Temporal perturbation of ERK dynamics reveals network architecture of FGF2/MAPK signaling.,Molecular Systems Biology

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Temporal perturbation of ERK dynamics reveals network architecture of FGF2/MAPK signaling.
Molecular Systems Biology ( IF 8.5 ) Pub Date : 2019-11-01 , DOI: 10.15252/msb.20198947
Yannick Blum ₁ , Jan Mikelson ₂ , Maciej Dobrzyński ₁ , Hyunryul Ryu ₃ , Marc-Antoine Jacques ₁ , Noo Li Jeon ₃ , Mustafa Khammash ₂ , Olivier Pertz ₁

Affiliation

Stimulation of PC-12 cells with epidermal (EGF) versus nerve (NGF) growth factors (GFs) biases the distribution between transient and sustained single-cell ERK activity states, and between proliferation and differentiation fates within a cell population. We report that fibroblast GF (FGF2) evokes a distinct behavior that consists of a gradually changing population distribution of transient/sustained ERK signaling states in response to increasing inputs in a dose response. Temporally controlled GF perturbations of MAPK signaling dynamics applied using microfluidics reveal that this wider mix of ERK states emerges through the combination of an intracellular feedback, and competition of FGF2 binding to FGF receptors (FGFRs) and heparan sulfate proteoglycan (HSPG) co-receptors. We show that the latter experimental modality is instructive for model selection using a Bayesian parameter inference. Our results provide novel insights into how different receptor tyrosine kinase (RTK) systems differentially wire the MAPK network to fine-tune fate decisions at the cell population level.

中文翻译：

ERK 动态的时间扰动揭示了 FGF2/MAPK 信号传导的网络结构。

用表皮 (EGF) 与神经 (NGF) 生长因子 (GF) 刺激 PC-12 细胞会导致瞬时和持续单细胞 ERK 活性状态之间的分布以及细胞群内增殖和分化命运之间的分布产生偏差。我们报告说，成纤维细胞 GF (FGF2) 会引起一种独特的行为，其中包括随着剂量反应输入的增加而逐渐改变瞬时/持续 ERK 信号状态的群体分布。使用微流体对 MAPK 信号动力学进行时间控制的 GF 扰动表明，这种更广泛的 ERK 状态混合是通过细胞内反馈以及 FGF2 与 FGF 受体 (FGFR) 和硫酸乙酰肝素蛋白聚糖 (HSPG) 共受体结合的竞争的组合而出现的。我们表明，后一种实验模式对于使用贝叶斯参数推断的模型选择具有指导意义。我们的结果提供了关于不同受体酪氨酸激酶（RTK）系统如何差异化地连接 MAPK 网络以在细胞群体水平上微调命运决策的新见解。

更新日期：2019-11-20

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