Rho和YAP介导的细胞力学信号转导的时空模型
Spatiotemporal model of cellular mechanotransduction via Rho and YAP
摘要：
细胞如何感知和响应机械刺激仍然是一个悬而未决的问题。最近的研究发现，Yes相关蛋白（YAP）在细胞核和细胞质之间的转位是感受机械力和调节机械力转导的中心机制。我们制定了一个时空模型的mechanotransduction信号通路，包括耦合的YAP与细胞力产生机械通过Rho家族的GTP酶。考虑到单个Rho蛋白（GTP/GDP结合）和YAP（非磷酸化/磷酸化）的活性和非活性形式，我们通过其核定位研究了由于活性Rho和YAP激活引起的细胞极化之间的串扰。对于固定的机械刺激，我们的模型预测固定的细胞核与细胞质的YAP比例与实验数据一致，在不同的粘附细胞面积。通过考虑最近报道的阳性和阴性YAP-Rho反馈，我们进一步预测YAP核质比的衰减甚至持续振荡。扩展的框架随时间变化的机械刺激，模拟周期性拉伸和压缩，我们表明，YAP核质比的时间依赖性如下的周期性机械刺激。该模型提出了理解时空YAP机械转导的第一个框架之一，提供了几个可能的YAP本地化动力学的预测，并提出了实验和理论研究的新方向。
英文摘要：
How cells sense and respond to mechanical stimuli remains an open question. Recent advances have identified the translocation of Yes-associated protein (YAP) between nucleus and cytoplasm as a central mechanism for sensing mechanical forces and regulating mechanotransduction. We formulate a spatiotemporal model of the mechanotransduction signalling pathway that includes coupling of YAP with the cell force-generation machinery through the Rho family of GTPases. Considering the active and inactive forms of a single Rho protein (GTP/GDP-bound) and of YAP (non-phosphorylated/phosphorylated), we study the cross-talk between cell polarization due to active Rho and YAP activation through its nuclear localization. For fixed mechanical stimuli, our model predicts stationary nuclear-to-cytoplasmic YAP ratios consistent with experimental data at varying adhesive cell area. We further predict damped and even sustained oscillations in the YAP nuclear-to-cytoplasmic ratio by accounting for recently reported positive and negative YAP-Rho feedback. Extending the framework to time-varying mechanical stimuli that simulate cyclic stretching and compression, we show that the YAP nuclear-to-cytoplasmic ratio's time dependence follows that of the cyclic mechanical stimulus. The model presents one of the first frameworks for understanding spatiotemporal YAP mechanotransduction, providing several predictions of possible YAP localization dynamics, and suggesting new directions for experimental and theoretical studies.
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