The extension and contraction of muscles that enables us to run (or amble) for the bus has its equivalent in moving cells, which extend and retract sheet-like protrusions known as lamellipodia. As they report in Cell, Michael Sheetz and colleagues have found that, under some circumstances, the lamellipodia stretch out and contract — but do not fully retract — in remarkably regular, repeated cycles, which depend on the length of the lamellipodium. The authors also uncover some of the molecular basis for this rhythmic stretching and squeezing.

Migrating cells use lamellipodia to sense the chemical nature and rigidity of their matrix substrate, treating these local cues as signposts to direct cellular movement. The lamellipodia are 'pushed out' by subcellular networks of actin filaments.

Sheetz and co-workers wanted to find out how matrix rigidity guides lamellipodial protrusion and cell migration. To do so, they started by using total internal reflection fluorescence microscopy to look at the contact region between a dye-loaded mouse embryonic fibroblast cell and a glass substrate that was coated with the tough matrix component fibronectin.

Intriguingly, they found that in cells that extend lamellipodia without filopodia (thread-like protrusions that are also often associated with movement), the contact region shrank and grew in a periodic way, which indicates that lamellipodia went through repeated cycles of stretching and squeezing — each cycle lasting about 24 seconds. The net protrusion in each cycle was about 840 nm. By testing the cells on a variety of substrates, Sheetz and colleagues discovered that this periodic behaviour required a rigid matrix: very soft surfaces would not do.

Using a laser trap and a bead attached to the edge of a lamellopodium, the authors deduced that the interruptions in lamellipodial extension were driven by an increase in the rate of retraction of the underlying actin network (this network is continually retracting in lamellipodia, but during extension the rate of polymerization at the front exceeds the retraction rate). Sheetz and co-workers also investigated the role of integrins — transmembrane receptors for matrix components — by studying the localization of integrin-β3 attached to green fluorescent protein. They found that this receptor formed rows in a periodic manner, every 23 seconds or so.

So what triggers the increased rate of retraction that underlies contraction? Sheetz and colleagues suggest that a molecule hitches a ride on the retreating actin filaments, from the front of the lamellipodium to the rear, signalling contraction when it gets to the back. The authors find that α-actinin and myosin-light-chain kinase (MLCK) are transported in this way, reaching the back of the lamellipodium in around 25 seconds in normal lamellipodia. They propose that MLCK could be a contraction-triggering signal, as inhibiting this enzyme significantly reduced the duration of, or even eliminated, the extension–contraction phase.

Now we need to know why cells behave in this way on tough substrates — is it, as Sheetz and co-workers suggest, that regular periods of contraction enable the locally protruding cell edge to get a better grip on the surface, allowing greater extension towards rigid regions? Is MLCK indeed a signal that triggers squeezing? And could the directed movement of signals along cytoskeletal filaments occur in other contexts, too?