Department of Pharmacology, Green Center for Systems Biology, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cell. 2012 May 25;149(5):1073-83. doi: 10.1016/j.cell.2012.03.044.
How complex signaling networks shape highly coordinated, multistep cellular responses is poorly understood. Here, we made use of a network-perturbation approach to investigate causal influences, or "crosstalk," among signaling modules involved in the cytoskeletal response of neutrophils to chemoattractant. We quantified the intensity and polarity of cytoskeletal marker proteins over time to characterize stereotyped cellular responses. Analyzing the effects of network disruptions revealed that, not only does crosstalk evolve rapidly during polarization, but also that intensity and polarity responses are influenced by different patterns of crosstalk. Interestingly, persistent crosstalk is arranged in a surprisingly simple circuit: a linear cascade from front to back to microtubules influences intensities, and a feed-forward network in the reverse direction influences polarity. Our approach provided a rational strategy for decomposing a complex, dynamically evolving signaling system and revealed evolving paths of causal influence that shape the neutrophil polarization response.
信号网络如何塑造高度协调的多步骤细胞反应尚不清楚。在这里，我们利用网络干扰方法来研究细胞骨架反应中涉及的信号模块之间的因果影响或“串扰”。我们随时间量化细胞骨架标记蛋白的强度和极性，以表征刻板的细胞反应。分析网络干扰的影响表明，不仅在极化过程中串扰迅速演变，而且强度和极性反应也受到不同模式的串扰影响。有趣的是，持续的串扰以一种令人惊讶的简单方式排列：从前到后到微管的线性级联影响强度，而相反方向的前馈网络影响极性。我们的方法为分解复杂的、动态演变的信号系统提供了一种合理的策略，并揭示了影响中性粒细胞极化反应的因果影响的演变路径。
