Neurotrophin receptor tyrosine kinase 3 (NTRK3) (TrkC)

Neurotrophin receptor tyrosine kinase 3 (NTRK3), commonly known as TrkC, is a high-affinity receptor for neurotrophin-3 (NT-3) and belongs to the tropomyosin receptor kinase family (UniProt: Q16288; NCBI Gene: 4916). Upon binding NT-3, TrkC undergoes dimerization and autophosphorylation, activating downstream signaling cascades such as the MAPK/ERK, PI3K/Akt, and PLC-gamma pathways, which are essential for the development and maintenance of the mammalian nervous system, particularly proprioceptive neurons (UniProt: Q16288; StatPearls: NBK545155). In oncology, chromosomal rearrangements leading to NTRK3 gene fusions result in constitutively active chimeric proteins that drive oncogenesis in various rare and common cancers, such as secretory breast carcinoma and infantile fibrosarcoma (Nature Reviews Clinical Oncology: PMID 29844115). Therapeutic targeting of the NT-3/TrkC pathway primarily involves small-molecule tyrosine kinase inhibitors (TKIs) like larotrectinib and entrectinib, which have shown significant efficacy in patients with NTRK-fusion-positive tumors (NEJM: PMID 29466156; Lancet Oncology: PMID 32066544). Beyond oncology, the pathway is investigated for its roles in neuroprotection and psychiatric disorders, though clinical applications in these areas remain experimental (StatPearls: NBK545155). Safety considerations for TrkC-targeted therapies include neurological effects and potential weight gain, reflecting the receptor's physiological role in the central and peripheral nervous systems (NEJM: PMID 29466156).

Other names

Tropomyosin receptor kinase CNT-3 receptorGP145-TrkCTrk-CNeurotrophic tyrosine kinase receptor type 3

Small molecule inhibition of the TrkC kinase domain to block downstream signaling (MAPK, PI3K/Akt, PLC-gamma) by competitively binding to the ATP-binding site (NEJM: PMID 29466156; Lancet Oncology: PMID 32066544).