Construction of large signaling pathways using an adaptive perturbation approach with phosphoproteomic data
Construction of large signaling pathways using an adaptive perturbation approach with phosphoproteomic data
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DOI：
10.1039/c2mb05482e
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发表时间：
2012-01-01
影响因子：
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通讯作者：
Alexopoulos, Leonidas G.
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文献类型：
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作者：
Melas, Ioannis N.;Mitsos, Alexander;Alexopoulos, Leonidas G.
构建大的细胞特异性信号通路对于理解正常和病理条件下的信息处理至关重要。在这方面，基于基因的方法提供了大的途径探索的优势，而磷酸蛋白质组学方法提供了一个更可靠的途径活动，但适用于小的途径大小。在本文中，我们展示了一个实验自适应的方法来构建大的信号通路磷酸化蛋白质组数据在3天的时间范围内。我们的方法-利用快速周转时间的xMAP技术-进行了四个步骤：（i）筛选最佳途径诱导剂，（ii）选择响应的，（iii）联合收割机，他们在一个组合的方式来构建一个磷酸化蛋白质组数据集，和（iv）优化减少通用途径通过一个线性规划公式。作为一个案例研究，我们发现新的球员和他们相应的途径在原代人肝细胞通过询问下游的81个受体的信号转导和构建一个详细的模型，包括177个物种（其中14个被测量）和365个相互作用的网络的响应部分。
Construction of large and cell-specific signaling pathways is essential to understand information processing under normal and pathological conditions. On this front, gene-based approaches offer the advantage of large pathway exploration whereas phosphoproteomic approaches offer a more reliable view of pathway activities but are applicable to small pathway sizes. In this paper, we demonstrate an experimentally adaptive approach to construct large signaling pathways from phosphoproteomic data within a 3-day time frame. Our approach-taking advantage of the fast turnaround time of the xMAP technology-is carried out in four steps: (i) screen optimal pathway inducers, (ii) select the responsive ones, (iii) combine them in a combinatorial fashion to construct a phosphoproteomic dataset, and (iv) optimize a reduced generic pathway via an Integer Linear Programming formulation. As a case study, we uncover novel players and their corresponding pathways in primary human hepatocytes by interrogating the signal transduction downstream of 81 receptors of interest and constructing a detailed model for the responsive part of the network comprising 177 species (of which 14 are measured) and 365 interactions.