Fig. 9

SIPA1L2 controls trafficking and signaling of TrkB-amphisomes at boutons. Signaling amphisomes result from the fusion of active TrkB containing late endosomes with autophagosomes (1). Retrograde trafficking and signaling of these amphisomes in axons are tightly regulated by SIPA1L2, which directly binds to TrkB, Snapin, and LC3b. While the binding to Snapin serves as a linker to a dynein motor, binding of LC3b enhances SIPA1L2 RapGAP activity which negatively interferes with TrkB/Rap1-signaling and also slows down the velocity of retrograde transport. (2) The amphisome halts at single presynaptic boutons in a PKA-dependent manner. PKA-dependent phosphorylation of Snapin triggers its dissociation from the motor complex and immobilizing the amphisome at individual axon terminals. (3) PKA activity also terminates RapGAP activity by phosphorylating SIPA1L2 and allows TrkB/Rap1 signaling that subsequently activates synaptic ERK and facilitates transmitter release.