Modeling of Biological Networks Laboratory, Department of Biomedical Engineering, University of California, 451 East Health Sciences Drive, Davis, CA 95616, USA.
J R Soc Interface. 2013 Jun 26;10(86):20130363. doi: 10.1098/rsif.2013.0363. Print 2013 Sep 6.
The transforming growth factor-β (TGF-β) signal transduction pathway controls many cellular processes, including differentiation, proliferation and apoptosis. It plays a fundamental role during development and it is dysregulated in many diseases. The factors that control the dynamics of the pathway, however, are not fully elucidated yet and so far computational approaches have been very limited in capturing the distinct types of behaviour observed under different cellular backgrounds and conditions into a single-model description. Here, we develop a detailed computational model for TGF-β signalling that incorporates elements of previous models together with crosstalking between Smad1/5/8 and Smad2/3 channels through a negative feedback loop dependent on Smad7. The resulting model accurately reproduces the diverse behaviour of experimental datasets for human keratinocytes, bovine aortic endothelial cells and mouse mesenchymal cells, capturing the dynamics of activation and nucleocytoplasmic shuttling of both R-Smad channels. The analysis of the model dynamics and its system properties revealed Smad7-mediated crosstalking between Smad1/5/8 and Smad2/3 channels as a major determinant in shaping the distinct responses to single and multiple ligand stimulation for different cell types.
转化生长因子-β（TGF-β）信号转导通路控制着许多细胞过程，包括分化、增殖和凋亡。它在发育过程中起着至关重要的作用，并且在许多疾病中失调。然而，控制该通路动态的因素尚未完全阐明，到目前为止，计算方法在将不同细胞背景和条件下观察到的不同类型的行为纳入单个模型描述方面非常有限。在这里，我们开发了一个详细的 TGF-β 信号转导计算模型，该模型结合了以前模型的元素，以及通过依赖于 Smad7 的负反馈环在 Smad1/5/8 和 Smad2/3 通道之间进行的串扰。所得到的模型准确地再现了人类角质形成细胞、牛主动脉内皮细胞和小鼠间充质细胞的实验数据集的多样化行为，捕获了两种 R-Smad 通道的激活和核质穿梭的动力学。对模型动力学及其系统特性的分析表明，Smad7 介导的 Smad1/5/8 和 Smad2/3 通道之间的串扰是决定不同细胞类型对单配体和多配体刺激产生不同反应的主要因素。
