How migrating cells build their leading edge: Master regulator may resolve long-standing debate
The ability of cells to move and change position is essential for various processes in our bodies. Immune cells move to sites of action, epithelial cells migrate during wound closure, and neurons extend their axons for signal transmission over long distances. In metastasis, cancer cells employ their motile machinery to spread throughout the body.
Cells' ability to move and change position is crucial for many biological processes, including immune responses, wound healing, and neuronal signaling. In cancer metastasis, cancer cells utilize their motile machinery to spread throughout the body. A research team led by Prof. Klemens Rottner from the Helmholtz Center for Infection Research (HZI) has uncovered new insights into the molecular mechanisms behind the formation of cytoskeletal networks at the leading edge of migrating cells.
The study, published in Nature Communications, focuses on the role of the actin-binding protein profilin in regulating lamellipodia formation.
Lamellipodia are flat, broad structures that push the cell front forward during migration. They are composed of dense networks of actin polymers and are dynamically renewed to translate pushing forces into forward movement. The central molecular interactions that accompany lamellipodia formation have long been a subject of debate. The research team addressed this controversy by using genome editing via CRISPR/Cas9 to disrupt various players in the process and observing the effects on lamellipodia formation and function.
The researchers discovered that profilin counteracts Ena/VASP and simultaneously promotes Arp2/3 complex activity. Profilin and Ena/VASP antagonize each other, while capping protein also plays a role in regulating lamellipodia formation. The study found that profilin influences both the Arp2/3 complex and capping protein through distinct and separable molecular pathways. This establishes profilin as a master regulator of Arp2/3 complex-dependent actin networks in lamellipodia.
The findings clarify the controversy surrounding profilin's role in actin structure formation and its regulation of Arp2/3 complex activity. Mathematical modeling conducted in collaboration with Prof. Martin Falcke from Max Delbrück Center Berlin further elucidated the molecular logic behind the branching of actin networks that drive membrane protrusion.
The researchers' mechanistic understanding of these molecular interactions has implications for examining aberrant migration in diseases such as cancer metastasis and infection-related cellular dysfunction.
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