Medical Proteomics Laboratory, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
PLoS One. 2010 Nov 10;5(11):e13926. doi: 10.1371/journal.pone.0013926.
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.
表皮生长因子受体（EGFR）的突变导致细胞信号的不和谐，从而导致各种疾病的发生。然而，这种突变导致下游信号改变的机制在系统水平上尚未完全理解。在这里，我们报告了一种基于磷酸化蛋白质组学的方法，用于通过计算网络建模来描述异常 EGFR 信号传导的调节机制。
方法/主要发现：我们对 EGFR 的多功能对接位点之一酪氨酸 992（Y992）的突变进行了磷酸化蛋白质组学分析，以时间分辨的方式揭示了突变对 EGF 信号的全网络影响。基于时间激活谱的计算模型不仅使我们能够重新发现已经知道的与 Y992 相互作用的蛋白质以及突变 EGFR 的内化特性，而且还进一步深入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提出了关键反应，有助于重建突变对磷酸蛋白质组动力学的各种影响。
结论/意义：我们的综合方法提供了对突变 EGFR 信号网络紊乱的机制描述，这有助于制定一种系统的策略来控制与疾病相关的细胞信号。
