Mechanical and biochemical cues intricately activate Yes-associated protein (YAP), which is pivotal for the cellular responses to these stimuli. Recent findings reveal an unexplored role of YAP in influencing the apoptotic process. It has been shown that, on soft matrices, YAP is recruited to small adhesions, phosphorylated at Y357, and translocated into the nucleus triggering apoptosis. Interestingly, YAP Y357 phosphorylation is significantly reduced in larger mature focal adhesions on stiff matrices. Building upon these novel insights, we have developed a stochastic model to delve deeper into the complex dynamics of YAP phosphorylation within integrin adhesions. Our findings emphasize several key points: firstly, increasing the cytosolic diffusion rate of YAP correlates with higher levels of phosphorylated YAP (pYAP); secondly, increasing the number of binding sites and distributing them across the membrane surface, mimicking smaller adhesions, leads to higher pYAP levels, particularly at lower diffusion rates. Moreover, we show that the binding and release rate of YAP to adhesions as well as adhesion lifetimes significantly influence the size effect of adhesion-induced YAP phosphorylation. The results highlight the complex and dynamic interplay between adhesion lifetime, the rate of pYAP unbinding from adhesions, and dephosphorylation rates, collectively shaping overall pYAP levels. In summary, our work advances the understanding of YAP mechanotransduction and opens avenues for experimental validation.

中文翻译：

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整合素粘附内的 YAP 磷酸化：来自计算模型的见解


机械和生化线索错综复杂地激活 Yes 相关蛋白 （YAP），这对于细胞对这些刺激的反应至关重要。最近的研究结果揭示了 YAP 在影响凋亡过程中尚未探索的作用。已经表明，在软基质上，YAP 被募集到小粘附处，在 Y357 位点被磷酸化，并转位到细胞核中，从而触发细胞凋亡。有趣的是，YAP Y357 磷酸化在刚性基质上较大的成熟黏着斑中显著降低。基于这些新的见解，我们开发了一个随机模型，以更深入地研究整合素粘附内 YAP 磷酸化的复杂动力学。我们的研究结果强调了几个关键点：首先，YAP 的胞质弥散速率增加与磷酸化 YAP （pYAP） 水平升高相关;其次，增加结合位点的数量并将它们分布在膜表面，模拟较小的粘附，导致更高的 pYAP 水平，尤其是在较低的扩散速率下。此外，我们表明 YAP 与粘附的结合和释放速率以及粘附寿命显着影响粘附诱导的 YAP 磷酸化的尺寸效应。结果突出了粘附寿命、pYAP 从粘附中分离的速率和去磷酸化速率之间的复杂和动态相互作用，共同塑造了整体 pYAP 水平。总之，我们的工作促进了对 YAP 机械转导的理解，并为实验验证开辟了途径。