美国威尔康奈尔医学院Tobias Meyer和Bo Gong共同合作，近期取得重要工作进展。他们研究提出，内质网-质膜接触梯度引导细胞迁移。相关研究成果2024年6月12日在线发表于《自然》杂志上。

据介绍，定向细胞迁移是由细胞内信号的前后极化驱动的。受体酪氨酸激酶和其他输入激活局部信号，触发前部的膜突起。同样重要的是一种长程抑制机制，它抑制后部的信号传导，以防止多个前沿的形成。然而，这种机制的身份是未知的。

研究人员报道了内质网-质膜（ER–PM）接触位点在单个和集体迁移细胞中极化。后部这些ER–PM接触密度的增加为ER驻留的PTP1B磷酸酶提供了更多接触PM底物的途径，从而将受体信号传导限制在前部并指导细胞迁移。ER–PM接触的极化是由于ER的微管调节极化，前部有更多富含RTN4的弯曲ER，后部有更多富含CLIMP63的扁平ER。由此产生的ER曲率梯度导致仅在前部的ER–PM接触较小且不稳定。这些接触向后流动，并在背面生长为大而稳定的接触，以形成前-后ER–PM接触梯度。

总之，这一研究表明，ER–PM接触梯度介导的结构极性使细胞信号极化，指导细胞迁移并延长细胞迁移。

附：英文原文

Title: Endoplasmic reticulum–plasma membrane contact gradients direct cell migration

Author: Gong, Bo, Johnston, Jake D., Thiemicke, Alexander, de Marco, Alex, Meyer, Tobias

Issue&Volume: 2024-06-12

Abstract: Directed cell migration is driven by the front–back polarization of intracellular signalling1,2,3. Receptor tyrosine kinases and other inputs activate local signals that trigger membrane protrusions at the front2,4,5,6. Equally important is a long-range inhibitory mechanism that suppresses signalling at the back to prevent the formation of multiple fronts7,8,9. However, the identity of this mechanism is unknown. Here we report that endoplasmic reticulum–plasma membrane (ER–PM) contact sites are polarized in single and collectively migrating cells. The increased density of these ER–PM contacts at the back provides the ER-resident PTP1B phosphatase more access to PM substrates, which confines receptor signalling to the front and directs cell migration. Polarization of the ER–PM contacts is due to microtubule-regulated polarization of the ER, with more RTN4-rich curved ER at the front and more CLIMP63-rich flattened ER at the back. The resulting ER curvature gradient leads to small and unstable ER–PM contacts only at the front. These contacts flow backwards and grow to large and stable contacts at the back to form the front–back ER–PM contact gradient. Together, our study suggests that the structural polarity mediated by ER–PM contact gradients polarizes cell signalling, directs cell migration and prolongs cell migration.

DOI: 10.1038/s41586-024-07527-5

Source: https://www.nature.com/articles/s41586-024-07527-5