Affinage

Showing NTRK3 — TRKC is a alias.

NTRK3

NT-3 growth factor receptor · UniProt Q16288

Length
839 aa
Mass
94.4 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NTRK3 (TrkC) is the high-affinity receptor tyrosine kinase for neurotrophin-3 (NT-3) and a central regulator of sensory neuron and neural crest development, generating multiple isoforms whose distinct signaling outputs underlie its diverse roles (PMID:8344249, PMID:8145824). The full-length kinase-active receptor (K1) autophosphorylates on NT-3 binding and engages PLCγ1, PI3K, and Ras-MAPK pathways to drive proliferation and neuronal differentiation, whereas insertion-bearing isoforms K2/K3 and truncated forms lack these substrate-coupled activities (PMID:8344249, PMID:8494647). Productive PI3K-Akt signaling by TrkC requires association with c-Src, while Ras-Erk1/2 activation proceeds independently of c-Src, and TrkC favors Shc-site-independent routes that distinguish it mechanistically from TrkB (PMID:17991742, PMID:11877382). The kinase-dead TrkCT1 isoform signals separately by binding the scaffold tamalin to activate Arf6 and Rac1, inducing membrane ruffling (PMID:16636148). Genetic ablation of TrkC eliminates Ia proprioceptive afferents and produces cardiac outflow tract and septal defects through impaired neural crest development, and human NTRK3 missense mutations that blunt NT-3-induced autophosphorylation are linked to congenital heart disease with ventricular septal defects (PMID:8145824, PMID:9405689, PMID:14550777, PMID:25196463). In the absence of NT-3, TrkC acts as a dependence receptor: its intracellular domain is cleaved to a proapoptotic killer fragment that recruits Cobra1 to mitochondria, driving Bax activation and apoptosome-dependent death, a tumor-suppressor function silenced by promoter methylation in colorectal cancer (PMID:20811452, PMID:23341610, PMID:24034695). Independently of neurotrophin, postsynaptic TrkC engages presynaptic PTPσ in a trans-synaptic adhesion complex that organizes excitatory glutamatergic synapses (PMID:21262467). As an oncogenic driver, the ETV6-NTRK3 fusion uses the ETV6 HLH domain to dimerize and constitutively activate the NTRK3 kinase, requiring a tripartite EN/IRS1/IGF1R complex for membrane localization and synergistic Ras-Erk1/2 and PI3K-Akt signaling to transform fibroblast, epithelial, and other lineages (PMID:10702799, PMID:11751416, PMID:14668342, PMID:21804605).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1993 High

    Established that NTRK3 is the high-affinity NT-3 receptor and that alternative kinase-domain isoforms differ in catalytic output, defining the receptor's isoform-specific signaling logic.

    Evidence In vitro kinase, mitogenesis, and PC12 differentiation assays with K1/K2/K3 isoforms plus truncated forms

    PMID:8344249 PMID:8494647

    Open questions at the time
    • Endogenous in vivo roles of K2/K3 versus K1 not resolved
    • Substrate specificity differences not mapped to structural determinants
  2. 1994 High

    Demonstrated TrkC is required for proprioceptive neuron development, linking receptor kinase activity to a defined neuroanatomical circuit.

    Evidence Targeted knockout of the TrkC kinase domain in mice with histology and behavior

    PMID:8145824

    Open questions at the time
    • Did not address roles of truncated isoforms
    • Downstream effectors in proprioceptive neurons not defined
  3. 1997 High

    Extended TrkC function to cardiac neural crest development and revealed NT-3 can act through non-TrkC receptors, refining ligand-receptor epistasis in vivo.

    Evidence Complete trkC locus knockout with cardiac histology and comparison to NT-3 null mice

    PMID:9405689

    Open questions at the time
    • Identity of alternative NT-3 receptors not established
    • Cell-autonomous versus non-autonomous cardiac requirement unclear
  4. 2002 High

    Showed TrkC drives neuronal survival mainly via Shc-site-independent pathways, distinguishing its mechanism from TrkB.

    Evidence trkC(shc/shc) knock-in mice with survival counts, innervation tracing, and autophosphorylation assays

    PMID:11877382

    Open questions at the time
    • The Shc-independent effectors mediating survival not identified
  5. 2003 High

    Defined kinase-active TrkC effector branches: NT-3 drives Schwann cell migration via Rac1/Cdc42/JNK independent of p75NTR.

