Mechanism of Lamellipodia Formation

Lamellipodia formation begins with the binding of the growth factors to receptor tyrosine kinase on the cell membrane, thus activating Rac1, a small GTPase, on the cytosolic side.

Next, GTP-bound active Rac1 recruits the WAVE regulatory complex or WRC to the plasma membrane.

WRC activation localizes the IRSp53 protein at the plasma membrane and stimulates the Arp2/3 complex.

The Arp2/3 complex binds pre-existing linear actin filaments and initiates branching, while the localized WRC-IRSp53 complex bends the membrane to form a saddle-shaped curve.

Next, Ena/VASP proteins regulate the capping protein from the plus-end of actin filaments, allowing them to elongate.

As the actin filaments continuously branch and grow, they push the lamellipodium tip forward.

The capping protein limits the length of the branches to form a web of short and rigid actin filaments that broadens the protrusion.

At the same time, cofilin depolymerizes the minus-end of older actin filaments at the back of the web, releasing monomers for reuse at the leading edge.

Thus, actin treadmilling is responsible for the unidirectional extension of the lamellipodia.