# NTRK3

## Overview
NTRK3 is a gene that encodes for neurotrophic receptor tyrosine kinase 3 (TrkC), a protein that functions as a receptor tyrosine kinase. This protein is integral to the development and function of the nervous system and is characterized by its structure which includes a ligand-binding extracellular domain, a transmembrane domain, and an intracellular tyrosine kinase domain. TrkC is activated by binding to its ligand, neurotrophin-3, leading to autophosphorylation and activation of downstream signaling pathways crucial for neural development and survival. The protein is also involved in various cellular processes including apoptosis and has been implicated in several types of cancer due to mutations and translocations that affect its gene (Luo2013NTRK3; Werner2014Mutations). The clinical significance of NTRK3 extends to its role in oncogenesis, particularly through the formation of fusion proteins that drive tumor growth in various cancers, making it a target for specific cancer therapies (Marchiò2019ESMO).

## Structure
NTRK3 encodes the TRKC protein, a member of the neurotrophic tyrosine receptor kinase (Trk) family, which plays a crucial role in the development and function of the nervous system. The molecular structure of TRKC includes a ligand-binding extracellular domain, a transmembrane domain, and an intracellular tyrosine kinase domain. The extracellular region contains two immunoglobulin-like domains (Ig1 and Ig2) and three leucine-rich repeat motifs (LRR1-3), flanked by two cysteine clusters (C1 and C2). These domains are involved in neurotrophin binding, with the Ig2 domain playing a crucial role in ligand interaction (Cocco2018NTRK; Khotskaya2017Targeting).

The intracellular region of TRKC includes a tyrosine kinase domain, which becomes active upon ligand binding and receptor homodimerization, triggering downstream signaling pathways such as PI3K, RAS/MAPK/ERK, and PLC-gamma (Khotskaya2017Targeting; Weiss2021NTRK). Several splice variants of TRKC have been identified, which contain variable-sized amino acid insertions in the kinase domain, retaining the ability to be activated by neurotrophin-3 but differing in their biological functions (Cocco2018NTRK).

In the context of NTRK3 fusions, the kinase domain is preserved and is crucial for the oncogenic activity of the fusion proteins. These fusions often involve a coiled-coil domain contributed by the fusion partners, important for dimerization and subsequent activation of the kinase domain (Yeh2016NTRK3; Wang2017Identification).

## Function
NTRK3 encodes the neurotrophic tyrosine kinase receptor type 3 (TrkC), which is primarily active in neural tissues and plays a significant role in the development and function of the nervous system. TrkC, upon binding with its ligand neurotrophin-3 (NT-3), undergoes autophosphorylation and activates downstream signaling pathways such as PI3K/AKT and MAPK. These pathways are crucial for regulating survival and differentiation in developing neural crest cells (Werner2014Mutations). In addition to its role in the nervous system, TrkC and NT-3 are also critical for heart development, as evidenced by severe cardiovascular anomalies observed in gene-targeted mice lacking TrkC or NT-3 expression (Werner2014Mutations).

NTRK3 also functions as a dependence receptor in various tissues, including the colon. In the absence of NT-3, NTRK3 can induce apoptosis, a process of programmed cell death crucial for maintaining cellular homeostasis and preventing uncontrolled cell proliferation. This dual functionality categorizes NTRK3 as a dependence receptor, which can have contrasting biological effects based on the presence or absence of its ligand (Luo2013NTRK3). Furthermore, NTRK3 has been shown to suppress in vitro anchorage-independent colony formation and in vivo tumor growth, suggesting its role in inhibiting tumorigenesis (Luo2013NTRK3).

## Clinical Significance
NTRK3 gene mutations and alterations are significantly linked to various cancers and medical conditions. The ETV6-NTRK3 fusion gene, resulting from a specific chromosomal translocation, is notably prevalent in over 95% of secretory carcinomas of the breast and salivary glands, particularly in mammary analogue secretory carcinoma of the salivary glands. This fusion leads to the constitutive activation of the TRKC kinase domain, promoting cancer cell proliferation and survival (Penault-Llorca2019Testing; Marchiò2019ESMO). Additionally, this gene fusion is commonly found in infantile fibrosarcoma and congenital mesoblastic nephroma, acting as a significant oncogenic driver in these tumors (Koopman2022Detection; Vaishnavi2015TRKing).

In lung adenocarcinoma, NTRK3 mutations enhance antitumor immunity and are associated with upregulation of immune activation-related genes and downregulation of immunosuppression-related genes, suggesting a role in tumor immunogenicity and response to anticancer drugs (Niu2020Prognosis). Furthermore, NTRK3 gene alterations, including mutations and fusions, are implicated in the development of various other cancers, highlighting their clinical significance in targeted cancer therapy, particularly with the use of TRK inhibitors like larotrectinib and entrectinib (Okamura2018Analysis).

## Interactions
NTRK3, a neurotrophic receptor tyrosine kinase, engages in several critical protein-protein interactions that influence various signaling pathways. The ETV6-NTRK3 (EN) fusion protein, which includes the tyrosine kinase domain of NTRK3, interacts with the insulin receptor substrate 1 (IRS1) through an NPXY motif in the EN C-terminus and the PTB domain of IRS1. This interaction is pivotal for the recruitment of Grb2 and p85, activating the Ras-Erk and PI3K-Akt signaling pathways, essential for EN-mediated transformation (Tognon2011A). Additionally, the EN protein interacts with c-Src, leading to increased phosphorylation of c-Src at Tyr 416, which suggests activation of c-Src by EN (Jin2007Cellular). Furthermore, EN has been shown to suppress TGF-β signaling by interacting with the TGF-β type II receptor (TβRII) in a kinase-dependent manner (Jin2005The). The interaction of EN with IRS-1 is crucial for its localization and transformation activity, particularly in the context of IGF1R-mediated membrane localization (Tognon2011A). These interactions underline the significant role of NTRK3 kinase activity in mediating interactions with other proteins, contributing to oncogenic processes.


## References


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