    Evidence p75NTR-null Schwann cell migration assay with K252a and dominant-negative Rho GTPases

    PMID:14614136

    Open questions at the time
    • Direct GEF/effector coupling TrkC to Rho GTPases not mapped
  6. 2006 High

    Revealed a kinase-independent signaling route through the truncated TrkCT1 isoform via tamalin-Arf6-Rac1, expanding TrkC output beyond catalysis.

    Evidence Reciprocal co-IP, Arf6 activation assay, live imaging, and dominant-negative epistasis

    PMID:16636148

    Open questions at the time
    • Physiological context of TrkCT1-tamalin signaling in vivo not defined
  7. 2006 Medium

    Identified Dok5 as a kinase-dependent TrkC/TrkB substrate competing with N-Shc, adding a MAPK-coupling adaptor to the effector network.

    Evidence Yeast two-hybrid, GST pull-down, co-IP, and competition/MAPK assays in PC12 cells

    PMID:16647839

    Open questions at the time
    • Single-lab finding without in vivo validation
    • Relative contribution of Dok5 versus Shc in neurons unresolved
  8. 2007 High

    Dissected the requirement for c-Src in TrkC PI3K-Akt activation, separating Akt and Erk1/2 branch dependencies.

    Evidence SYF (Src/Yes/Fyn-deficient) cells, siRNA, and co-IP from primary breast cancer tissue

    PMID:17991742

    Open questions at the time
    • Mechanism by which c-Src couples TrkC to PI3K not structurally defined
  9. 2010 High

    Established TrkC (with TrkA, unlike TrkB) as a dependence receptor instructing neuronal death in the absence of ligand, reframing trophic dependency.

    Evidence Engineered ES cell differentiation with gain-of-function and in vivo knockout comparison

    PMID:20811452

    Open questions at the time
    • Molecular machinery of death signaling not addressed in this study
  10. 2011 High

    Uncovered a neurotrophin-independent synaptic adhesion role: postsynaptic TrkC binds presynaptic PTPσ to organize excitatory glutamatergic synapses.

    Evidence Coculture screen, reciprocal co-IP, neutralizing antibody, and in vivo shRNA knockdown

    PMID:21262467

    Open questions at the time
    • Postsynaptic clustering effectors downstream of TrkC not fully defined
    • Interplay between adhesion and kinase functions unclear
  11. 2013 High

    Resolved the molecular machinery of TrkC dependence-receptor apoptosis, identifying killer-fragment cleavage and Cobra1-mediated mitochondrial Bax activation, and its tumor-suppressor role in colorectal cancer.

    Evidence Killer fragment/Cobra1 co-IP, mitochondrial fractionation, Bax/cytochrome c assays, chick neural tube epistasis, plus colorectal reconstitution and methylation analysis

    PMID:23341610 PMID:23874207 PMID:24034695

    Open questions at the time
    • Protease responsible for the double cleavage not identified
    • Switch governing survival versus death output not fully defined
  12. 2011 High

    Defined the oncogenic ETV6-NTRK3 mechanism: HLH-mediated dimerization plus a tripartite EN/IRS1/IGF1R complex drives membrane localization and dual Ras-Erk and PI3K-Akt activation for transformation.

    Evidence Domain/point mutagenesis, co-IP, membrane fractionation, dominant-negative IRS1, IGF1R inhibitors, and soft agar/in vivo tumor assays

    PMID:10702799 PMID:11751416 PMID:14668342 PMID:21804605

    Open questions at the time
    • Lineage determinants of EN-driven tumor phenotype not fully resolved
  13. 2014 Medium

    Linked NTRK3 to human disease beyond fusions, showing congenital heart disease mutations impair NT-3-induced autophosphorylation and downstream signaling.

    Evidence Patient-derived NTRK3 mutants in neuroblastoma cells with autophosphorylation, signaling, and growth assays

    PMID:25196463

    Open questions at the time
    • Causality in patients not established by genetic rescue
    • Only one mutation fully mechanistically characterized
  14. 2016 Medium

    Generalized NTRK3 fusion oncogenicity across tumor types (Spitz tumors, GIST) and confirmed druggability of constitutive MAPK/PI3K/PLCγ1 signaling.

