Robustness of MEK-ERK Dynamics and Origins of Cell-to-Cell Variability in MAPK Signaling.
Robustness of MEK-ERK Dynamics and Origins of Cell-to-Cell Variability in MAPK Signaling.
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DOI：
10.1016/j.celrep.2016.05.024
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发表时间：
2016-06-14
期刊：
影响因子：
8.8
通讯作者：
Stumpf MP
中科院分区：
文献类型：
--
作者：
Filippi S;Barnes CP;Kirk PD;Kudo T;Kunida K;McMahon SS;Tsuchiya T;Wada T;Kuroda S;Stumpf MP
细胞信号传导过程可以在遗传上相同的细胞中表现出明显的细胞间变异性。这会影响单个细胞对相同环境刺激的不同反应。然而，细胞信号系统中细胞间变异性的起源仍然知之甚少。在这里，我们测量磷酸化MEK和ERK在细胞群中的动态，并使用高通量图像细胞术定量随时间推移的群体异质性水平。我们使用一个统计建模框架，以表明，外在的噪音，特别是来自上游MEK，是导致细胞间ERK磷酸化的变异性，而不是随机性的ERK的磷酸化/去磷酸化的主导因素。我们还表明，在核心模块中没有外部噪声，变量（包括嘈杂的）信号将被忠实地复制下游，但模块内的外部可变性扭曲这些信号，并导致传入信号和ERK活性之间的互信息急剧减少。活性MEK和ERK水平在遗传上相同的细胞之间有很大的差异。建立了一个统计框架来确定这种变异性的原因。分析表明，外源性噪声上游MEK-ERK模块导致细胞变异性模块内外源性变异性扭曲信号细胞信号传导过程可以在遗传上相同的细胞中表现出明显的细胞间变异性，但这种变异性的起源仍然知之甚少。Filippi等人通过结合统计建模方法和高通量图像细胞仪测量，对ERK磷酸化过程中细胞间的变异性进行了全面分析。
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. Active MEK and ERK levels differ profoundly among genetically identical cells A statistical framework is developed to identify the causes of this variability Analysis shows that extrinsic noise upstream MEK-ERK module causes cell variability Within-module extrinsic variability distorts signals Cellular signaling processes can exhibit pronounced cell-to-cell variability in genetically identical cells, but the origins of such variability remain poorly understood. Filippi et al. present a comprehensive analysis of cell-to-cell variability in the ERK phosphorylation process by combining a statistical modeling approach with high-throughput image cytometry measurements.