Phosphoproteomics-based modeling defines the regulatory mechanism underlying aberrant EGFR signaling.
Phosphoproteomics-based modeling defines the regulatory mechanism underlying aberrant EGFR signaling.
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DOI：
10.1371/journal.pone.0013926
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发表时间：
2010-11-10
期刊：
影响因子：
3.7
通讯作者：
Oyama M
中科院分区：
文献类型：
--
作者：
Tasaki S;Nagasaki M;Kozuka-Hata H;Semba K;Gotoh N;Hattori S;Inoue J;Yamamoto T;Miyano S;Sugano S;Oyama M
表皮生长因子受体(EGFR)突变导致细胞信号不协调，导致多种疾病的发生。然而，这种突变引起的下游信号变化的机制在系统水平上还没有完全被理解。在这里，我们报告了一种基于磷蛋白质组学的方法，用于使用计算网络建模来表征异常EGFR信号的调节机制。我们对EGFR多功能对接位点之一酪氨酸992(Y992)突变的磷酸蛋白质组学分析表明，该突变以时间分辨的方式在整个网络中对EGF信号转导产生影响。基于时间激活分布的计算模型使我们不仅能够重新发现已知的与Y992的蛋白质相互作用和突变的EGFR的内化特性，而且还能够进一步获得模型驱动的洞察力，以了解细胞内容物的影响和EGFR降解的调节。我们的动力学模型还表明，关键反应促进了突变对磷酸蛋白质组动力学的各种影响的重建。我们的综合方法为突变的EGFR信号网络的紊乱提供了一种机械性的描述，这可以促进控制疾病相关细胞信号的系统策略的发展。
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. 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. 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.
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影响因子：
4.8
作者：
Emlet, DR;Moscatello, DK;Wong, AJ
通讯作者：
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影响因子：
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作者：
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通讯作者：
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