Endoplasmic reticulum-plasma membrane contact gradients direct cell migration
成果类型：
Article
署名作者：
Gong, Bo; Johnston, Jake D.; Thiemicke, Alexander; de Marco, Alex; Meyer, Tobias
署名单位：
Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Columbia University; Columbia University
刊物名称：
Nature
ISSN/ISSBN：
0028-5686
DOI：
10.1038/s41586-024-07527-5
发表日期：
2024-07-11
关键词：
front
chemotaxis
proteins
polarity
ptp1b
rear
inhibition
signals
kinase
sites
摘要：
Directed cell migration is driven by the front-back polarization of intracellular signalling 1-3 . Receptor tyrosine kinases and other inputs activate local signals that trigger membrane protrusions at the front 2,4-6 . Equally important is a long-range inhibitory mechanism that suppresses signalling at the back to prevent the formation of multiple fronts 7-9 . 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. The density and size of contact gradients between the endoplasmic reticulum and the plasma membrane control the speed and direction of cell migration by restricting receptor signalling to the front.