Shc has been implicated in a variety of growth factor- and cytokine receptor-signaling through its specific binding to phosphotyrosine residues of the activated receptors. In neuronal cells, such as PC12, Shc has been shown to be involved in Ras-dependent MAP kinase activation following Trk receptor stimulation with NGF. While the ubiquitous role of Shc as an adaptor molecule in signal transduction is increasing in both neuronal and non-neuronal cells and tissues, the expression level of Shc is surprisingly low in the brain. We demonstrated here the isolation of a neural-specific member of the Shc family. This novel protein, named N-Shc (neuronal Shc), contains two potential phosphotyrosine-binding domains, PTB and SH2, and is expressed exclusively in the brain; whereas Shc is present in all other non-neuronal tissues. As in Shc, N-Shc can bind activated EGF receptor, become tyrosine phosphorylated, and form a complex with Grb2 adapter protein following EGF stimulation. Furthermore, N-Shc can bind activated TrkB receptor following the stimulation with brain-derived neurotrophic factor (BDNF), which is the most abundant neurotrophin in the brain. These data suggest that N-Shc, rather than Shc, mediates neurotrophin and other neuronal signalings in the central nervous system.