The family of Trk receptor tyrosine kinases consists of TrkA, TrkB, and TrkC. While the sequence of these family members is highly conserved, they are activated by different neurotrophins: TrkA by NGF, TrkB by BDNF or NT4, and TrkC by NT3. Neurotrophin signaling through these receptors regulates a number of physiological processes, such as cell survival, proliferation, neural development, and axon and dendrite growth and patterning. In the adult nervous system, the Trk receptors regulate synaptic strength and plasticity. TrkA regulates proliferation and is important for development and maturation of the nervous system. Phosphorylation at Tyr490 is required for Shc association and activation of the Ras-MAP kinase cascade. Residues Tyr674/675 lie within the catalytic domain, and phosphorylation at these sites reflects TrkA kinase activity. Point mutations, deletions, and chromosomal rearrangements (chimeras) cause ligand-independent receptor dimerization and activation of TrkA. TrkA is activated in many malignancies including breast, ovarian, prostate, and thyroid carcinomas. Research studies suggest that expression of TrkA in neuroblastomas may be a good prognostic marker as TrkA signals growth arrest and differentiation of cells originating from the neural crest.
The phosphorylation sites are conserved between TrkA and TrkC: Tyr490 of TrkA corresponds to Tyr516 in TrkC, and Tyr674/675 of TrkA to Tyr709/710 in TrkC of the human sequence . Research studies have demonstrated altered TrkC expression and corresponding gene mutations in various forms of cancer, with increased expression as a potential positive prognostic indicator in patients with medulloblastoma.