Department of Physiology, McGill University, Montreal, Quebec, Canada.
Department of Physiology, McGill University, Montreal, Quebec, Canada.
Biophys J. 2019 Sep 17;117(6):1057-1073. doi: 10.1016/j.bpj.2019.08.004. Epub 2019 Aug 12.
Cellular migration is a tightly regulated process that involves actin cytoskeleton, adaptor proteins, and integrin receptors. Forces are transmitted extracellularly through protein complexes of these molecules, called adhesions. Adhesions anchor the cell to its substrate, allowing it to migrate. In Chinese hamster ovary cells, three classes of adhesion can be identified: nascent adhesions (NAs), focal complexes, and focal adhesions, ranked here ascendingly based on size and stability. To understand the dynamics and mechanosensitive properties of NAs, a biophysical model of these NAs as colocalized clusters of integrins and adaptor proteins is developed. The model is then analyzed to characterize the dependence of NA area on biophysical parameters that regulate the number of integrins and adaptor proteins within NAs through a mechanosensitive coaggregation mechanism. Our results reveal that NA formation is triggered beyond a threshold of adaptor protein, integrin, or extracellular ligand densities, with these three factors listed in descending order of their relative influence on NA area. Further analysis of the model also reveals that an increase in coaggregation or reductions in integrin mobility inside the adhesion potentiate NA formation. By extending the model to consider the mechanosensitivity of the integrin bond, we identify mechanical stress, rather than mechanical load, as a permissive mechanical parameter that allows for noise-dependent and independent NA assembly, despite both parameters producing a bistable switch possessing a hysteresis. Stochastic simulations of the model confirm these results computationally. This study thus provides insight into the mechanical conditions defining NA dynamics.
细胞迁移是一个受到严格调控的过程，涉及肌动蛋白细胞骨架、衔接蛋白和整合素受体。细胞外的力通过这些分子的蛋白质复合物传递，这些复合物称为黏附。黏附将细胞锚定在其基质上，使其能够迁移。在中华仓鼠卵巢细胞中，可以识别出三类黏附：新生黏附（NAs）、焦点复合物和焦点黏附，这里根据大小和稳定性递增排列。为了了解 NAs 的动力学和力敏特性，开发了一个关于这些 NAs 的生物物理模型，将它们作为整合素和衔接蛋白的共定位簇。然后，通过机械敏感的共聚集机制，对模型进行分析以描述 NA 面积对调节 NAs 内整合素和衔接蛋白数量的生物物理参数的依赖性。我们的结果表明，NA 的形成是在衔接蛋白、整合素或细胞外配体密度的阈值之上触发的，这三个因素按其对 NA 面积的相对影响程度降序排列。对模型的进一步分析还表明，共聚集的增加或黏附内整合素的流动性降低会促进 NA 的形成。通过将模型扩展到考虑整合素键的力敏性，我们确定机械应力而不是机械负荷是允许噪声依赖和独立的 NA 组装的许可机械参数，尽管这两个参数都产生具有滞后的双稳态开关。模型的随机模拟在计算上证实了这些结果。因此，这项研究提供了对定义 NA 动力学的机械条件的深入了解。
