NTRK3

NTRK3, or neurotrophic receptor tyrosine kinase 3, encodes the receptor tyrosine kinase TRKC, a member of the TRK family involved in neurotrophic signaling. The protein features an extracellular domain with immunoglobulin-like motifs, a single transmembrane segment, and an intracellular tyrosine kinase domain. Its preferred ligand is neurotrophin-3 (NT-3), which binds TRKC to promote receptor dimerization and autophosphorylation, initiating downstream signaling.

Activated TRKC engages multiple signaling pathways, including MAPK/ERK, PI3K/AKT, and PLCγ, to regulate neuronal survival, differentiation, and synaptic plasticity. NTRK3 expression is highest in the developing nervous system and in certain sensory neurons, with roles in neuronal maintenance and pain signaling.

Clinical relevance is most evident in oncogenic NTRK3 rearrangements. The best characterized fusion is ETV6-NTRK3, resulting from a t(12;15) translocation, which yields a constitutively active kinase driving tumorigenesis in infantile fibrosarcoma, secretory breast carcinoma, and congenital mesoblastic nephroma, among others. In these contexts, NTRK3 alterations can act as actionable drivers.

Therapeutics and diagnostics: tumors harboring NTRK gene fusions may respond to TRK inhibitors such as larotrectinib and entrectinib, which are approved for NTRK fusion–positive cancers irrespective of tissue origin. Diagnostic detection relies on sequencing-based assays, fluorescence in situ hybridization (FISH), or RT-PCR to identify NTRK3 rearrangements or fusions.

Alternative names for the gene and protein include NTRK3 and TRKC.