The neurotrophins, including NGF, BDNF, NT-3, and NT-4/5, constitute a group of structurally related, secreted proteins that play an important role in the development and function of the nervous system. Binding to and activating two unrelated receptor types mediate the biological activities of the neurotrophins. These receptors include the p75 neurotrophin receptor (p75NTR) and the Trk family of receptor tyrosine kinases (1 - 2). P75NTR is a member of the tumor necrosis factor receptor superfamily (TNFRSF) and has been designated TNFRSF16. It binds all neurotrophins and transduces cellular signaling pathways that may synergize or antagonize those activated by the Trk receptors. Three Trk family proteins, TrkA, TrkB, and TrkC, have been identified. TrkA preferentially binds NGF and NT-3, TrkB preferentially binds BDNF, NT-3, and NT-4/5, and TrkC preferentially binds NT-3 (1 - 2).
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 (3). Natural splice variants of the different Trks lacking the first cysteine-rich domain, the first and second or all three of the leucine-rich motifs, or the tyrosine kinase domain have been described (4). At the protein sequence level, Trks are highly conserved between species with the extracellular domains of human and mouse TrkC exhibiting 94% amino acid sequence identity (5). The proteins also exhibit cross-species activity. Although TrkC is widely expressed, the highest levels are found in the nervous system (6).
1. Huang, E.J. and L.F. Reichardt. 2003, Annu. Rev. Biochem. 72: 609.
2. Dechant, G., 2001, Cell Tissue Res. 305:229.
3. Schneider, R. and M. Schweiger, 1991, Oncogene 6:1807.
4. Ninkina, N. et al., 1997, J. Biol. Chem. 272:13019.
5. Menn, B. et al., 1998, J. Comp. Neurol. 401:47.
6. Shelton, D. et al., 1995, J. Neurosci. 15:477.
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