Amplification of PIP3 signalling by macropinocytic cups

In a role distinct from and perhaps more ancient than that in signal transduction, PIP3 and Ras help to spatially organize the actin cytoskeleton into macropinocytic cups. These large endocytic structures are extended by actin polymerization from the cell surface and have at their core an intense patch of active Ras and PIP3, around which actin polymerizes, creating cup-shaped projections. We hypothesize that active Ras and PIP3 self-amplify within macropinocytic cups, in a way that depends on the structural integrity of the cup. Signalling that triggers macropinocytosis may therefore be amplified downstream in a way that depends on macropinocytosis. This argument provides a context for recent findings that signalling to Akt (an effector of PIP3) is sensitive to cytoskeletal and macropinocytic inhibitors.