Regulation of Trafficking of Activated TrkA Is Critical for NGF‐Mediated Functions

Abstract

Upon activation by nerve growth factor (NGF), TrkAis internalized, trafficked and sorted through differentendosomal compartments. Proper TrkA trafficking andsorting are crucial events as alteration of these processeshinders NGF-mediated functions. However, it is not fullyknown which proteins are involved in the traffickingand sorting of TrkA. Here we report that Nedd4-2regulates the trafficking of TrkA and NGF functionsin sensory neurons. Depletion of Nedd4-2 disrupts thecorrect sorting of activated TrkA at the early andlate endosome stages, resulting in an accumulation ofTrkA in these compartments and, as a result of thereduced trafficking to the degradative pathway, TrkAis either reverted to the cell surface through the recyclingpathway or retrogradely transported to the cell body.In addition, Nedd4-2 depletion enhances TrkA signalingand the survival of NGF-dependent dorsal root ganglionneurons, but not those of brain-derived neurotrophicfactor-dependent neurons. Furthermore, neurons from aknock-in mouse expressing a TrkA mutant that does notbind Nedd4-2 protein exhibit increased NGF-mediatedsignaling and cell survival. Our data indicate that TrkAtrafficking and sorting are regulated by Nedd4-2 protein.