Tropomyosin receptor kinase C
|, GP145-TrkC, TRKC, gp145(trkC), neurotrophic receptor tyrosine kinase 3|
Tropomyosin receptor kinase C (TrkC), also known as NT-3 growth factor receptor, neurotrophic tyrosine kinase receptor type 3, or TrkC tyrosine kinase is a protein that in humans is encoded by the NTRK3 gene.
TrkC is the high affinity catalytic receptor for the neurotrophin NT-3 (neurotrophin-3). As such, TrkC mediates the multiple effects of this neurotrophic factor, which includes neuronal differentiation and survival.
The TrkC receptor is part of the large family of receptor tyrosine kinases. A "tyrosine kinase" is an enzyme which is capable of adding a phosphate group to the certain tyrosines on target proteins, or "substrates". A receptor tyrosine kinase is a "tyrosine kinase" which is located at the cellular membrane, and is activated by binding of a ligand via its extracellular domain. Other example of tyrosine kinase receptors include the insulin receptor, the IGF-1 receptor, the MuSK protein receptor, the vascular endothelial growth factor (VEGF) receptor, etc. The "substrate" proteins which are phosphorylated by TrkC include PI3 kinase.
TrkC is part of a sub-family of protein kinases which includes TrkA and TrkB. Also, there are other neurotrophic factors structurally related to NT-3: NGF (for Nerve Growth Factor), BDNF (for Brain Derived Neurotrophic Factor) and NT-4 (for Neurotrophin-4). While TrkB mediates the effects of BDNF, NT-4 and NT-3, TrkA is bound and thereby activated only by NGF. Further, TrkC binds and is activated only by NT-3.
TrkB binds BDNF and NT-4 more strongly than it binds NT-3. TrkC binds NT-3 more strongly than TrkB does.
There is one other NT-3 receptor family besides the Trks (TrkC & TrkB), called the "LNGFR" (for "low affinity nerve growth factor receptor"). As opposed to TrkC, the LNGFR plays a somewhat less clear role in NT-3 biology. Some researchers have shown the LNGFR binds and serves as a "sink" for neurotrophins. Cells which express both the LNGFR and the Trk receptors might therefore have a greater activity - since they have a higher "microconcentration" of the neurotrophin. It has also been shown, however, that the LNGFR may signal a cell to die via apoptosis - so therefore cells expressing the LNGFR in the absence of Trk receptors may die rather than live in the presence of a neurotrophin.
It has been demonstrated that NTRK3 is a dependence receptor, meaning that it can be capable of inducing proliferation when it binds to its ligand NT-3, however, the absence of the NT-3 will result in the induction of apoptosis by NTRK3.
Role in cancer
Although originally identified as an oncogenic fusion in 1982, only recently has there been a renewed interest in the Trk family as it relates to its role in human cancers because of the identification of NTRK1 (TrkA), NTRK2 (TrkB) and NTRK3 (TrkC) gene fusions and other oncogenic alterations in a number of tumor types. A number of Trk inhibitors are (in 2015) in clinical trials and have shown early promise in shrinking human tumors. Family of neurotrophin receptors including NTRK3 have been shown to induce a variety of pleiotorpic response in malignant cells, including enhanced tumor cell invasiveness and chemotoxis. Increased NTRK3 expression has been demonstrated in neuroblastoma, in medulloblastoma, and in neuroectodermal brain tumors.
The promoter region of NTRK3 contains a dense CpG island located relatively adjacent to the transcription start site (TSS). Using HumanMethylation450 arrays, quantitative methylation-specific PCR (qMSP), and Methylight assays, it has been indicated that NTRK3 is methylated in all CRC cell lines and non of the normal epithelium samples. In light of its preferential methylation in CRCs and because of its role as a neurotrophin receptor, it has been suggested to have a functional role in colorectal cancer formation. It has also been suggested that methylation status of NTRK3 promoter is capable of discriminating CRC tumor samples from normal adjacent tumor-free tissue. Hence it can be considered as a biomarker for molecular detection of CRC, specially in combination with other markers like SEPT9. NTRK3 has also been indicated as one of the genes in the panel of nine CpG methylation probes located at promoter or exon 1 region of eight genes (including DDIT3, FES, FLT3, SEPT5, SEPT9, SOX1, SOX17, and NTRK3) for prognostic prediction in ESCC (esophageal squamous cell carcinoma) patients.
TrkC (NTRK3 gene) inhibitors in development
Entrectinib (formerly RXDX-101) is an investigational drug developed by Ignyta, Inc., which has potential antitumor activity. It is a selective pan-trk receptor tyrosine kinase inhibitor (TKI) targeting gene fusions in trkA, trkB, and trkC (coded by NTRK1, NTRK2, and NTRK3 genes) that is currently in phase 2 clinical testing.
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