    Evidence Fusion identification with pathway activation Westerns and pharmacological NTRK/IGF1R inhibition in melanocytes and GIST models

    PMID:26606880 PMID:27477320

    Open questions at the time
    • Single-lab functional studies
    • Fusion-partner-specific signaling differences not systematically compared
  15. 2022 High

    Explained NT-3/TrkC selectivity through ligand concentration thresholds and showed TrkC activation reshapes synaptic-plasticity gene programs in human neurons.

    Evidence Human ESC-derived neurons with CRISPR TrkB knockout, dose-response signaling, and transcriptome analysis

    PMID:35536742

    Open questions at the time
    • In vivo relevance of concentration-dependent crosstalk not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TrkC integrates its multiple modes — catalytic survival signaling, ligand-independent dependence-receptor apoptosis, and synaptic adhesion — into a single decision at the cell level remains unresolved.
  • The molecular switch between trophic and apoptotic output is undefined
  • Isoform-specific contributions to physiological versus pathological roles not delineated
  • The protease executing dependence-receptor cleavage is unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 3 GO:0060089 molecular transducer activity 3 GO:0001618 virus receptor activity 1 GO:0060090 molecular adaptor activity 1 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005886 plasma membrane 2 GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-112316 Neuronal System 2
Partners
BMPR2COBRA1DOK5IGF1RIRS1NTF3PTPRSSRC
Complex memberships
ETV6-NTRK3/IRS1/IGF1R tripartite complexTrkC-PTPσ trans-synaptic adhesion complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 TrkC (NTRK3) is a high-affinity signaling receptor for neurotrophin-3 (NT-3). The trkC locus encodes at least three tyrosine protein kinase receptor isoforms (K1, K2, K3) differing by 14 or 25 amino acid insertions between kinase subdomains VII and VIII. All three isoforms autophosphorylate on tyrosine and induce DNA synthesis upon NT-3 binding; however, only TrkC K1 has mitogenic activity in NIH3T3 cells, induces neuronal differentiation of PC12 cells, and phosphorylates PLCγ1 and PI3-kinase. TrkC K2 and K3 do not phosphorylate these substrates. In vitro kinase assay, autophosphorylation assay, NIH3T3 mitogenesis assay, PC12 differentiation assay, substrate phosphorylation (PLCγ1, PI3K) The EMBO journal High 8344249
1993 TrkC encodes truncated isoforms lacking the intracytoplasmic kinase domain. Forms containing kinase domain insertions retain autophosphorylation in response to NT-3 but cannot mediate proliferation in fibroblasts or neuronal differentiation in PC12 cells. Molecular cloning, expression in fibroblasts and PC12 cells, autophosphorylation assay, proliferation and differentiation assays Neuron High 8494647
1994 Homozygous disruption of the TrkC tyrosine kinase domain in mice eliminates Ia muscle afferent projections to spinal motor neurons, reduces large myelinated axons in dorsal root and posterior spinal cord, and causes abnormal movements and postures, establishing TrkC as essential for proprioceptive sensory neuron development. Targeted gene knockout (loss-of-function mouse model), histological analysis, behavioral assessment Nature High 8145824
1997 Mice lacking all trkC isoforms display proprioceptive neuron loss, severe cardiac defects (atrial and ventricular septal defects, pulmonic stenosis), implicating TrkC-mediated NT-3 signaling in cardiac neural crest development. NT-3 null mice show more severe sensory neuron losses, suggesting NT-3 can signal through receptors other than TrkC in vivo. Complete trkC locus knockout (null mutant mice), neuronal counts, histological examination of cardiac structures, comparison with NT-3 null mice (epistasis) Proceedings of the National Academy of Sciences of the United States of America High 9405689
1998 ETV6-NTRK3 (EN) fusion gene, arising from t(12;15)(p13;q25), encodes the HLH dimerization domain of ETV6 fused to the PTK domain of NTRK3, and is expressed as a chimeric transcript in congenital fibrosarcoma but not in adult-type fibrosarcoma or infantile fibromatosis. Chromosomal breakpoint cloning, RT-PCR, mRNA expression analysis Nature genetics High 9462753
