Endoplasmic reticulum-plasma membrane contact gradients direct cell migration.

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.