Filippi Sarah, Barnes Chris P, Kirk Paul D W, Kudo Takamasa, Kunida Katsuyuki, McMahon Siobhan S, Tsuchiya Takaho, Wada Takumi, Kuroda Shinya, Stumpf Michael P H
Centre for Integrative Systems Biology and Bioinformatics, Imperial College London, London SW7 2AZ, UK.
Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK; Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK.
Cell Rep. 2016 Jun 14;15(11):2524-35. doi: 10.1016/j.celrep.2016.05.024. Epub 2016 Jun 2.
Cellular signaling processes can exhibit pronounced cell-to-cell variability in genetically identical cells. This affects how individual cells respond differentially to the same environmental stimulus. However, the origins of cell-to-cell variability in cellular signaling systems remain poorly understood. Here, we measure the dynamics of phosphorylated MEK and ERK across cell populations and quantify the levels of population heterogeneity over time using high-throughput image cytometry. We use a statistical modeling framework to show that extrinsic noise, particularly that from upstream MEK, is the dominant factor causing cell-to-cell variability in ERK phosphorylation, rather than stochasticity in the phosphorylation/dephosphorylation of ERK. We furthermore show that without extrinsic noise in the core module, variable (including noisy) signals would be faithfully reproduced downstream, but the within-module extrinsic variability distorts these signals and leads to a drastic reduction in the mutual information between incoming signal and ERK activity.
细胞信号传导过程在基因相同的细胞中可表现出明显的细胞间变异性。这影响了单个细胞如何对相同的环境刺激做出不同反应。然而，细胞信号系统中细胞间变异性的起源仍知之甚少。在这里，我们通过高通量图像细胞术测量了细胞群体中磷酸化MEK和ERK的动态变化，并随时间量化了群体异质性水平。我们使用一个统计建模框架来表明，外在噪声，特别是来自上游MEK的噪声，是导致ERK磷酸化细胞间变异性的主要因素，而不是ERK磷酸化/去磷酸化的随机性。我们还表明，在核心模块中没有外在噪声的情况下，可变（包括有噪声的）信号将在下游被忠实地再现，但模块内的外在变异性会扭曲这些信号，并导致输入信号与ERK活性之间的互信息急剧减少。
