Theoretical and experimental analysis links isoform-specific ERK signalling to cell fate decisions.
Theoretical and experimental analysis links isoform-specific ERK signalling to cell fate decisions.
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DOI：
10.1038/msb.2009.91
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发表时间：
2009
影响因子：
9.9
通讯作者：
Klingmueller, Ursula
中科院分区：
文献类型：
--
作者：
Schilling, Marcel;Maiwald, Thomas;Hengl, Stefan;Winter, Dominic;Kreutz, Clemens;Kolch, Walter;Lehmann, Wolf D.;Timmer, Jens;Klingmueller, Ursula
细胞命运的决定是由协调激活的信号传导途径，如细胞外信号调节激酶（ERK）级联，但个别激酶亚型的贡献大多是未知的。通过将来自初级红系祖细胞（集落形成单位红系阶段，CFU-E）中促红细胞生成素诱导的途径活化的定量数据与数学建模相结合，我们预测并实验证实了CFU-E细胞中的分布性ERK磷酸化机制。模型分析显示蝶形信号处理和固有的瞬时信号转导的精氨酸诱导的ERK信号。敏感性分析预测，通过反馈介导的过程，增加一种ERK亚型减少了另一种亚型的激活，这通过蛋白质过表达得到了验证。我们计算了ERK激活的生化不可寻址，但生理相关的配体浓度显示，双磷酸化的ERK 1衰减超过一定的激活水平的增殖，而激活的ERK 2增强增殖与饱和动力学。因此，我们提供了一个早期不可观察的信号动态和细胞命运的决定之间的定量联系。
Cell fate decisions are regulated by the coordinated activation of signalling pathways such as the extracellular signal-regulated kinase (ERK) cascade, but contributions of individual kinase isoforms are mostly unknown. By combining quantitative data from erythropoietin-induced pathway activation in primary erythroid progenitor (colony-forming unit erythroid stage, CFU-E) cells with mathematical modelling, we predicted and experimentally confirmed a distributive ERK phosphorylation mechanism in CFU-E cells. Model analysis showed bow-tie-shaped signal processing and inherently transient signalling for cytokine-induced ERK signalling. Sensitivity analysis predicted that, through a feedback-mediated process, increasing one ERK isoform reduces activation of the other isoform, which was verified by protein over-expression. We calculated ERK activation for biochemically not addressable but physiologically relevant ligand concentrations showing that double-phosphorylated ERK1 attenuates proliferation beyond a certain activation level, whereas activated ERK2 enhances proliferation with saturation kinetics. Thus, we provide a quantitative link between earlier unobservable signalling dynamics and cell fate decisions.
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