FIG. 9.

Model depicting the interactions between TrkA, GIPC, and APPL and their trafficking on early endosomes. NGF binds to TrkA in clathrin-coated pits, and clathrin-coated vesicles containing TrkA pinch off from the cell membrane and undergo uncoating to become peripheral signaling endosomes (PSE). APPL binds to TrkA on PSEs and recruits GIPC and Rab5. GIPC then binds myosin VI, which serves to move the TrkA PSEs across the cortical actin barrier at the cell periphery. As the PSEs with TrkA travel from the cell periphery to the juxtanuclear region, GIPC is released, but APPL follows TrkA to the juxtanuclear region, where the endosomes acquire the early endosome marker EEA1. APPL is required for recruitment of GIPC, and both GIPC and APPL are required for TrkA signaling from peripheral endosomes, because when GIPC's recruitment and interaction with APPL are prevented, TrkA signaling is inhibited.