Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
Proc Natl Acad Sci U S A. 2017 Apr 4;114(14):E2975-E2982. doi: 10.1073/pnas.1611428114. Epub 2017 Mar 20.
How signaling pathways function reliably despite cellular variation remains a question in many systems. In the transforming growth factor-β (Tgf-β) pathway, exposure to ligand stimulates nuclear localization of Smad proteins, which then regulate target gene expression. Examining Smad3 dynamics in live reporter cells, we found evidence for fold-change detection. Although the level of nuclear Smad3 varied across cells, the fold change in the level of nuclear Smad3 was a more precise outcome of ligand stimulation. The precision of the fold-change response was observed throughout the signaling duration and across Tgf-β doses, and significantly increased the information transduction capacity of the pathway. Using single-molecule FISH, we further observed that expression of Smad3 target genes (, , and ) correlated more strongly with the fold change, rather than the level, of nuclear Smad3. These findings suggest that some target genes sense Smad3 level relative to background, as a strategy for coping with cellular noise.
尽管细胞间存在差异，但信号通路如何可靠地发挥作用，在许多系统中仍是一个问题。在转化生长因子-β（TGF-β）信号通路中，配体的暴露会刺激 Smad 蛋白的核定位，然后调节靶基因的表达。在活报告细胞中研究 Smad3 的动力学，我们发现了折叠变化检测的证据。尽管核 Smad3 的水平在细胞间存在差异，但核 Smad3 水平的折叠变化是配体刺激更精确的结果。这种折叠变化反应的精度在整个信号持续时间和 TGF-β剂量范围内都可以观察到，显著提高了该途径的信息传递能力。通过单分子 FISH，我们进一步观察到 Smad3 靶基因（、和）的表达与核 Smad3 的折叠变化而非水平相关性更强。这些发现表明，一些靶基因感知 Smad3 水平相对于背景，作为应对细胞噪声的一种策略。
