Adherens junctions (AJs) physically link two cells at their contact interface via extracellular homophilic interactions between cadherin molecules and intracellular connections between cadherins and the actomyosin cortex. Both cadherin and actomyosin cytoskeletal dynamics are reciprocally regulated by mechanical and chemical signals, which subsequently determine the strength of cell-cell adhesions and the emergent organization and stiffness of the tissues they form. However, an understanding of the integrated system is lacking. We present a new mechanistic computational model of intercellular junction maturation in a cell doublet to investigate the mechano-chemical crosstalk that regulates AJ formation and homeostasis. The model couples a 2D lattice-based model of cadherin dynamics with a continuum, reaction-diffusion model of the reorganizing actomyosin network through its regulation by Rho signaling at the intercellular junction. We demonstrate that local immobilization of cadherin induces cluster formation in a cis less dependent manner. We further investigate how cadherin and actin regulate and cooperate. By considering the force balance during AJ maturation and the force-sensitive property of the cadherin/F-actin linking molecules, we show that cortical tension applied on the contact rim can explain the ring distribution of cadherin and F-actin on the cell-cell contact of the cell-doublet. Meanwhile, the positive feedback loop between cadherin and F-actin is necessary for maintenance of the ring. Different patterns of cadherin distribution can be observed as an emergent property of disturbances of this feedback loop. We discuss these findings in light of available experimental observations on underlying mechanisms related to cadherin/F-actin binding and the mechanical environment.

中文翻译：

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皮质张力引发E-钙粘着蛋白和F-肌动蛋白之间的正反馈回路

粘附连接（AJs）通过钙粘着蛋白分子之间的细胞外同源相互作用以及钙粘着蛋白与放线菌素皮层之间的细胞内连接，在其接触界面上物理连接两个细胞。钙黏着蛋白和肌动球蛋白的细胞骨架动力学都受到机械和化学信号的相互调节，这些信号随后决定了细胞间粘附的强度以及它们形成的组织的新生组织和刚度。但是，缺乏对集成系统的了解。我们提出了一种新的机制计算模型的细胞联结成熟在细胞双峰中，以研究调节AJ形成和动态平衡的机械化学串扰。该模型将基于2D网格的钙粘蛋白动力学模型与一个连续体耦合在一起，重组肌动球蛋白网络的反应扩散模型，该模型通过细胞间连接处的Rho信号进行调控。我们证明，钙粘着蛋白的局部固定以顺式较少依赖性的方式诱导簇形成。我们进一步研究钙粘蛋白和肌动蛋白如何调节和合作。通过考虑AJ成熟过程中的力平衡和钙黏着蛋白/ F-肌动蛋白连接分子的力敏感特性，我们表明施加在接触缘上的皮质张力可以解释钙黏着蛋白和F-肌动蛋白在细胞上的环分布细胞双联体的接触。同时，钙黏着蛋白和F-肌动蛋白之间的正反馈回路对于维持环是必要的。可以观察到钙黏着蛋白分布的不同模式，作为该反馈回路扰动的一种新兴特征。