ERK builds a population of short-lived nascent adhesions that produce persistent edge protrusion and cell migration

Cell migration is realized through the fast and persistent protrusion of a leading edge in the direction of movement. The actin and adhesion structures that build edge protrusions are integrated such that pro-migration signaling pathways must control both assemblies to induce protrusion. Understanding the contribution of adhesion regulation has been complicated by the inability to selectively assay the nascent adhesions that promote edge protrusion. Here, we dissect how the core RAS[->]RAF[->]MEK[->]ERK pathways control of nascent adhesions contributes to edge protrusion and cell migration by targeting an ERK FRET biosensor to adhesions and quantifying ERKs spatial and temporal activity. We find that ERK is activated in the assembling, membrane-proximal region of nascent adhesions through adhesion scaffold paxillin, which interacts with the ERK activator MEK. Tracking nascent adhesion dynamics during cell migration showed that ERK promotes both nascent adhesion assembly and disassembly to create a population of nascent adhesions with short lifetimes. MEK inhibition is partially complemented by expression of a talin R8vvv mutant that increases the nascent adhesion population, demonstrating the significance of ERKs adhesion regulation for edge protrusion and migration persistence. These findings suggest that when new adhesions initiate, the ERK activation level dictates adhesion assembly and disassembly rates to specifically build nascent adhesions that rapidly turnover, an adhesion population that promotes protrusion persistence and migration. SignificanceCell migration is essential for development, healing, and cancer spread. To move, cells need to build and break tiny structures called nascent adhesions, specifically at their edge that protrudes in the direction of movement. We discovered that ERK, a key signaling protein activated during development and cancer, helps create a fast-turning-over population of these adhesions, which supports steady movement. Using new biosensors and adhesion tracking, we showed ERK is active in the assembling part of the adhesion, where it promotes both assembly and disassembly. Increasing the nascent adhesion population helps cells move when ERK is blocked. This work reveals how ERK controls cell movement by balancing adhesion dynamics and introduces tools to study similar processes in other signaling pathways.