Reverse Fountain Flow of Phosphatidylinositol-3,4-Bisphosphate Polarizes Migrating Cells

The ability of cells to polarize and move toward external stimuli plays a crucial role in development, as well as normal and pathological physiology. Migrating cells maintain dynamic complementary distributions of Ras activity and phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2). Here we show lagging edge component PI(3,4)P2 also localizes to retracting leading edge protrusions and nascent macropinosomes, even in the absence of phosphatidylinositol 3,4,5-trisphosphate (PIP3). Once internalized, the macropinosomes break up into smaller PI(3,4)P2-enriched vesicles, which fuse to the plasma membrane at the cell rear. The phosphoinositide then diffuses towards the front, where it is degraded. A computational model confirmed that this cycle brings about a stable back-to-front gradient. These results uncover a surprising "reverse fountain flow" of PI(3,4)P2 that regulates polarity.