Rho GTPase: A molecular compass for directional cell migration.

Ras GTPases and phosphatidylinositol 3-kinases mediate intracellular signaling in directed cell migration. During chemotaxis, cells spatially control the activation of Ras/PI (3,4,5)-trisphosphate (PIP3) signaling and translate extracellular chemical gradients into intracellular signal cascades. This process is called directional sensing, and enables persistent cell migration with extraordinary sensitivity in shallow, unstable gradients of chemoattractants. In our recent study, we identified a Rho GTPase and its guanine nucleotide exchange factor (GEF) as molecular modulators that transmit signals from G protein-coupled receptors to Ras/PIP3 signaling pathways. The proteins spatially stabilize Ras activation and PIP3 production toward higher concentrations of chemoattractants. Unlike known roles of Rho GTPases and GEFs, the function of these proteins in directional sensing is independent of the actin cytoskeleton and cell morphology. Our findings provide novel mechanistic insight into the precision of directional cell migration.