Cofilin-Mediated Actin Dynamics in Cancer Cell Motility

Cancer cell motility underpins invasion and metastasis, driven by dynamic remodelling of the actin cytoskeleton. Cofilin, a member of the actin‐depolymerising factor family, severs and depolymerises filamentous actin (F-actin), generating free barbed ends that fuel protrusive structures such as lamellipodia and invadopodia. In malignant cells, aberrant regulation of cofilin activity enhances directional migration, supports extracellular matrix degradation and promotes dissemination. Activation of cofilin is controlled by phosphorylation at serine 3, interactions with phosphoinositides and post-translational modifications such as SUMOylation. Spatially restricted cofilin turnover drives rapid filament turnover at the leading edge, while cooperation with nucleation and crosslinking factors establishes force-generating networks. Dysregulated cofilin-mediated dynamics also facilitate epithelial–mesenchymal transition, enabling cells to detach from primary tumours and intravasate. Therapeutic strategies targeting cofilin activation or its recruitment to F-actin are emerging, offering new routes to impede metastatic spread.

Research from Nature Portfolio

Recent studies have defined a novel post-translational modification that fine-tunes cofilin-mediated actin turnover. N-terminal α-SUMOylation of cofilin-1 enhances its affinity for F-actin and increases severing activity in vitro and in cells. SUMO conjugation at the α-amino group, mediated by E1, E2 and E3 enzymes and reversed by SENP1, promotes filament disassembly and accelerates protrusion formation. This mechanism reveals an additional regulatory axis by which cofilin function can be modulated in highly motile cells.

Cofilin-Mediated Actin Dynamics in Cancer Cell Motility publication trend

The graph below shows the total number of articles in cofilin-mediated actin dynamics in cancer cell motility across all publications each year (not limited to Nature Index journals).

Technical terms

Cofilin-1: An actin-binding protein that severs and depolymerises F-actin, regulating filament turnover.

F-actin: Polymerised actin filaments forming the structural network driving cell shape and motility.

SUMOylation: A reversible modification involving conjugation of small ubiquitin-like modifier (SUMO) proteins to target residues.

PI(4,5)P₂: A phosphoinositide in the plasma membrane that binds and sequesters proteins, modulating actin dynamics.

Epithelial–mesenchymal transition (EMT): A programme whereby epithelial cells acquire mesenchymal traits, enhancing motility and invasiveness.

References

1. N-terminal α-amino SUMOylation of cofilin-1 is critical for its regulation of actin depolymerization. Nature Communications (2023).
2. PTPRN2 and PLCβ1 promote metastatic breast cancer cell migration through PI(4,5)P2‐dependent actin remodeling. The EMBO Journal (2015).
3. Actin Cytoskeleton Regulation of Epithelial Mesenchymal Transition in Metastatic Cancer Cells. PLOS ONE (2015).
4. Cofilin-1 and Other ADF/Cofilin Superfamily Members in Human Malignant Cells. International Journal of Molecular Sciences (2016).