TRKC

Official Full Name

neurotrophic receptor tyrosine kinase 3

Organism

Homo sapiens

GeneID

4916

Background

This gene encodes a member of the neurotrophic tyrosine receptor kinase (NTRK) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. Signalling through this kinase leads to cell differentiation and may play a role in the development of proprioceptive neurons that sense body position. Mutations in this gene have been associated with medulloblastomas, secretory breast carcinomas and other cancers. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2011]

Synonyms

TRKC; GP145-TrkC; gp145(trkC);

Bio Chemical Class

Kinase

Protein Sequence

MDVSLCPAKCSFWRIFLLGSVWLDYVGSVLACPANCVCSKTEINCRRPDDGNLFPLLEGQDSGNSNGNASINITDISRNITSIHIENWRSLHTLNAVDMELYTGLQKLTIKNSGLRSIQPRAFAKNPHLRYINLSSNRLTTLSWQLFQTLSLRELQLEQNFFNCSCDIRWMQLWQEQGEAKLNSQNLYCINADGSQLPLFRMNISQCDLPEISVSHVNLTVREGDNAVITCNGSGSPLPDVDWIVTGLQSINTHQTNLNWTNVHAINLTLVNVTSEDNGFTLTCIAENVVGMSNASVALTVYYPPRVVSLEEPELRLEHCIEFVVRGNPPPTLHWLHNGQPLRESKIIHVEYYQEGEISEGCLLFNKPTHYNNGNYTLIAKNPLGTANQTINGHFLKEPFPESTDNFILFDEVSPTPPITVTHKPEEDTFGVSIAVGLAAFACVLLVVLFVMINKYGRRSKFGMKGPVAVISGEEDSASPLHHINHGITTPSSLDAGPDTVVIGMTRIPVIENPQYFRQGHNCHKPDTYVQHIKRRDIVLKRELGEGAFGKVFLAECYNLSPTKDKMLVAVKALKDPTLAARKDFQREAELLTNLQHEHIVKFYGVCGDGDPLIMVFEYMKHGDLNKFLRAHGPDAMILVDGQPRQAKGELGLSQMLHIASQIASGMVYLASQHFVHRDLATRNCLVGANLLVKIGDFGMSRDVYSTDYYRLFNPSGNDFCIWCEVGGHTMLPIRWMPPESIMYRKFTTESDVWSFGVILWEIFTYGKQPWFQLSNTEVIECITQGRVLERPRVCPKEVYDVMLGCWQREPQQRLNIKEIYKILHALGKATPIYLDILG

Open

Disease

Adrenal cancer, Alzheimer disease, Breast cancer, Chronic pain, Colorectal cancer, General pain disorder, Non-small-cell lung cancer, Pruritus, Solid tumour/cancer, Thymoma

Approved Drug

2 +

Clinical Trial Drug

2 +

Discontinued Drug

1 +

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Detailed Information

TRKC, encoded by the NTRK3 gene, is the third member of the neurotrophin receptor family and is located on human chromosome 15q25.3. Its gene structure comprises 17 exons and generates multiple isoforms through alternative splicing. The full-length TRKC receptor consists of 839 amino acids and features a typical extracellular ligand-binding domain, a single transmembrane helix, and an intracellular tyrosine kinase domain. Structurally, the extracellular region contains conserved cysteine clusters and leucine-rich repeats, conferring high-affinity binding to neurotrophin-3 (NTF3). Unlike TRKA and TRKB, TRKC exhibits strict ligand selectivity, primarily responding to NTF3 signals. TRKC is widely expressed in the developing nervous system, including the dorsal root ganglia, trigeminal ganglia, and multiple regions of the central nervous system, highlighting its specialized role in sensory neuron development.

TRKC expression is also physiologically significant in non-neuronal tissues. During cardiac development, TRKC expression in myocardial progenitors and endocardial cushions is crucial for the migration and differentiation of cardiac neural crest cells. In mammary tissue, TRKC shows stage-specific expression, and its levels are associated with molecular subtypes and prognosis in breast cancer. Bioinformatic analyses indicate that TRKC expression is lower in breast tumors than in normal tissue, and higher expression correlates with favorable outcomes. Epigenetic studies suggest that promoter hypermethylation may contribute to TRKC downregulation in tumor contexts.

Figure 1. Diagram of TrkC biology and signaling identified in various cancers. (Jin W. et al., 2020.)

Physiological Functions and Developmental Significance

The TRKC-NTF3 signaling pathway is indispensable for the survival, differentiation, and functional maintenance of specific neuronal subpopulations. In the dorsal root ganglia, TRKC is predominantly expressed in proprioceptive neurons, responsible for transmitting limb position and movement information. Experimental studies demonstrate that TRKC-deficient mice exhibit proprioceptive deficits and impaired motor coordination without affecting pain and temperature sensation. Within the sympathetic nervous system, TRKC works in concert with TRKA to regulate the migration and differentiation of neural crest cells. Mechanistically, NTF3 binding induces TRKC dimerization and autophosphorylation, activating two main downstream pathways: the PI3K-AKT survival pathway and the Ras-MAPK differentiation pathway. TRKC signaling is critical for neuronal subtype specification, and its expression level influences sensory neurons' differentiation into distinct functional phenotypes.

Beyond the nervous system, TRKC plays an important role in cardiovascular development. During embryonic heart formation, TRKC regulates neural crest cell migration and differentiation, contributing to outflow tract and valve morphogenesis. Its signaling may influence neuronal resilience and tissue responses under stress conditions, providing potential protective effects in contexts such as migraine and cardiac malformations.

Tumor Associations and Therapeutic Applications

In oncology, TRKC is recognized as a member of the TRK family and is a target in tumors harboring NTRK3 gene rearrangements. These fusions, detected in various solid tumors including secretory breast carcinoma, congenital mesoblastic nephroma, and infantile fibrosarcoma, result in constitutively active chimeric proteins that drive proliferation and survival. Although NTRK3 fusions are rare in common tumors, their high prevalence in certain rare cancers has established TRKC as a paradigm for tissue-agnostic targeted therapy.

TRKC fusion inhibitors have achieved notable clinical success. First-generation TRK inhibitors, including larotrectinib and entrectinib, exhibit high response rates and durable effects in patients with NTRK fusion-positive cancers. These ATP-competitive inhibitors bind conserved regions of the kinase domain, blocking downstream signaling. Next-generation inhibitors are under investigation to overcome resistance due to kinase domain mutations or bypass pathway activation.

In non-fusion-dependent tumors, TRKC exhibits context-dependent functions. In breast cancer, higher NTRK3 expression is associated with improved survival, suggesting potential tumor-suppressive roles. Mechanistic studies indicate that certain microRNAs can downregulate TRKC, promoting tumor progression and providing potential targets for therapeutic intervention. In contrast, in some cancers such as colorectal carcinoma, full-length TRKC may enhance invasiveness through non-canonical pathways, demonstrating tissue-specific functional variability.

Emerging research also explores TRKC-targeted strategies in cardiovascular and neurological diseases. Modulating TRKC expression or activity may hold promise for congenital heart defect prevention and migraine management. Advances in viral vector and antisense oligonucleotide technologies may enable tissue-specific TRKC modulation, offering new avenues for precision intervention. Future studies integrating multi-omics data are expected to clarify TRKC's roles across physiological and pathological contexts, guiding therapeutic development.

Reference

Jin W. Roles of TrkC Signaling in the Regulation of Tumorigenicity and Metastasis of Cancer. Cancers (Basel). 2020 Jan 8;12(1):147.
Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018 Dec;15(12):731-747.

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