteomics (BML), Institute of Medical Science and ^|| Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan, ^** Department of Life Science and Medical Bio-Science, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan, and ^¶¶ Department of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan

Signal transduction systems are known to widely regulate complex biological events such as cell proliferation and differentiation. Because phosphotyrosine-dependent networks play a key role in transmitting signals, a comprehensive and fine description of their dynamic behavior can lead us to systematically analyze the regulatory mechanisms that result in each biological effect. Here we established a mass spectrometry-based framework for analyzing tyrosine phosphoproteome dynamics through temporal network perturbation. A highly time-resolved description of the epidermal growth factor-dependent signaling pathways in human A431 cells revealed a global view of their multiphase network activation, comprising a spike signal transmission within 1 min of ligand stimulation followed by the prolonged activation of multiple Src-related molecules. Temporal perturbation of Src family kinases with the corresponding inhibitor PP2 in the prolonged activation phase led to the down-regulation of the molecules related to cell adhesion and receptor degradation, whereas the canonical cascades as well as the epidermal growth factor receptor relatively maintained their activities. Our methodology provides a system-wide view of the regulatory network clusters involved in signal transduction that is essential to refine the literature-based network structures for a systems biology analysis.

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