Cell migration involves extension of actin-rich protrusions (lamellipodia) at the cell's leading edge, which depends on the signal transducer phosphoinositide 3-kinase (PI3K). Ras and Rac GTPases can both activate PI3K but what are their relative contributions during migration? On , Jonathan Backer and co-workers reveal distinct roles for these two proteins in PI3K-dependent extension of lamellipodia in rat adenocarcinoma cells stimulated with epidermal growth factor (EGF). They show that the activation kinetics of Ras but not Rac match the production of phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3], a measure of PI3K activation, at the leading edge. Knocking down K-Ras by RNAi, they report, abolishes PtdIns(3,4,5)P3 production at the leading edge and inhibits EGF-stimulated protrusion. By contrast, knocking down Rac1 has no effect on PtdIns(3,4,5)P3 levels or EGF-stimulated protrusion but nevertheless inhibits cell migration. It does this, report Backer and colleagues, by inhibiting the formation of focal complexes, which anchor cells to the substrate and thus provide traction. The authors propose, therefore, that Ras and Rac play distinct but coordinated roles during the movement of these cells.
