Mechanism of Lamellipodia Formation

Growth factors bind to receptor tyrosine kinases on the cell membrane, activating Rac1, a small GTPase. GTP-bound active Rac1 recruits the WAVE regulatory complex (WRC) to the plasma membrane. WRC activation then localizes the IRSp53 protein and stimulates the Arp2/3 complex, triggering actin branching and membrane bending to form the lamellipodium.

The Arp2/3 complex binds pre-existing linear actin filaments and initiates branching, creating a web of short, rigid actin filaments. This branched network broadens the membrane protrusion at the leading edge. The capping protein limits branch length, while Ena/VASP proteins regulate capping to allow filament elongation and continuous forward extension.

Actin monomers continuously attach to the plus ends of filaments at the leading edge while cofilin depolymerizes the minus ends at the rear of the actin mesh. This cyclic assembly and disassembly, called actin treadmilling, causes unidirectional extension of the lamellipodium. Individual filaments remain stationary while the entire network moves forward.

The branched actin mesh at the leading edge of lamellipodia contributes to the formation of focal adhesion points on the extracellular matrix (ECM). These adhesion sites prevent retraction of the lamellipodium and anchor the cell to the substrate, enabling stable membrane protrusion during migration.

Behind the dynamic lamellipodial meshwork lies the lamella, a stable network of bundled linear actin filaments. The lamella develops mature, strong adhesion sites that resist cell compression during migration. Stable actin filaments of the lamella associate with myosin proteins, using contractility to propel the cell forward.

The localized WRC-IRSp53 complex bends the plasma membrane to form a saddle-shaped curve, creating the initial membrane protrusion. This curvature, combined with continuous actin polymerization pushing from beneath, generates the lamellipodium's characteristic thin, sheet-like structure that extends forward during cell migration.

Members of the formin family localize at lamellipodia formation sites and elongate unbranched actin filaments. While the Arp2/3 complex creates branched filaments, formins extend linear filaments, contributing to the diverse actin network architecture that supports membrane protrusion and cytoskeletal coordination in cell migration.