Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh EH4 2XR, UK.
Cell Syst. 2016 Jan 27;2(1):38-48. doi: 10.1016/j.cels.2016.01.003.
Dynamic interactions between RhoA and Rac1, members of the Rho small GTPase family, play a vital role in the control of cell migration. Using predictive mathematical modeling, mass spectrometry-based quantitation of network components, and experimental validation in MDA-MB-231 mesenchymal breast cancer cells, we show that a network containing Rac1, RhoA, and PAK family kinases can produce bistable, switch-like responses to a graded PAK inhibition. Using a small chemical inhibitor of PAK, we demonstrate that cellular RhoA and Rac1 activation levels respond in a history-dependent, bistable manner to PAK inhibition. Consequently, we show that downstream signaling, actin dynamics, and cell migration also behave in a bistable fashion, displaying switches and hysteresis in response to PAK inhibition. Our results demonstrate that PAK is a critical component in the Rac1-RhoA inhibitory crosstalk that governs bistable GTPase activity, cell morphology, and cell migration switches.
RhoA 和 Rac1 之间的动态相互作用，Rho 小 GTPase 家族的成员，在控制细胞迁移中起着至关重要的作用。使用预测数学模型、基于质谱的网络成分定量分析和 MDA-MB-231 间充质乳腺癌细胞的实验验证，我们表明包含 Rac1、RhoA 和 PAK 家族激酶的网络可以对 PAK 抑制的梯度产生双稳态、开关样反应。使用 PAK 的一种小分子化学抑制剂，我们证明细胞 RhoA 和 Rac1 的激活水平对 PAK 抑制表现出依赖于历史的双稳态反应。因此，我们表明下游信号转导、肌动蛋白动力学和细胞迁移也以双稳态方式表现出对 PAK 抑制的开关和滞后。我们的结果表明，PAK 是 Rac1-RhoA 抑制性串扰的关键组成部分，该串扰控制双稳态 GTPase 活性、细胞形态和细胞迁移开关。
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