30.5:
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.
30.5:
Mechanism of Filopodia Formation
Filopodia are thin, actin-rich cellular protrusions that play an important role in many fundamental cellular functions. They vary in their occurrence, length, and positioning in different cell types, suggesting their diverse roles.
Their main function is to guide migrating cells during normal tissue morphogenesis or cancer metastasis by recognizing and making initial contacts with the extracellular matrix. However, they can also act as stationary cell anchors or help to establish communication between two cells. For example, the formation of filopodial bridges between two adjacent endothelial or epithelial cells is important for the subsequent establishment of adherens junctions. In addition, filopodia can also help the cells to reach and internalize distant targets, such as pathogens.
Filopodia Formation and Disassembly
Actin nucleation, elongation, and bundling are critical for filopodia formation and function. The filopodia core comprises 12-20 actin filaments spaced 12 nm apart. Bundling of these filaments by fascin is crucial to give filopodia the rigidity to maintain its elongated shape.
The disassembly of actin filaments during the retraction phase involves periodic helical and rotational motion of the actin shaft and is regulated by several factors. For instance, capping proteins promote filopodial retraction by shielding the polymerizing ends of the filaments from further elongation. RhoA kinase activity also regulates actin polymerization within filopodia.
Suggested Reading
- Yang.C & Svitkina. T. Filopodia initiation. Cell Adh Migr. 2011; 5: 402-408. 10.4161/cam.5.5.16971
- Mattila. P & Lappalainen. Filopodia: molecular architecture and cellular functions. Nature Reviews Molecular Cell Biology. 2008: DOI:10.1038/nrm2406
- Ridley. A. Life at the Leading Edge. ScienceDirect. 2011; 145: 1012-1022. https://doi.org/10.1016/j.cell.2011.06.010