Bistability in the Rac1, PAK, and RhoA Signaling Network Drives Actin Cytoskeleton Dynamics and Cell Motility Switches.
Bistability in the Rac1, PAK, and RhoA Signaling Network Drives Actin Cytoskeleton Dynamics and Cell Motility Switches.
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DOI：
10.1016/j.cels.2016.01.003
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发表时间：
2016-01-27
期刊：
影响因子：
9.3
通讯作者：
Kholodenko BN
中科院分区：
文献类型：
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作者：
Byrne KM;Monsefi N;Dawson JC;Degasperi A;Bukowski-Wills JC;Volinsky N;Dobrzyński M;Birtwistle MR;Tsyganov MA;Kiyatkin A;Kida K;Finch AJ;Carragher NO;Kolch W;Nguyen LK;von Kriegsheim A;Kholodenko BN
RhoA和Rac 1是Rho小GTdR家族的成员，它们之间的动态相互作用在控制细胞迁移中起着至关重要的作用。使用预测数学建模，基于质谱的网络组件的定量，并在MDA-MB-231间充质乳腺癌细胞中进行实验验证，我们表明，包含Rac 1，RhoA和PAK家族激酶的网络可以对分级PAK抑制产生类似开关的响应。使用一个小的化学抑制剂PAK，我们表明，细胞RhoA和Rac 1激活水平响应的历史依赖性，PAK抑制的方式。因此，我们表明，下游信号，肌动蛋白动力学和细胞迁移也表现在一个快速的方式，显示开关和滞后反应PAK抑制。我们的研究结果表明，PAK是Rac 1-RhoA抑制性串扰的一个关键组成部分，它控制着细胞生长因子的活性、细胞形态和细胞迁移开关。RhoA和Rac 1通过双负反馈环连接。模型预测了在生理参数范围内系统的双稳态Rac 1和RhoA活性对PAK抑制的响应。在PAK抑制后，肌动蛋白动力学、细胞形态和迁移显示滞后。数学模型和实验表明，RhoA、Rac 1、肌动蛋白动力学、细胞形态和迁移对扰动的响应是不稳定的。
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 and Rac1 are linked by a double-negative feedback loop A model predicts bistability of the system within a physiological parameter range Rac1 and RhoA activity is bistable in response to PAK inhibition Actin dynamics, cell morphology, and migration show hysteresis upon PAK inhibition A mathematical model and experiments demonstrate that RhoA, Rac1, actin dynamics, cell morphology, and migration respond in a bistable manner to perturbations.