NGF binding induces a conformational change in TRKA, which entails the activation of the receptor kinase domain. TRK receptor activation results in phosphorylation of several of ten evolutionary conserved tyrosines present in the cytoplasmic domain of each receptor. Phosphorylation of the three tyrosines in the activation loop of the kinase domain (Y670, Y674, and Y675 in TRKA) enhances tyrosine kinase activity. Phosphorylation of TRKA Y490 and Y785 creates docking sites for proteins containing SH2 or PTB domains: Y490 is the docking site for SHC, FRS2 and IRS1/2, Y785 interacts with PLC-gamma-1. Three other tyrosine residues are important for signalling but it is not clear how. It is possible that they play a structural role in the receptor. Therefore, full activity of TRKA receptor requires eight tyrosine residues.
Human TRKA comes in two isoforms, named TRKA- I (790 a.a long) and TRKA- II (796 a.a. long). The tyrosine phosphorylation site numbering refers to TRKA- I. The site numbering in TRK-II is equal to TRK- I numbering + 6 (that is: Y490 in TRK- I corresponds to Y496 in TRK- II, and so on).The same modifications occur at the homologous sites of rat TrkA, which also comes in the two isoforms I and II.