Endothelial cell migration is essential to angiogenesis, enabling the outgrowth of new blood vessels both in physiological and pathological contexts. Migration requires the activation of several signaling pathways, the elucidation of which expands the opportunity to develop new drugs to be used in antiangiogenic therapy. In the proliferating endothelium, the interaction between the transmembrane glycoprotein CD93 and the extracellular matrix activates signaling pathways that regulate cell adhesion, migration, and vascular maturation. Here we identify a pathway, comprising CD93, the adaptor proteins Cbl and Crk, and the small GTPases Rac1, Cdc42, and RhoA, which we propose acts as a regulator of cytoskeletal movements responsible for endothelial cell migration. In this framework, phosphorylation of Cbl on tyrosine 774 leads to the interaction with Crk, which acts as a downstream integrator in the CD93-mediated signaling regulating cell polarity and migration. Moreover, confocal microscopy analyses of GTPase biosensors show that CD93 drives coordinated activation of Rho-proteins at the cell edge of migratory endothelial cells. In conclusion, together with the demonstration of the key contribution of CD93 to the migratory process in living cells, these findings suggest that the signaling triggered by CD93 converges to the activation and modulation of the Rho GTPase signaling pathways regulating cell dynamics.

内皮细胞迁移对血管生成至关重要，使新血管在生理和病理环境中都能长出。迁移需要激活几个信号通路，对其的阐明扩大了开发用于抗血管生成治疗的新药的机会。在增殖的内皮中，跨膜糖蛋白 CD93 和细胞外基质之间的相互作用激活了调节细胞粘附、迁移和血管成熟的信号通路。在这里，我们确定了一个途径，包括 CD93、衔接蛋白 Cbl 和 Crk，以及小 GTPases Rac1、Cdc42 和 RhoA，我们建议它们充当负责内皮细胞迁移的细胞骨架运动的调节剂。在这个框架下，酪氨酸 774 上 Cbl 的磷酸化导致与 Crk 的相互作用，后者在 CD93 介导的调节细胞极性和迁移的信号传导中充当下游整合子。此外，GTPase 生物传感器的共聚焦显微镜分析表明，CD93 驱动迁移内皮细胞细胞边缘的 Rho 蛋白的协调激活。总之，连同 CD93 对活​​细胞迁移过程的关键贡献的证明，这些发现表明由 CD93 触发的信号传导收敛于调节细胞动力学的 Rho GTPase 信号通路的激活和调节。GTPase 生物传感器的共聚焦显微镜分析表明，CD93 在迁移内皮细胞的细胞边缘驱动 Rho 蛋白的协调激活。总之，连同 CD93 对活​​细胞迁移过程的关键贡献的证明，这些发现表明由 CD93 触发的信号传导收敛于调节细胞动力学的 Rho GTPase 信号通路的激活和调节。GTPase 生物传感器的共聚焦显微镜分析表明，CD93 在迁移内皮细胞的细胞边缘驱动 Rho 蛋白的协调激活。总之，连同 CD93 对活​​细胞迁移过程的关键贡献的证明，这些发现表明由 CD93 触发的信号传导收敛于调节细胞动力学的 Rho GTPase 信号通路的激活和调节。