Mahdavi Alborz, Davey Ryan E, Bhola Patrick, Yin Ting, Zandstra Peter W
Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada.
PLoS Comput Biol. 2007 Jul;3(7):e130. doi: 10.1371/journal.pcbi.0030130.
Directing stem cell fate requires knowledge of how signaling networks integrate temporally and spatially segregated stimuli. We developed and validated a computational model of signal transducer and activator of transcription-3 (Stat3) pathway kinetics, a signaling network involved in embryonic stem cell (ESC) self-renewal. Our analysis identified novel pathway responses; for example, overexpression of the receptor glycoprotein-130 results in reduced pathway activation and increased ESC differentiation. We used a systematic in silico screen to identify novel targets and protein interactions involved in Stat3 activation. Our analysis demonstrates that signaling activation and desensitization (the inability to respond to ligand restimulation) is regulated by balancing the activation state of a distributed set of parameters including nuclear export of Stat3, nuclear phosphatase activity, inhibition by suppressor of cytokine signaling, and receptor trafficking. This knowledge was used to devise a temporally modulated ligand delivery strategy that maximizes signaling activation and leads to enhanced ESC self-renewal.
引导干细胞命运需要了解信号网络如何整合时空上分离的刺激。我们开发并验证了一种信号转导和转录激活因子3（Stat3）途径动力学的计算模型，该信号网络参与胚胎干细胞（ESC）的自我更新。我们的分析确定了新的途径反应；例如，受体糖蛋白-130的过表达导致途径激活减少和ESC分化增加。我们使用系统的计算机筛选来识别参与Stat3激活的新靶点和蛋白质相互作用。我们的分析表明，信号激活和脱敏（无法对配体再刺激作出反应）是通过平衡一组分布式参数的激活状态来调节的，这些参数包括Stat3的核输出、核磷酸酶活性、细胞因子信号抑制因子的抑制作用以及受体运输。这些知识被用于设计一种时间调制的配体递送策略，该策略可使信号激活最大化并导致ESC自我更新增强。
