Monoclonal antibody (mAb) 5C3 directed against human p140 TrkA is a structural and functional mimic of nerve growth factor (NGF) and an artificial receptor agonist. mAb 5C3 binds in the NGF-docking site and, like NGF, it promotes TrkA internalization, TrkA and phosphatidylinositol-3 kinase tyrosine phosphorylation, and increased transformation of TrkA-expressing fibroblasts. More important, mAb 5C3 protects human TrkA-expressing cells from apoptotic death in serum-free media. Interestingly, agonistic activity is observed with monomeric F(ab) 5C3 fragments. mAb 5C3 (Kd approximately 2 nM) was used to study features of ligand binding by TrkA and the distribution of TrkA protein in normal human brain.