Actin Polymerization and Cell Motility

Actin is a multi-functional, globular protein that polymerizes to form polarized F-actin filaments, creating a tough and flexible framework supporting the cell membrane. It comprises 1-5% of total cell protein and is essential for cell migration. Actin filament reorganization at the cell's leading edge generates directional forces that push the membrane outward, enabling cells to move in response to environmental signals.

Actin monomers assemble at the plus ends of filaments or branch at existing filament sides, while simultaneously the minus ends depolymerize and sever. This directional polymerization creates continuous force that pushes the cell membrane outward, forming membrane protrusions. These protrusions allow cells to adhere to the matrix, sense their environment, and achieve forward displacement through retraction cycles.

Actin filaments are polarized structures with two distinguished ends: plus and minus. The plus end is where actin monomers preferentially assemble and polymerize during active filament growth. The minus end simultaneously depolymerizes and severs, releasing monomers that recycle back to the polymerizing plus end, maintaining a continuous cycle of filament reorganization.

Cells respond to environmental cues by rearranging internal actin components, primarily at the leading edge. Directional actin polymerization creates asymmetric forces that establish cell polarity and push the membrane forward. This polarized organization, combined with cytoskeletal coordination in cell migration, allows cells to sense their immediate environment and migrate toward specific signals.

Mutations in any of the six human actin genes or genes encoding actin-binding proteins can cause disease. For example, mutations in ACTA1 cause Nemaline Myopathy, leading to muscle weakness and breathing difficulties. Mutations in the WAS gene, which regulates actin filament nucleation, cause Wiskott Aldrich syndrome, affecting immune cell adhesion, chemotaxis, and phagocytosis.

Cells migrate through recurrent cycles where actin polymerization creates membrane protrusions at the front that adhere to the substratum. Simultaneously, the rear end detaches and retracts as actin filaments depolymerize. This coordinated process of protrusion, attachment, detachment, and retraction enables forward cell displacement and allows cells to respond to chemotaxis and direction cell migration signals.

Actin cytoskeleton dynamics generate pushing, pulling, and resistance forces essential for cell migration. Pushing forces arise from polymerization at the leading edge, while pulling forces develop through myosin interactions and filament contraction. These coordinated forces, combined with different types of membrane protrusions depending on cell type and extracellular signals, enable diverse migration strategies including cancer cell migration through invadopodia.