Ca2+ Pulses Control Local Cycles of Lamellipodia Retraction and Adhesion along the Front of Migrating Cells

Ca2+ signals regulate polarization, speed, and turning of migrating cells [1-4]. However, the molecular mechanism by which Ca2+ acts on moving cells is not understood. Here we show that local Ca2+ pulses along the front of migrating human endothelial cells trigger cycles of retraction of local lamellipodia and, concomitantly, strengthen local adhesion to the extracellular matrix. These Ca2+ release pulses had small amplitudes and diameters and were triggered repetitively near the leading plasma membrane with only little coordination between different regions. We show that each Ca2+ pulse triggers contraction of actin filaments by activating myosin light-chain kinase and myosin II behind the leading edge. The cyclic force generated by myosin II operates locally, causing a partial retraction of the nearby protruding lamellipodia membrane and a strengthening of paxillin-based focal adhesion within the same lamellipodia [5-7]. Photo release of Ca2+ demonstrated a direct role of Ca2+ in triggering local retraction and adhesion. Together, our study suggests that spatial sensing, forward movement, turning, and chemotaxis are in part controlled by confined Ca2+ pulses that promote local lamellipodia retraction and adhesion cycles along the leading edge of moving cells.