Mechanism of Filopodia Formation

Filopodia formation requires actin cytoskeleton reorganization at the cell's leading edge into thin parallel bundles by IRSp53.

IRSp53, a multi-domain protein, impacts the actin cytoskeleton and the membrane.

When a cell receives an appropriate signal, Cdc42— a small Rho family protein, switches to its GTP-bound active state. 

The GTP-bound Cdc42 recruits IRSp53 dimers to the cell membrane, forming activated Cdc42-IRSp53 complexes.

The activated complex then mobilizes actin nucleators such as Ena/VASP proteins to the filament ends near the membrane.

Ena/VASP accumulation displaces the capping proteins and promotes filament elongation.

Simultaneously, IRSp53 clusters phosphatidylinositol 4,5-bisphosphate molecules at the inner leaflet of the membrane, inducing a curvature.

The combined outcome of increased membrane asymmetry and actin elongation deforms the membrane, structuring the filopodium.

As the filopodium extends, fascin proteins cross-link the actin filaments to form tight bundles.

This bundle gives rigidity to the filopodial structure to sustain the extracellular force and membrane tension.