Abstract

Neurotrophins bind to two structurally unrelated receptors, the trk tyrosine kinases and the neurotrophin receptor p75^NTR. Ligand activation of these two types of receptor can lead to opposite actions, in particular the prevention or activation of programmed cell death. Many cells co-express trk receptors and p75^NTR, and we found that p75^NTR was co-precipitated with trkA, trkB and trkC in cells transfected with both receptor types. Co-precipitation of p75^NTR was not observed with the epidermal growth factor receptor. Experiments with deletion constructs of trkB (the most abundant trk receptor in the brain) and p75^NTR revealed that both the extracellular and intracellular domains of trkB and p75^NTR contribute to the interaction. Blocking autophosphorylation of trkB substantially reduced the interactions between p75^NTR and trkB constructs containing the intracellular, but not the extracellular, domains. We also found that co-expression of p75^NTR with trkB resulted in a clear increase in the specificity of trkB activation by brain-derived neurotrophic factor, compared with neurotrophin-3 and neurotrophin-4/5. These results indicate a close proximity of the two neurotrophin receptors within cell membranes, and suggest that the signalling pathways they initiate may interact soon after their activation.