Lamellipodin branches out

M igrating cells move forward by harnessing the force of actin polymerization to form a protru-sive lamellipodium at the leading edge. A protein called Lamellipodin (Lpd) promotes lamellipodium formation, but how it does so is unclear. Law et al. reveal that Lpd generates membrane protrusions in association with a key regulator of actin branching called the Scar/WAVE complex and that this interaction is essential for the migration of a variety of cell types in multiple organisms (1). Lpd localizes to lamellipodia and promotes actin polymerization by recruiting members of the Ena/VASP family of actin regulators (2). Together, Lpd and Ena/VASP proteins promote the endocytosis of clathrin-coated vesicles (3), but whether the proteins combine to stimulate lamellipodium formation is much less clear. Matthias Krause, from King's College London, who identifi ed Lpd as a postdoc, explains that depleting Lpd has a much stronger effect on lamellipo-dia than the loss of Ena/VASP proteins does. " Lamellipodia show different dynamics in cells that don't express Ena/VASP proteins, " Krause says. " But cells lacking Lpd have a hard time making any lamellipodia at all. " Lpd might, therefore, stimulate membrane protrusion by interacting with additional actin regulators. " The most likely suspect was the Scar/WAVE complex, a major regulator [of lamellipodia and cell migration], " Krause says. By recruiting the actin-nucleating Arp2/3 complex to the leading edge of migrating cells, the Scar/WAVE complex helps generate the branched actin network that drives lamellipodial membrane protrusion. Krause and colleagues, led by postdoc Ah-Lai Law, found that Lpd bound to the Abi subunit of the Scar/WAVE complex (1). Lpd also bound to active Rac GTPase, a well-known regulator of the Scar/WAVE complex, and this interaction boosted Lpd's association with Abi. " The binding of Rac to Lpd may lead to a structural change that allows it to bind Abi, " Krause suggests. The researchers then examined the functional signifi cance of Lpd's interaction with the Scar/WAVE complex. Although loss of Lpd inhibits lamellipodia formation, the protein's effects on cell migration have never been tested. Law et al. found that fi broblasts lacking Lpd migrated slowly and aimlessly in comparison to wild-type cells. On the other hand, breast cancer cells overexpressing Lpd migrated faster than normal. Crucially, however, Lpd promoted migration independently of Ena/VASP proteins but couldn't enhance the movement of cells lacking the Scar/WAVE complex. Law et al. then generated Lpd knockout mice. Many of these …