Neurotrophins bind to two structurally unrelated receptors, the trk tyrosine kinases and the neurotrophin receptor p75NTR. 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 p75NTR, and we found that p75NTR was co-precipitated with trkA, trkB and trkC in cells transfected with both receptor types. Co-precipitation of p75NTR was not observed with the epidermal growth factor receptor. Experiments with deletion constructs of trkB (the most abundant trk receptor in the brain) and p75NTR revealed that both the extracellular and intracellular domains of trkB and p75NTR contribute to the interaction. Blocking autophosphorylation of trkB substantially reduced the interactions between p75NTR and trkB constructs containing the intracellular, but not the extracellular, domains. We also found that co-expression of p75NTR 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. [ABSTRACT FROM AUTHOR] more...