Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):14485-90. doi: 10.1073/pnas.1018266108. Epub 2011 Aug 15.
Despite large cell-to-cell variations in the concentrations of individual signaling proteins, cells transmit signals correctly. This phenomenon raises the question of what signaling systems do to prevent a predicted high failure rate. Here we combine quantitative modeling, RNA interference, and targeted selective reaction monitoring (SRM) mass spectrometry, and we show for the ubiquitous and fundamental calcium signaling system that cells monitor cytosolic and endoplasmic reticulum (ER) Ca(2+) levels and adjust in parallel the concentrations of the store-operated Ca(2+) influx mediator stromal interaction molecule (STIM), the plasma membrane Ca(2+) pump plasma membrane Ca-ATPase (PMCA), and the ER Ca(2+) pump sarco/ER Ca(2+)-ATPase (SERCA). Model calculations show that this combined parallel regulation in protein expression levels effectively stabilizes basal cytosolic and ER Ca(2+) levels and preserves receptor signaling. Our results demonstrate that, rather than directly controlling the relative level of signaling proteins in a forward regulation strategy, cells prevent transmission failure by sensing the state of the signaling pathway and using multiple parallel adaptive feedbacks.
尽管单个信号蛋白的浓度在细胞间存在很大差异，但细胞仍能正确传递信号。这一现象引发了一个问题，即信号系统采取了什么措施来防止预测的高故障率。在这里，我们结合定量建模、RNA 干扰和靶向选择性反应监测 (SRM) 质谱法，针对普遍存在且基本的钙信号系统进行了研究，结果表明细胞可以监测细胞质和内质网 (ER) Ca(2+) 水平，并平行调整储存操作 Ca(2+) 内流介质基质相互作用分子 (STIM)、质膜 Ca(2+) 泵质膜 Ca-ATP 酶 (PMCA) 和 ER Ca(2+) 泵肌浆/内质网 Ca(2+)-ATP 酶 (SERCA) 的浓度。模型计算表明，这种蛋白质表达水平的联合平行调节有效地稳定了基础细胞质和 ER Ca(2+) 水平，并维持了受体信号。我们的结果表明，细胞不是通过正向调控策略直接控制信号蛋白的相对水平，而是通过感知信号通路的状态并利用多种并行自适应反馈来防止信号传递失败。
