McClean Megan N, Mody Areez, Broach James R, Ramanathan Sharad
FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Nat Genet. 2007 Mar;39(3):409-14. doi: 10.1038/ng1957. Epub 2007 Jan 28.
Cells must respond specifically to different environmental stimuli in order to survive. The signal transduction pathways involved in sensing these stimuli often share the same or homologous proteins. Despite potential cross-wiring, cells show specificity of response. We show, through modeling, that the physiological response of such pathways exposed to simultaneous and temporally ordered inputs can demonstrate system-level mechanisms by which pathways achieve specificity. We apply these results to the hyperosmolar and pheromone mitogen-activated protein (MAP) kinase pathways in the yeast Saccharomyces cerevisiae. These two pathways specifically sense osmolar and pheromone signals, despite sharing a MAPKKK, Ste11, and having homologous MAPKs (Fus3 and Hog1). We show that in a single cell, the pathways are bistable over a range of inputs, and the cell responds to only one stimulus even when exposed to both. Our results imply that these pathways achieve specificity by filtering out spurious cross-talk through mutual inhibition. The variability between cells allows for heterogeneity of the decisions.
细胞必须对不同的环境刺激做出特异性反应才能存活。参与感知这些刺激的信号转导通路通常共享相同或同源的蛋白质。尽管存在潜在的交叉连接，但细胞仍表现出反应的特异性。我们通过建模表明，暴露于同时且按时间顺序排列的输入的此类通路的生理反应可以展示通路实现特异性的系统水平机制。我们将这些结果应用于酿酒酵母中的高渗和信息素丝裂原活化蛋白（MAP）激酶通路。这两条通路尽管共享一个MAPKKK（Ste11）且具有同源的MAPK（Fus3和Hog1），但它们能特异性地感知渗透压和信息素信号。我们表明，在单个细胞中，这些通路在一系列输入范围内是双稳态的，并且即使同时暴露于两种刺激，细胞也仅对其中一种刺激做出反应。我们的结果表明，这些通路通过相互抑制滤除虚假的串扰来实现特异性。细胞之间的变异性允许决策的异质性。
