Desmosomes have a central role in mediating extracellular adhesion between cells, but they also coordinate other biological processes such as proliferation, differentiation, apoptosis and migration. In particular, several lines of evidence have implicated desmosomal proteins in regulating the actin cytoskeleton and attachment to the extracellular matrix, indicating signaling crosstalk between cell–cell junctions and cell–matrix adhesions. In our study, we found that cells lacking the desmosomal cadherin Desmoglein-2 (Dsg2) displayed a significant increase in spreading area on both fibronectin and collagen, compared to control A431 cells. Intriguingly, this effect was observed in single spreading cells, indicating that Dsg2 can exert its effects on cell spreading independent of cell–cell adhesion. We hypothesized that Dsg2 may mediate cell–matrix adhesion via control of Rap1 GTPase, which is well known as a central regulator of cell spreading dynamics. We show that Rap1 activity is elevated in Dsg2 knockout cells, and that Dsg2 harnesses Rap1 and downstream TGFβ signaling to influence both cell spreading and focal adhesion protein phosphorylation. Further analysis implicated the Rap GEF PDZ-GEF2 in mediating Dsg2-dependent cell spreading. These data have identified a novel role for Dsg2 in controlling cell spreading, providing insight into the mechanisms via which cadherins exert non-canonical junction-independent effects.

桥粒在介导细胞间的细胞外粘附方面发挥着核心作用，但它们也协调其他生物过程，如增殖、分化、凋亡和迁移。特别是，一些证据表明桥粒蛋白参与调节肌动蛋白细胞骨架和细胞外基质的附着，表明细胞 - 细胞连接和细胞 - 基质粘附之间的信号串扰。在我们的研究中，我们发现与对照 A431 细胞相比，缺乏桥粒钙粘蛋白 Desmoglein-2 (Dsg2) 的细胞在纤连蛋白和胶原蛋白上的扩散面积均显着增加。有趣的是，在单个扩散细胞中观察到了这种效应，表明 Dsg2 可以独立于细胞 - 细胞粘附对细胞扩散发挥作用。我们假设 Dsg2 可能通过控制 Rap1 GTPase 介导细胞 - 基质粘附，Rap1 GTPase 是众所周知的细胞扩散动力学的中心调节剂。我们表明 Rap1 活性在 Dsg2 敲除细胞中升高，并且 Dsg2 利用 Rap1 和下游 TGFβ 信号传导来影响细胞扩散和粘着斑蛋白磷酸化。进一步分析表明 Rap GEF PDZ-GEF2 介导 Dsg2 依赖性细胞扩散。这些数据确定了 Dsg2 在控制细胞扩散方面的新作用，提供了对钙粘蛋白发挥非经典连接独立效应的机制的深入了解。并且 Dsg2 利用 Rap1 和下游 TGFβ 信号传导来影响细胞扩散和粘着斑蛋白磷酸化。进一步分析表明 Rap GEF PDZ-GEF2 介导 Dsg2 依赖性细胞扩散。这些数据已经确定了 Dsg2 在控制细胞扩散方面的新作用，提供了对钙粘蛋白发挥非经典连接独立效应的机制的深入了解。并且 Dsg2 利用 Rap1 和下游 TGFβ 信号传导来影响细胞扩散和粘着斑蛋白磷酸化。进一步分析表明 Rap GEF PDZ-GEF2 介导 Dsg2 依赖性细胞扩散。这些数据已经确定了 Dsg2 在控制细胞扩散方面的新作用，提供了对钙粘蛋白发挥非经典连接独立效应的机制的深入了解。