Model of endosomal branched actin network regulation by PI(3,5)P2. (A) Branched actin nucleation is initiated by the WASH complex which is bound to the surface of late endosomes by signaling molecules that likely include PI(3)P (Jia et al., 2010). WASH-induced activation of the Arp2/3 complex recruits cortactin to nascent branch points (Fig. 4), where it synergistically promotes actin assembly. (B) Conversion of PI(3)P to PI(3,5)P2 is accomplished by the enzymatic activity of PIKfyve within the three-member PIKfyve complex that includes the scaffold protein Vac14 and the opposing 5′ phosphatase Fig. 4 (Shisheva, 2008; Dove et al., 2009). (C) PI(3,5)P2 binds to cortactin, releasing actin filaments (Fig. 5) and potentially the WASH complex from endosomes (Fig. 8). (D) Without cortactin binding to the branchpoint, Arp2/3 complex loses affinity for the mother filament (Uruno et al., 2001) causing debranching (Weaver et al., 2001; Fig. 6). Disassembly of branched actin networks leads to diminished recruitment of cortactin. (E) Conversion of PI(3,5)P2 back to PI(3)P should release cortactin from the endosome surface unless new branched actin networks are available for rebinding. Interconversion of PI(3)P and PI(3,5)P2 by the PIKfyve complex may facilitate dynamic cycling of actin assembly and disassembly through control of cortactin–actin interactions.
