Nerve growth factor (NGF) receptor-mediated signaling was studied using specific monoclonal antibodies (mAbs) as ligands that discriminate between the receptors TrkA and p75. mAb-induced trophic signals were compared with the signals of the natural ligand NGF. In cells expressing TrkA but no p75 receptors (TrkA+ p75(-)), binding of TrkA with mAb 5C3 leads to optimal signals. In cells expressing both TrkA and p75 (TrkA+ p75(+)), binding of TrkA with mAb 5C3 leads to significant but suboptimal signals, and optimal trophic signals are obtained by concomitant binding of TrkA and p75 with mAbs 5C3 and MC192. In TrkA+ p75(+) cells, binding of anti-p75 mAb MC192 also enhances the trophic effect of suboptimal concentrations of NGF. In contrast, in cells expressing p75 receptors singly (TrkA- p75(+)), binding with mAb MC192 or NGF causes very limited or no trophic effects. Thus, the data support the hypothesis that unbound p75 may modulate TrkA trophic signals. Importantly, the data also demonstrate for the first time that in multireceptor systems appropriate combinations of anti-receptor mAbs can fully mimic the signals of a polypeptide growth factor.