The RAS - Extracellular signal-regulated kinase (RAS-ERK) pathway plays a conserved role in promoting cell migration and invasion. Growth factors, adhesion, and oncogenes activate ERK. While historically studied with respect to its control of cell proliferation and differentiation, the signaling pattern and effectors specific for cell migration are now coming to light. New advances in pathway probes have revealed how steady-state ERK activity fluctuates within individual cells and propagates to neighboring cells. We review new findings on the different modes of ERK pathway stimulation and how an increased baseline level of activity promotes single cell and collective migration and invasion. We discuss how ERK drives actin polymerization and adhesion turnover for edge protrusion and how cell contraction stimulates cell movement and ERK activity waves in epithelial sheets. With the steady development of new biosensors for monitoring spatial and temporal ERK activity, determining how cells individually interpret the multiple in vivo signals to ERK is within reach.

Cell migration is essential to physiological and pathological biology. Migration is driven by the motion of a leading edge, in which actin polymerization pushes against the edge and adhesions transmit traction to the substrate while membrane tension increases. How the actin and adhesions synergistically control edge protrusion remains elusive. We addressed this question by developing a computational model in which the Brownian ratchet mechanism governs actin filament polymerization against the membrane and the molecular clutch mechanism governs adhesion to the substrate (BR-MC model). Our model predicted that actin polymerization is the most significant driver of protrusion, as actin had a greater effect on protrusion than adhesion assembly. Increasing the lifetime of nascent adhesions also enhanced velocity, but decreased the protrusion’s motional persistence, because filaments maintained against the cell edge ceased polymerizing as membrane tension increased. We confirmed the model predictions with measurement of adhesion lifetime and edge motion in migrating cells. Adhesions with longer lifetime were associated with faster protrusion velocity and shorter persistence. Experimentally increasing adhesion lifetime increased velocity but decreased persistence. We propose a mechanism for actin polymerization-driven, adhesion-dependent protrusion in which balanced nascent adhesion assembly and lifetime generates protrusions with the power and persistence to drive migration.