Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA.
Science. 2018 Aug 31;361(6405). doi: 10.1126/science.aao3048.
The Ras-Erk (extracellular signal-regulated kinase) pathway encodes information in its dynamics; the duration and frequency of Erk activity can specify distinct cell fates. To enable dynamic encoding, temporal information must be accurately transmitted from the plasma membrane to the nucleus. We used optogenetic profiling to show that both oncogenic B-Raf mutations and B-Raf inhibitors can cause corruption of this transmission, so that short pulses of input Ras activity are distorted into abnormally long Erk outputs. These changes can reshape downstream transcription and cell fates, resulting in improper decisions to proliferate. These findings illustrate how altered dynamic signal transmission properties, and not just constitutively increased signaling, can contribute to cell proliferation and perhaps cancer, and how optogenetic profiling can dissect mechanisms of signaling dysfunction in disease.
Ras-Erk（细胞外信号调节激酶）通路在其动态变化中编码信息；Erk 活性的持续时间和频率可以指定不同的细胞命运。为了实现动态编码，必须将时间信息从质膜准确地传递到细胞核。我们使用光遗传学分析表明，致癌性 B-Raf 突变和 B-Raf 抑制剂都可能导致这种传递的破坏，从而导致输入 Ras 活性的短脉冲被扭曲成异常长的 Erk 输出。这些变化可以重塑下游转录和细胞命运，导致增殖的不当决策。这些发现说明了改变动态信号传输特性，而不仅仅是组成性增加信号，如何有助于细胞增殖，甚至癌症，以及光遗传学分析如何剖析疾病中信号功能障碍的机制。
