The small GTPase KRas moves between different membranes within the cell by diffusion, but Lu et al. find it can use an alternative mode of transport to travel to another destination.
Ras proteins control many cellular functions including proliferation, differentiation, and apoptosis. Their location within the cell affects the downstream signals they send; KRas has been identified at the plasma membrane and on intracellular membranes. Previous reports suggested that KRas associates with negatively charged membranes via its positively charged C-terminus and moves between compartments by diffusing through the cytosol along an electrostatic gradient.
But when Lu et al. tracked GFP-labeled KRas, they discovered that the protein moves to early endosomes by internalizing from the plasma membrane in clathrin-coated vesicles. Unlike other Ras family members, KRas then gets sorted into late endosomes (LEs) before traveling to the lysosomes for degradation. Fluorescent probes revealed that KRas was active on LEs, where it colocalized with a scaffolding complex called p14-MP1 and initiated a MAP kinase signaling cascade.
KRas' journey to the lysosomes is stimulated by EGF and its receptor, which share the ride all the way to the end, suggesting that lysosomal-degradation may be important for switching off the EGF/KRas signal. Indeed, when lysosomal degradation was blocked, the MAP kinase cascade remained active for longer on the LEs. The researchers now want to look at how LE KRas signaling is propagated and determine how it differs from KRas signaling at the plasma membrane.