Visualizing Ras signalling in real-time

Ras GTPases are universal molecular switches that act as kinetic timers of signal transduction events. They are post-translationally modified by the addition of lipid groups to their hypervariable carboxyl termini, which plug the proteins to membranes and influence their dynamic sorting and trafficking. For the past twenty years, the plasma membrane has been considered to be the predominant platform from which Ras operates. Recent work using live-cell imaging and novel probes to visualize where and when Ras is active has supported this long-held belief. However, an equally fascinating aspect of these imaging studies has been the discovery of dynamic Ras activity, as well as distinct signal output, from intracellular organelles. Activation of Ras on the Golgi exhibits kinetics different from Ras activation on the plasma membrane, and compartmentalized Ras signalling seems particularly prominent in lymphocytes. However, data on the spatial and temporal regulation of Ras activity has frequently differed depending on the nature of the probe, the cell type and the stimulus. Nevertheless, because Ras traffics through endomembranes en route to the plasma membrane, it seems likely that Ras can signal from such compartments. The burning question in this field concerns the significance of this observation for endogenous Ras signalling output.