The leading edge of a migrating cell is built up via one or more positive feedback loops. Kunisaki et al. (page 647) present evidence for a feedback loop that is required for the greater localization, although not greater overall abundance, of the critical migration mediator phosphatidylinositol 3,4,5-triphosphate (PIP3). The loop is driven by the newly identified Rac activator DOCK2.

Kunisaki et al. had earlier identified DOCK2 as a regulator of lymphocyte migration. They now find that DOCK2 is also required for directed migration in neutrophils. DOCK2-deficient neutrophils migrated at almost half the speed of wild-type cells, and wandered rather than taking a straight path toward a chemoattractant. The leading edge in these cells was not as stable as that found in wild-type neutrophils.

In the presence of chemoattractant, DOCK2 translocated to the neutrophil leading edge in a PI3K-dependent manner. Its presence there was necessary for the full activation of Rac (which drives actin polymerization) and accumulation of PIP3. Cells lacking DOCK2 still activated PI3K and thus produced high levels of PIP3, but without DOCK2 the PIP3 did not find its way to the leading edge.

A positive feedback loop is believed to maintain high PIP3 levels and Rac activity at the leading edge. The new results suggest that this loop regulates the localization of PIP3, not the activity of the PI3K that generates the PIP3.