2000 ETV6-NTRK3 (EN) homodimerizes via its ETV6 HLH domain, forms heterodimers with wild-type ETV6, possesses constitutive PTK activity with autophosphorylation on tyrosine, and transforms NIH3T3 cells. Deletion of the HLH domain abolishes dimerization and transformation; an ATP-binding mutant lacks autophosphorylation and transformation activity. Mutations of NTRK3 PTK activation-loop tyrosines reduce PTK activity and transformation. PLCγ associates with EN, but a PLCγ-binding mutant retains transformation, indicating PLCγ binding is not required for transformation. Retroviral transduction of NIH3T3 cells, in vitro kinase/autophosphorylation assay, soft agar colony formation, SCID mouse tumor formation, co-immunoprecipitation, domain-deletion and point mutagenesis Oncogene High 10702799
2001 ETV6-NTRK3 transformation of NIH3T3 fibroblasts requires both the Ras-Raf1-Mek1-Erk1/2 pathway and the PI3K-Akt pathway; inhibition of either pathway almost completely abolishes soft agar colony formation. EN expression leads to constitutive activation of Mek1 and Akt and constitutively high cyclin D1 expression. Both pathways act synergistically to mediate transformation. Pharmacological inhibition of MEK and PI3K in EN-expressing NIH3T3 cells, soft agar colony formation assay, Western blotting for Mek1, Akt, and cyclin D1 Cancer research High 11751416
2002 Expression of ETV6-NTRK3 (EN) in murine mammary epithelial cells via retroviral transfer results in transformed cells forming tumors in nude mice, with tumors exhibiting epithelial differentiation, establishing EN as a primary transforming oncogene in secretory breast carcinoma. Retroviral gene transfer into murine mammary epithelial cells, nude mouse tumor formation assay, immunohistochemistry Cancer cell High 12450792
2003 EN binds the phosphotyrosine binding (PTB) domain of IRS-1 via a conserved 19 amino acid C-terminal sequence of NTRK3. Deletion of this C-terminal sequence abolishes IRS-1 binding and transforming activity. Expression of a dominant-negative IRS-1 PTB domain inhibits EN transformation, while IRS-1 overexpression potentiates EN transformation, establishing EN–IRS-1 complex formation as essential for EN oncogenesis. Co-immunoprecipitation, deletion mutagenesis, dominant-negative IRS-1 expression, soft agar transformation assay The Journal of biological chemistry High 14668342
2003 NT-3 activation of TrkC induces Schwann cell migration through a signaling pathway involving Rho GTPases (Rac1 and Cdc42) and c-Jun N-terminal kinase (JNK). This effect is blocked by K252a (Trk inhibitor) and is independent of p75NTR, as demonstrated in p75NTR-null Schwann cells. Schwann cell migration assay (p75NTR-/- mice), pharmacological inhibition (K252a), dominant-negative Rho GTPase constructs, TrkC-expressing Cos-7 cells Proceedings of the National Academy of Sciences of the United States of America High 14614136
2003 TrkC null mice exhibit precocious fate restriction of neural crest stem cells (>50% decrease in stem cell numbers with equivalent increase in fate-restricted cells) and disorganization of the outflow tract endothelium, contributing to cardiac outflow tract malformations. TrkC null mouse analysis, neural crest stem cell isolation and characterization, histological analysis of outflow tract Molecular and cellular neurosciences Medium 14550777
2006 The kinase-deficient truncated TrkC isoform TrkCT1 binds the scaffold protein tamalin in a ligand (NT-3)-dependent manner. NT-3 activation of TrkCT1-tamalin complex leads to Arf6 activation, Arf6 translocation to the membrane, and subsequent membrane ruffling and cellular protrusion formation via Rac1 GTPase. This identifies NT-3 as an upstream regulator of Arf6 through the kinase-independent TrkCT1 receptor. Co-immunoprecipitation, pull-down assay, live cell imaging, Arf6 activation assay, dominant-negative constructs, cell morphology analysis The Journal of cell biology High 16636148
2007 TrkC directly binds the BMP type II receptor (BMPRII), preventing BMPRII interaction with BMPRI and thereby suppressing BMP-2-induced Smad1 phosphorylation and transcriptional activation. This requires functional TrkC PTK activity. BMPRII appears to be a direct phosphorylation target of TrkC. Co-immunoprecipitation, siRNA knockdown of TrkC, TrkC overexpression, Smad1 phosphorylation assay, BMP transcriptional reporter assay Cancer research Medium 17942918
