The mDia1 formin (green) creates protruding actin (red) bundles in the periphery when N-WASP and WAVE2 are inhibited (bottom).

The actin-organizing activities in a reaching lamellipod fight back the trailing lamella, say Sarmiento et al. The feedback might coordinate inchworm-like migration in normal and cancerous cells.

Tumor cells such as breast cancer carcinomas become dangerously motile because they have hyperactive actin-polymerizing pathways that respond to epidermal growth factor (EGF). On flat surfaces, migrating cells extend separate actin-filled structures such as filopodia, invadopodia, and lamellipodia, which in 3D tumors combine into a single structure at the leading edge. The group wondered how these individual compartments are initiated and maintained and how they interact.

They now identify the main actin-polymerizing activity that creates and maintains lamellipodia as WAVE2, a member of the WASP family that works with Arp2/3 to form branched actin networks. The only other prominent WASP member in the carcinoma cells was N-WASP, which was not needed for lamellipod formation.

When both WAVE2 and N-WASP were depleted from the carcinoma line, the group noticed an explosion of jagged protrusions with filopod-like tips. The filopodia seemed to stem from merging and bundling lamellar actin, as they colocalized with the lamellar marker, tropomyosin.

Filopodia are often associated with actin-bundling formins. The authors found that the mDia1 formin created the odd filopod protrusions in these deletion lines. Loss of mDia1 blocked the jagged extensions, whereas an overactive version replicated the effect of WAVE2 and N-WASP inhibition. The WASP activities seem to prevent filopodia by somehow blocking one of mDia1 activators, RhoA GTPase.

The group suggests that the combination of WAVE2 and WASP in extending lamellipodia keeps back the trailing lamella, which contains the machinery to stabilize the new cell boundary. This inhibition would allow lamellipodia to search the environment and select the correct direction (toward an EGF source) before shutting down and permitting lamella to inch forward as well.

Sarmiento, C., et al.
J. Cell Biol.