Division of Systems Biology of Signal Transduction, DKFZ-ZMBH Alliance, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, Germany.
Mol Syst Biol. 2011 Jul 19;7:516. doi: 10.1038/msb.2011.50.
Cellular signal transduction is governed by multiple feedback mechanisms to elicit robust cellular decisions. The specific contributions of individual feedback regulators, however, remain unclear. Based on extensive time-resolved data sets in primary erythroid progenitor cells, we established a dynamic pathway model to dissect the roles of the two transcriptional negative feedback regulators of the suppressor of cytokine signaling (SOCS) family, CIS and SOCS3, in JAK2/STAT5 signaling. Facilitated by the model, we calculated the STAT5 response for experimentally unobservable Epo concentrations and provide a quantitative link between cell survival and the integrated response of STAT5 in the nucleus. Model predictions show that the two feedbacks CIS and SOCS3 are most effective at different ligand concentration ranges due to their distinct inhibitory mechanisms. This divided function of dual feedback regulation enables control of STAT5 responses for Epo concentrations that can vary 1000-fold in vivo. Our modeling approach reveals dose-dependent feedback control as key property to regulate STAT5-mediated survival decisions over a broad range of ligand concentrations.
细胞信号转导受多种反馈机制控制，以引发稳健的细胞决策。然而，个别反馈调节剂的具体贡献仍不清楚。基于原代红细胞祖细胞中的广泛的时间分辨数据集，我们建立了一个动态途径模型，以剖析细胞因子信号转导抑制剂（SOCS）家族的两个转录负反馈调节剂 CIS 和 SOCS3 在 JAK2/STAT5 信号中的作用。借助该模型，我们计算了实验上不可观测的 Epo 浓度下的 STAT5 反应，并在细胞核中提供了 STAT5 整体反应与细胞存活之间的定量联系。模型预测表明，由于其不同的抑制机制，两种反馈 CIS 和 SOCS3 在不同的配体浓度范围内最有效。这种双重反馈调节的分工功能使 STAT5 对 Epo 浓度的反应能够在体内变化 1000 倍的范围内得到控制。我们的建模方法揭示了剂量依赖性反馈控制是调节 STAT5 介导的存活决策的关键特性，其涉及广泛的配体浓度范围。