2007 TrkC requires c-Src for activation of the PI3K-Akt pathway but not for Ras-Erk1/2 activation. Endogenous TrkC associates with c-Src in cancer cells and in primary breast cancer tissues. In c-Src-deficient SYF cells, TrkC fails to activate PI3K-Akt but retains Ras-Erk1/2 activation. Co-immunoprecipitation from cancer cell lines and primary tissues, siRNA knockdown of c-Src, SYF (c-Src/Yes/Fyn-deficient) cells, Western blotting for Akt and Erk1/2, soft agar colony formation The Journal of biological chemistry High 17991742
2010 TrkA and TrkC, but not TrkB, instruct developing neurons to die (dependence receptor behavior) both in vitro and in vivo. Engineered embryonic stem cells expressing TrkA or TrkC show increased neuronal death in the absence of ligand, identifying TrkA and TrkC as dependence receptors that explain trophic factor dependency of developing sympathetic and sensory neurons. Engineered embryonic stem cell differentiation, gain-of-function expression of TrkA/B/C, in vivo knockout comparison, cell death quantification Nature High 20811452
2011 Postsynaptic TrkC (all isoforms, including noncatalytic) binds presynaptic PTPσ (protein tyrosine phosphatase receptor sigma) via neurotrophin-independent high-affinity trans interaction. This bidirectional adhesion complex promotes excitatory glutamatergic synapse formation: PTPσ triggers presynaptic differentiation and TrkC mediates clustering of postsynaptic molecules. TrkC knockdown in culture and in vivo reduces glutamatergic synapse number. Hippocampal neuron-fibroblast coculture screen, co-immunoprecipitation, pull-down, TrkC-neutralizing antibody, shRNA knockdown in culture and in vivo, immunostaining of synaptic markers Neuron High 21262467
2011 A tripartite complex of ETV6-NTRK3 (EN), IRS1, and IGF1R is required for EN membrane localization and transformation. Kinase-active IGF1R and the IGF1R Y950 IRS1-docking site are required for EN oncogenesis. Tyrosine-phosphorylated IRS1 forms high-molecular-weight complexes with EN and IGF1R, and EN colocalizes with IGF1R at the plasma membrane. IGF1R/INSR inhibitor BMS-536924 blocks EN transformation and disrupts EN-IRS protein interactions. Co-immunoprecipitation, membrane fractionation/colocalization, IGF1R point mutants, pharmacological inhibition, soft agar transformation assay Oncogene High 21804605
2013 TrkC is a dependence receptor in colorectal cancer: it triggers apoptosis in the absence of NT-3, and reconstitution of TrkC expression in colorectal cancer cell lines induces apoptosis (NT-3-free conditions) and inhibits in vivo tumor growth. TrkC silencing by promoter methylation provides a selective advantage for colorectal cells. A naturally occurring cancer-associated TrkC mutant lacks proapoptotic function. Promoter methylation analysis, TrkC reconstitution in cancer cell lines, apoptosis assay, in vitro transformation assay, in vivo xenograft tumor growth, loss-of-function mutation characterization Proceedings of the National Academy of Sciences of the United States of America High 23341610
2013 TrkC dependence receptor activity in colorectal cancer: NTRK3 methylation suppresses expression in 60–67% of colon neoplasms; reconstituted NTRK3 expression induces apoptosis in colorectal cancer cells only when NT-3 is absent; loss of NTRK3 expression associates with neoplastic transformation in vitro and in vivo; a naturally occurring NTRK3 mutant found in colorectal cancer inhibits this tumor suppressor activity. Genome-wide methylation screen, methylation-specific assays, NTRK3 reconstitution, apoptosis assay, in vitro transformation assay, in vivo tumor formation, mutant NTRK3 functional analysis PLoS genetics High 23874207
2013 The dependence receptor TrkC triggers mitochondria-dependent apoptosis via double cleavage of its intracellular domain, generating a proapoptotic 'killer fragment' (TrkC KF) that recruits Cobra1. Cobra1 shuttles TrkC KF to mitochondria, where it promotes Bax activation, cytochrome c release, and apoptosome-dependent apoptosis. In developing chick neural tube, NT-3 silencing causes neuroepithelial cell death rescued by Cobra1 silencing. Co-immunoprecipitation of TrkC KF with Cobra1, mitochondrial fractionation, Bax activation assay, cytochrome c release assay, in vivo chick neural tube NT-3 and Cobra1 silencing Molecular cell High 24034695
