A TrkA-selective, fast internalizing nerve growth factor-antibody complex induces trophic but not neuritogenic signals

Nerve growth factor (NGF) is a neurotrophin that induces neuritogenic and t rophic signals by binding to TrkA and/or p75 receptors. We report a compara tive study of the binding, internalization, and biological activity of NGF versus that of NGF in association with an anti-NGF monoclonal antibody (mAb NGF30), directed against the C termini of NGF. NGF mAb complexes do not bi nd p75 effectively but bind TrkA with high affinity. After binding, NGF mAb complexes stimulate internalization faster and to a larger degree than NGF . NGF.mAb-induced activation of TrkA, Shc, and MAPK is transient compared w ith NGF-induced activation; yet NGF and NGF mAb afford identical trophic re sponses. In contrast, NGF induces Suc-1-associated neurotrophic activating protein phosphorylation and neuritogenic differentiation, but NGF mAb does not. Thus, an absolute separation of trophic and neuritogenic function is s een for NGF.mAb, suggesting that biological response modifiers of neurotrop hins can afford ligands with selected activities.