The p75 neurotrophin receptor enhances TrkA signalling by binding to Shc and augmenting its phosphorylation

Nerve growth factor (NGF) is an important neuronal survival factor, especially during development. Optimal sensitivity of the survival response to NGF requires the presence of TrkA and the p75 neurotrophin receptor, p75(NTR). Signalling pathways used by TrkA are well established, but the mechanisms by which p75(NTR) enhances NGF signalling remain far from clear. A prevalent view is that p75(NTR) and TrkA combine to form a high-affinity receptor, but definitive evidence for this is still lacking. We therefore investigated the possibility that p75(NTR) and TrkA interact via their signal transduction pathways. Using antisense techniques to down-regulate p75(NTR) and TrkA, we found that p75(NTR) specifically enhanced phosphorylation of the 46- and 52-kDa isoforms of Shc during nerve growth factor-induced TrkA activation. p75(NTR) did not enhance tyrosine phosphorylation of other TrkA substrates. Serine phosphorylation of Akt, downstream of Shc activation, was also p75(NTR)-dependent. We consistently detected co-immunoprecipitation of p75(NTR) and Shc. These data indicate that p75(NTR) interacts with Shc physically, via a binding interaction, and functionally, by assisting its phosphorylation. Whilst providing evidence that p75(NTR) augments TrkA signal transduction, these results do not preclude the presence of a p75(NTR)-TrkA high-affinity NGF receptor.