Modulation of nerve growth factor internalization by direct interaction between p75 and TrkA receptors

While the central role played by TrkA in nerve growth factor (NGF) signalling has been established by dissecting its signal transduction pathways, insight into the mechanism of action of p75LNR, the low-affinity neurotrophin receptor, has only recently been achieved. The relative contribution of p75LNR and TrkA to the constitution of high-affinity receptors for NGF and, similarly, with TrkB an TrkC to the formation of those for other neurotrophins, is presently under debate. Some form of collaboration in mediating neurotrophin activities has been observed between the Trk and p75LNR receptors, but only recent indirect evidence indicates a molecular interaction. In the present work, we have ectopically coexpressed p75LNR and TrkA in Sf9 insect cells by using baculovirus vectors, and show a direct association between the two NGF receptors. In addition, we show that the intracellular and extracellular domains of both receptors contribute to this interaction. Finally, we demonstrate that NGF becomes endocytosed in TrkA-expressing cells but not in p75LNR-expressing cells, and that such function can be modulated by the presence of the intracellular domain of p75LNR receptor.