Cells can migrate randomly, to explore their local environment, or in a particular direction, for example during chemotaxis and embryonic cell migration. The small GTPase Rac is central to many migratory processes, but its exact role in the mechanisms controlling the persistence and direction of movement is unclear. In the Journal of Cell Biology, Pankov et al. examine the intrinsic control of cell migration and demonstrate that small changes in the level of Rac activity can dictate whether a cell moves persistently in a particular direction or in a more random manner.

The key to this study was that the authors used different approaches, including RNA interference and integrin mutagenesis, to downregulate Rac activity to different extents, allowing them to uncover the way cells respond to small changes in Rac levels. In all cases, partial suppression of Rac activity prevented random motility and increased the directional persistence of migration. The effect was rescued by restoring Rac activity.

To begin to understand how Rac activity affects the mode of migration, the number and width of lamellae were examined using time-lapse microscopy. While cells with reduced Rac activity were elongated and displayed only axial lamellae (at one or both ends of the cell), cells with higher levels of Rac activity had more peripheral lamellae — extending in directions other than the direction of cell movement — which could explain the problems they have keeping their migration on track.

Interestingly, Rac's ability to regulate migration does not require phosphatidylinositol 3'-kinase, a key regulator of chemotactic-directed migration. Rac levels are, however, sensitive to the extracellular environment: cells cultured in three-dimensional matrices had less active Rac, moved persistently in one direction and had fewer peripheral lamellae, compared with cells migrating on a two-dimensional substrate of identical molecular composition.

Taken together, these findings suggest that in addition to localization, the quantity of active Rac in a cell is important for controlling motility. While large increases or decreases in Rac activity quickly bring a cell to an abrupt halt, more subtle shifts in its activity will determine whether a cell migrates randomly or in a more directed manner. That these changes in migration mode occur without greatly affecting cell velocity highlights the complexity of Rac signalling in the cell.

Author: Monica Hoyos-Flight