SHIP2 uncoupled from Mena destabilizes actin-rich membrane protrusions. SHIP2-depleted MDA-MB-231 cells were rescued with either WT-SHIP2 or SHIP2ΔFP4, transiently transfected with tagRFP-LifeAct, cultured on unconjugated matrix for 24 h, and subjected to time-lapse video microscopy. Images were acquired every 5 s for 5 min and are displayed at 3/10 of a second per frame. Actin-rich membrane protrusions found in SHIP2-knockdown cells rescued with WT-SHIP2 are depicted on the left and F-actin protrusions from SHIP2 knockdown cells rescued with SHIP2ΔFP4 on the right.