School of Biology, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA.
Cells. 2023 Jun 15;12(12):1638. doi: 10.3390/cells12121638.
Rho-GTPases are central regulators within a complex signaling network that controls cytoskeletal organization and cell movement. The network includes multiple GTPases, such as the most studied Rac1, Cdc42, and RhoA, along with their numerous effectors that provide mutual regulation through feedback loops. Here we investigate the temporal and spatial relationship between Rac1 and Cdc42 during membrane ruffling, using a simulation model that couples GTPase signaling with cell morphodynamics and captures the GTPase behavior observed with FRET-based biosensors. We show that membrane velocity is regulated by the kinetic rate of GTPase activation rather than the concentration of active GTPase. Our model captures both uniform and polarized ruffling. We also show that cell-type specific time delays between Rac1 and Cdc42 activation can be reproduced with a single signaling motif, in which the delay is controlled by feedback from Cdc42 to Rac1. The resolution of our simulation output matches those of time-lapsed recordings of cell dynamics and GTPase activity. Our data-driven modeling approach allows us to validate simulation results with quantitative precision using the same pipeline for the analysis of simulated and experimental data.
Rho-GTPases 是控制细胞骨架组织和细胞运动的复杂信号网络中的核心调节剂。该网络包括多个 GTPases，如最受研究的 Rac1、Cdc42 和 RhoA，以及它们众多的效应物，通过反馈环提供相互调节。在这里，我们使用一种将 GTPase 信号与细胞形态动力学耦合的模拟模型，研究了在细胞膜皱襞过程中 Rac1 和 Cdc42 之间的时空关系，该模型捕捉了基于 FRET 的生物传感器观察到的 GTPase 行为。我们表明，膜速度受 GTPase 激活的动力学速率而不是活性 GTPase 的浓度调节。我们的模型可以捕捉到均匀和极化的皱襞。我们还表明，具有单个信号基序的 Rac1 和 Cdc42 激活之间的细胞类型特定时间延迟可以重现，其中延迟受 Cdc42 对 Rac1 的反馈控制。我们的模拟输出分辨率与细胞动力学和 GTPase 活性的时移记录相匹配。我们的数据驱动建模方法允许我们使用相同的分析模拟和实验数据的管道，以定量精度验证模拟结果。
