Cell migration requires cells to establish front–back polarity, a process regulated by multiple signalling inputs that drive actin polymerization and the localized formation of membrane protrusions at the leading edge of the cell. How the formation of multiple fronts is prevented remains poorly understood but is thought to involve a long-range inhibitory mechanism. In a recent study in Nature, Gong et al. report that the front-to-back polarized distribution of endoplasmic reticulum (ER)–plasma membrane (PM) contact sites provides a mechanism to restrict migration-mediating signalling to the front.

The authors speculated that this polarized structure might be based on contact sites between the ER and the PM. Using the ER–PM contacts marker MAPPER, which consists of a transmembrane domain anchored in the ER and a C-terminal motif that binds to PM lipids if the two membranes are within less than 25 nm of each other, they found a polarized pattern of ER–PM contacts in multiple migrating cell lines, with higher numbers of contacts at the cell cortex opposite the migration front. Analysis of the endogenous staining pattern of the synaptotagmin E-Syt1, which is responsible for maintaining these contact sites, confirmed the polarized distribution of ER–PM contacts.