Wang Chun-Chao, Cirit Murat, Haugh Jason M
Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695-7905, USA.
Mol Syst Biol. 2009;5:246. doi: 10.1038/msb.2009.4. Epub 2009 Feb 17.
Although it is appreciated that canonical signal-transduction pathways represent dominant modes of regulation embedded in larger interaction networks, relatively little has been done to quantify pathway cross-talk in such networks. Through quantitative measurements that systematically canvas an array of stimulation and molecular perturbation conditions, together with computational modeling and analysis, we have elucidated cross-talk mechanisms in the platelet-derived growth factor (PDGF) receptor signaling network, in which phosphoinositide 3-kinase (PI3K) and Ras/extracellular signal-regulated kinase (Erk) pathways are prominently activated. We show that, while PI3K signaling is insulated from cross-talk, PI3K enhances Erk activation at points both upstream and downstream of Ras. The magnitudes of these effects depend strongly on the stimulation conditions, subject to saturation effects in the respective pathways and negative feedback loops. Motivated by those dynamics, a kinetic model of the network was formulated and used to precisely quantify the relative contributions of PI3K-dependent and -independent modes of Ras/Erk activation.
尽管人们认识到经典信号转导通路是嵌入更大相互作用网络中的主要调节模式，但在量化此类网络中的通路串扰方面所做的工作相对较少。通过系统地考察一系列刺激和分子扰动条件的定量测量，以及计算建模和分析，我们阐明了血小板衍生生长因子（PDGF）受体信号网络中的串扰机制，其中磷脂酰肌醇3激酶（PI3K）和Ras/细胞外信号调节激酶（Erk）通路被显著激活。我们表明，虽然PI3K信号传导与串扰绝缘，但PI3K在Ras的上游和下游位点增强Erk激活。这些效应的大小强烈依赖于刺激条件，受到各自通路中的饱和效应和负反馈环的影响。受这些动力学的驱动，构建了该网络的动力学模型，并用于精确量化Ras/Erk激活的PI3K依赖性和非依赖性模式的相对贡献。
