Trk A, the product of the proto-oncogene trk, is a member of the neurotrophin tyrosine kinase receptor family. TrkA, TrkB and TrkC 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 TrkA isoforms that differ by a 6 amino acid insertion in their extracellular domain have been identified. The longer TrkA isoform is the only isoform expressed within neuronal tissues, whereas, the shorter Trk A 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).