Trk A, the product of the proto-oncogene trk, is a member of the neurotrophic tyrosine kinase receptor family that has three members. Trk A, Trk B and Trk C preferentially bind NGF, NT-4 and BDNF, and NT-3, respectively. All Trk family proteins share a conserved complex subdomain organization consisting of a signal peptide, two cysteine-rich domains, a cluster of three leucine-rich motifs, and two immunoglobulin-like domains in the extracellular region, as well as an intracellular region that contains the tyrosine kinase domain. Two distinct rat Trk A isoforms (TrkA-I and Trk-A-II) that differ by a 6-amino acid insertion in their extracellular domain have been identified. The longer Trk A isoform is the only isoform expressed within neuronal tissues whereas the shorter Trk A-I is expressed mainly in non-neuronal tissues. NGF binds to Trk A with low affinity and activates its cytoplasmic kinase, initiating a signaling cascade that mediates neuronal survival and differentiation. Higher affinity binding of NGF requires the coexpression of Trk A with the p75 NGF receptor (NGF R), a member of the tumor necrosis factor receptor superfamily. NGF R binds all neurotrophins with low affinity and modulates Trk activity as well as alters the specificity of Trk receptors for their ligands. NGF R can also mediate cell death when expressed independent of Trk (Esposito, D. et al., 2001, J. Biol. Chem. 276:32687; Sofroniew, M.V. et al., 2001, Annu. Rev. Neurosci. 24:1217).