a | The inset image indicates the ligand specificity of the TRK proteins for the neurotrophins, brain-derived neurotrophic factor (BDNF), nerve-growth factor (NGF), neutrotrophin 3 (NT-3), and/or neurotrophin 4 (NT-4), which each bind to their cognate receptors as a homodimer. TRKA is the high affinity receptor for NGF, whereas TRKB has high affinity for both BDNF and NT-4. NT-3 can bind to all TRK receptors but has highest affinity for TRKC and is the sole ligand of this receptor. Additionally, the TNF receptor superfamily member p75NTR can bind to all neurotrophins with low affinity, resulting in enhanced TRK signalling and/or the activation of distinct signalling pathways. The main image depicts the structure of the TRK–neurotrophin complex and the signalling pathways activated by TRK upon neurotrophin stimulation. The cysteine clusters C1 and C2, leucine-rich regions (LRR) 1–3, the Ig1 and Ig2 immunoglobulin-like motifs, and the kinase domain (KD) are indicated. The binding of neurotrophins to the extracellular region of TRK proteins, predominantly at the Ig2 domain, results in ligand-dependent receptor homodimerization followed by transactivation of the intracellular tyrosine kinase domains and the recruitment of various cytoplasmic adaptors. The phosphorylation events that mediate activation of the kinase domain or binding of SHC-transforming protein (SHC), fibroblast growth factor receptor substrate 2 (FRS2), and phosphoinositide phospholipase Cɣ (PLCɣ) to TRK proteins are depicted. The recruited adaptor proteins activate downstream signalling pathways, including the MAPK, PI3K, and PKC pathways. Each of these signalling pathways also activates the transcription of genes involved in the differentiation and survival of neurons. b | The schematic domain structures of known splice variants of TRKA, TRKB, and TRKC are shown. The docking residues for SHC–FRS2, and PLCɣ, and the three phosphorylated tyrosines within the activation loop of the kinase domain are also displayed. The ctrkB-S, TrkC, and TrkC-TK− schematics were generated using the amino acid sequences of chicken TrkB and porcine TrkC, respectively — the organisms in which these variants were initially discovered. Of note, an alternative ATG transcription-initiation site in the NTRK2 gene has been reported; transcripts starting from this alternative site give rise to multiple additional TRKB-derived transcripts (not shown). 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; DAG, diacylgycerol; GAB1, GRB2-associated-binding protein 1; GRB2, growth factor receptor-bound protein 2; IP3, inositol triphosphate; mTORC, mechanistic target of rapamycin complex; NF1, neurofibromin; p85, PI3K 85 kDa regulatory subunit α; PIP3, phosphatidylinositol 3,4,5-trisphosphate; SHP2, SH-PTP2 (also known as tyrosine-protein phosphatase non-receptor type 11); SOS, son of sevenless homologue.