TRKC

TrkC, or tropomyosin receptor kinase C, is a receptor tyrosine kinase in the neurotrophin receptor family. In humans, the functional receptor is encoded by the NTRK3 gene. TrkC binds the neurotrophin NT-3 with high affinity and transduces signals that influence neuronal survival, differentiation, and connectivity. The receptor is expressed in various parts of the nervous system, including developing and mature neurons, and plays roles in sensory and proprioceptive pathways as well as synaptic plasticity.

Structurally, TrkC has an extracellular ligand-binding domain, a single transmembrane helix, and an intracellular tyrosine kinase domain. Upon NT-3 binding, TrkC dimerizes and undergoes autophosphorylation, which activates several downstream signaling cascades. In addition to the canonical full-length receptor, alternative splicing can generate truncated isoforms that lack kinase activity; these variants can modulate signaling by acting as decoys or regulators of the pathway.

Ligand specificity centers on NT-3 as the primary high-affinity ligand, although in some contexts other neurotrophins may engage Trk receptors at lower efficiency. Downstream, TrkC signaling commonly engages the PI3K-Akt, Ras-MAPK/ERK, and PLCγ pathways, promoting neuronal survival, growth, differentiation, and synaptic modulation.

Clinical relevance includes oncogenic NTRK3 alterations, such as gene fusions that produce constitutively active TrkC kinases in various cancers. These fusions are therapeutic targets for TRK inhibitors (e.g., larotrectinib, entrectinib) in tissue-agnostic cancer treatments. Beyond cancer, NT-3/TrkC signaling has been implicated in pain pathways and neural development.