Inferring Signaling Pathway Topologies from Multiple Perturbation Measurements of Specific Biochemical Species
Inferring Signaling Pathway Topologies from Multiple Perturbation Measurements of Specific Biochemical Species
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DOI：
10.1126/scisignal.2000517
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发表时间：
2010-03-16
影响因子：
7.3
通讯作者：
Kolch, Walter
中科院分区：
文献类型：
--
作者：
Xu, Tian-Rui;Vyshemirsky, Vladislav;Kolch, Walter
信号通路对生物决策的规范是由激活动力学和网络拓扑之间的相互作用编码的。虽然我们可以描述复杂的网络，但我们不能轻易确定细胞实际使用哪种拓扑结构来转导特定的信号。对所有可能的拓扑进行实验测试是不可行的，因为探索完整的假设空间需要组合大量的实验。在这里，我们证明了基于贝叶斯推理的建模提供了一种方法来探索和约束这个假设空间，允许路径模型的合理排序。我们的方法可以使用有限数量的生化物种的测量，当与多个扰动相结合时。作为概念的证明，我们研究了表皮生长因子对细胞外信号调节激酶（ERK）途径的激活。预测和实验验证的模型表明，在两种不同的细胞系中，Raf-1和B-Raf都需要完全激活ERK。因此，即使在有限数量的生化和动力学测量可用时，我们的形式化方法也能合理地推断出证据支持的途径拓扑。
The specification of biological decisions by signaling pathways is encoded by the interplay between activation dynamics and network topologies. Although we can describe complex networks, we cannot easily determine which topology the cell actually uses to transduce a specific signal. Experimental testing of all plausible topologies is infeasible because of the combinatorially large number of experiments required to explore the complete hypothesis space. Here, we demonstrate that Bayesian inference-based modeling provides an approach to explore and constrain this hypothesis space, permitting the rational ranking of pathway models. Our approach can use measurements of a limited number of biochemical species when combined with multiple perturbations. As proof of concept, we examined the activation of the extracellular signal-regulated kinase (ERK) pathway by epidermal growth factor. The predicted and experimentally validated model shows that both Raf-1 and, unexpectedly, B-Raf are needed to fully activate ERK in two different cell lines. Thus, our formal methodology rationally infers evidentially supported pathway topologies even when a limited number of biochemical and kinetic measurements are available.