PDF(Pubmed)
Abstract：
Cells use signaling pathways to sense and respond to their environments. The transforming growth factor-β (TGF-β) pathway produces context-specific responses. Here, we combined modeling and experimental analysis to study the dependence of the output of the TGF-β pathway on the abundance of signaling molecules in the pathway. We showed that the TGF-β pathway processes the variation of TGF-β receptor abundance using Liebig\'s law of the minimum, meaning that the output-modifying factor is the signaling protein that is most limited, to determine signaling responses across cell types and in single cells. We found that the abundance of either the type I (TGFBR1) or type II (TGFBR2) TGF-β receptor determined the responses of cancer cell lines, such that the receptor with relatively low abundance dictates the response. Furthermore, nuclear SMAD2 signaling correlated with the abundance of TGF-β receptor in single cells depending on the relative expression levels of TGFBR1 and TGFBR2. A similar control principle could govern the heterogeneity of signaling responses in other signaling pathways.
摘要：
细胞使用信号通路来感知和响应它们的环境。转化生长因子-β(TGF-β)途径产生背景特异性应答。这里,我们结合建模和实验分析来研究TGF-β通路的输出对通路中信号分子丰度的依赖性。我们发现TGF-β通路是用最小的李比格定律来处理TGF-β受体丰度的变化,这意味着输出修饰因子是最有限的信号蛋白，以确定跨细胞类型和单个细胞中的信号应答。我们发现I型（TGFBR1）或II型（TGFBR2）TGF-β受体的丰度决定了癌细胞系的反应。这样具有相对低丰度的受体决定了反应。此外，核SMAD2信号传导与单个细胞中TGF-β受体的丰度相关，取决于TGFBR1和TGFBR2的相对表达水平。类似的控制原理可以控制其他信号通路中信号应答的异质性。
