Information flow in a mammalian signal transduction pathway

哺乳动物信号转导途径中的信息流

• 批准号: 214348751
• 负责人: Professor Dr. Nils Blüthgen
• 金额: --
• 依托单位: Institut für Pathologie (CCM)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/214348751?language=en
• 关键词: Information; flow; mammalian; signal; transduction

The mammalian signal transduction network relays detailed information about the presence and concentration of ligands on the outside of the cell to the nucleus, and alters cellular behavior by changing gene expression. Since signal transduction pathways exhibit striking similarities to typical communication systems, the framework of information theory can be directly applied to better understand cellular signaling. During the current funding period of the priority program InKoMBio, we determined the information transmission capacities of the prototypic MAPK pathway using a combination of single cell experimentation and information theoretical calculations. Surprisingly, our results indicate that the signaling network transmits less than one bit of information. Rather than faithfully reporting extracellular concentrations of the ligand EGF, it responds in a binary manner. In addition, molecular noise interferes with a robust encoding of the presence of the input signal, limiting the information content even further. We observed similarly limited channel capacities for two other signaling pathways, the TGFbeta/SMAD and p53 networks.As many studies in different biological model systems suggest that cells can gain more information than one bit about their environment using signaling pathways, we aim to investigate what is limiting the information transmission capabilities at the single cell level and how cells maximize the amount of information gained from external and internal sources to ensure a proper physiological response. We hypothesize that the pathways integrate information from the cellular context, which could explain the apparently low channel capacity. We therefore propose to use information theory, single cell experimentation and mathematical modeling to study the influence of contextual information, by addressing the following specific questions: (i) how does the state of a cell influence the response to an external signal, (ii) how does the context of previous stimuli influence the response and (iii) what are common principles of context-dependent signaling across different pathways? We will use live-cell imaging and immunofluorescence assays to measure signaling and context, and calculate the contribution of contextual information using conditional mutual information, context trees and parsimonious Bayesian networks. To gain a predictive understanding of the underlying molecular mechanisms, we will expand existing mathematical models of the pathways to include the interacting regulatory processes that provide context and analyze their information theoretical properties. Using network perturbations, we will experimentally validate model predictions.

哺乳动物信号转导网络将细胞外配体的存在和浓度的详细信息传递到细胞核，并通过改变基因表达来改变细胞行为。由于信号转导途径与典型的通信系统表现出惊人的相似性，信息论的框架可以直接应用于更好地理解细胞信号。在优先项目InKoMBio的当前资助期内，我们使用单细胞实验和信息理论计算相结合的方法确定了原型MAPK途径的信息传输能力。令人惊讶的是，我们的研究结果表明，信号网络传输不到一个比特的信息。而不是如实地报告细胞外浓度的配体EGF，它响应在一个二元的方式。此外，分子噪声干扰输入信号的存在的鲁棒编码，甚至进一步限制了信息内容。我们观察到另外两种信号通路，TGF β/SMAD和p53网络的通道容量也同样有限。由于在不同生物模型系统中的许多研究表明，细胞可以通过信号通路获得更多关于其环境的信息，我们的目标是调查是什么限制了单细胞水平的信息传输能力，以及细胞如何最大限度地从外部和外部环境获得信息量。内部来源，以确保适当的生理反应。我们推测，这些通路整合了来自细胞环境的信息，这可以解释明显低的通道容量。因此，我们建议使用信息论，单细胞实验和数学建模来研究上下文信息的影响，通过解决以下具体问题：（i）细胞的状态如何影响对外部信号的反应，（ii）先前刺激的背景如何影响反应，以及（iii）不同途径的上下文依赖性信号传导的共同原则是什么？我们将使用活细胞成像和免疫荧光检测来测量信号和背景，并使用条件互信息，上下文树和简约贝叶斯网络计算上下文信息的贡献。为了获得对潜在分子机制的预测性理解，我们将扩展现有的途径数学模型，以包括提供背景并分析其信息理论特性的相互作用的调节过程。使用网络扰动，我们将通过实验验证模型预测。