Figure 8. Working model depicting LPA₁ endocytic trafficking and signaling and its interactions with GIPC and APPL.

In the absence of ligand LPA₁ is found at the plasma membrane in a complex with GIPC. When LPA is added, LPA₁ and GIPC move into clathrin-coated pits (1). Clathrin-coated vesicles containing LPA₁-GIPC complexes pinch off the cell membrane and uncoat and APPL is recruited (2). APPL binds pAkt to form peripheral signaling endosomes. GIPC, by binding to APPL and the motor protein myosin VI, facilitates movement of these endosomes to the juxtanuclear region (3). In juxtanuclear early endosomes, GIPC and APPL are released into the cytoplasm thus terminating APPL-pAkt signaling. Depletion of GIPC inhibits LPA₁ trafficking to EEA1 endosomes and prolongs LPA₁ signaling from APPL endosomes whereas depletion of APPL inhibits Akt signaling.