Molecular Origin and Functional Consequences of Digital Signaling and Hysteresis During Ras Activation in Lymphocytes
Molecular Origin and Functional Consequences of Digital Signaling and Hysteresis During Ras Activation in Lymphocytes
复制标题
DOI：
10.1126/scisignal.266pt2
复制
发表时间：
2009-04-14
影响因子：
7.3
通讯作者：
Roose, Jeroen
中科院分区：
文献类型：
--
作者：
Chakraborty, Arup K.;Das, Jayajit;Roose, Jeroen
Ras蛋白的激活是不同细胞类型中功能决定的基础。两种分子Ras-GRP和SOS（分别为Ras-鸟嘌呤核苷酸释放蛋白和Son of Sevenless）催化淋巴细胞中的Ras活化。活性Ras与SOS的变构口袋的结合显著增加SOS的活性。因此，存在调节SOS的正反馈回路。结合计算机模拟和体外研究，我们证明了淋巴细胞中的“数字”信号（细胞是“开”或“关”）是基于SOS的变构调节。SOS反馈回路导致剂量-反应曲线中的滞后，这可能使T细胞能够表现出对过去与抗原相遇的“记忆”。单独Ras-GRP的Ras激活是“类似的”（响应于刺激幅度的增加的激活的分级增加）。我们描述了互补模拟（Ras-GRP）和数字（SOS）途径如何作用于Ras，以有效地将模拟输入转换为数字输出，并预测数字信号在淋巴细胞功能和发育中的重要性。
Activation of Ras proteins underlies functional decisions in diverse cell types. Two molecules, Ras-GRP and SOS (Ras-guanine nucleotide-releasing protein and Son of Sevenless, respectively), catalyze Ras activation in lymphocytes. Binding of active Ras to the allosteric pocket of SOS markedly increases the activity of SOS. Thus, there is a positive feedback loop regulating SOS. Combining in silico and in vitro studies, we demonstrate that "digital" signaling in lymphocytes (cells are "on" or "off") is predicated on this allosteric regulation of SOS. The SOS feedback loop leads to hysteresis in the dose-response curve, which may enable T cells to exhibit "memory" of past encounters with antigen. Ras activation by Ras-GRP alone is "analog" (a graded increase in activation in response to an increase in the amplitude of the stimulus). We describe how the complementary analog (Ras-GRP) and digital (SOS) pathways act on Ras to efficiently convert analog input to digital output and make predictions regarding the importance of digital signaling in lymphocyte function and development.