2014 EWSR1-WT1 chimeric transcription factor directly binds upstream of NTRK3 and activates its transcription in desmoplastic small round cell tumor (DSRCT). NTRK3 expression is required for DSRCT cell growth (RNAi silencing reduces growth), and pharmacological NTRK3 inhibition with entrectinib reduces growth in vitro and in vivo. ChIP (EWSR1-WT1 binding upstream of NTRK3), RNAi silencing, in vitro growth assay, in vivo patient-derived xenograft models, pharmacological NTRK3 inhibition Clinical cancer research High 33229458
2016 NTRK3 kinase fusions (ETV6-NTRK3, MYO5A-NTRK3, MYH9-NTRK3) in Spitz tumors constitutively activate the MAPK, PI3K, and PLCγ1 signaling pathways in melanocytes, and this signaling is inhibited by the small-molecule NTRK1/2/3 and ROS1 inhibitor DS-6051a. Identification of fusion transcripts by sequencing, signaling pathway activation assays (Western blotting for MAPK, PI3K, PLCγ1), pharmacological inhibition with DS-6051a in melanocytes The Journal of pathology Medium 27477320
2016 An ETV6-NTRK3 fusion variant in GIST (exon 4 of ETV6 fused to exon 14 of NTRK3, differing from canonical infantile fibrosarcoma fusion) retains the ability to induce IRS1 phosphorylation and activate IGF1R downstream signaling, and can be targeted by IGF1R and ALK inhibitors. Transcriptome sequencing, RT-PCR, IRS1 phosphorylation assay, pharmacological inhibition with IGF1R/ALK inhibitors The Journal of pathology Medium 26606880
2016 TrkC promotes metastatic breast cancer via inhibition of SOCS3-mediated JAK2 degradation, increasing total JAK2/STAT3 expression, and leading to upregulation of Twist-1 through JAK2/STAT3 activation. TrkC also increases IL-6 secretion, creating an autocrine loop maintaining mesenchymal state. TrkC interacts with the c-Src/JAK2 complex to increase Twist-1 and Twist-2 via JAK2/STAT3. Co-immunoprecipitation (TrkC-c-Src/JAK2 complex), siRNA knockdown, Western blotting (SOCS3, JAK2, STAT3, Twist), IL-6 secretion assay, in vivo pulmonary metastasis and tumor formation Scientific reports Medium 27654855
2006 Dok5 is a substrate of TrkB and TrkC receptors. Dok5 interacts with the intracellular domain of TrkB and TrkC via its PTB domain, binding the NPQY motif in a kinase-activity-dependent manner, but not with TrkA. Dok5 co-localizes with TrkB and TrkC in differentiated PC12 cells and competes with N-Shc for binding at the same site. Dok5 is involved in neurotrophin-induced MAPK pathway activation downstream of TrkB/C. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, co-localization in PC12 cells, mutational analysis, competition binding assay, MAPK activation assay Cellular signalling Medium 16647839
2002 TrkC promotes neuronal survival mainly through Shc site-independent pathways (unlike TrkB which uses Shc site for target innervation). In trkC(shc/shc) knock-in mice, surviving TrkC-dependent neurons maintain target innervation and function. Biochemically, phosphorylation at the Shc site positively regulates TrkB autophosphorylation but not TrkC autophosphorylation, revealing mechanistic divergence between TrkB and TrkC signaling. Knock-in mice with Shc-docking site mutations (trkC(shc/shc)), neuronal survival counts, target innervation tracing, autophosphorylation biochemical assay Genes & development High 11877382
1999 TrkC activation in medulloblastoma cells by NT-3 promotes apoptosis through activation of multiple parallel signaling pathways and induction of immediate-early gene expression (c-jun and c-fos). In vivo, TrkC overexpression inhibits intracerebral xenograft growth of medulloblastoma cells in nude mice. In vitro NT-3 treatment of medulloblastoma cells, apoptosis assay, TrkC overexpression in xenograft model, immediate-early gene expression analysis Cancer research Medium 9973222
2007 TrkC is expressed by perisynaptic and myelinating Schwann cells from birth through adulthood, as determined by immunostaining, Western blotting, and RT-PCR. Overexpression of NT-3 in muscle fibers during development increases the number of perisynaptic Schwann cells at neuromuscular synapses, suggesting muscle-derived NT-3 signals via TrkC on Schwann cells as a mitogen or trophic factor. Immunostaining, Western blotting, RT-PCR, transgenic NT-3 overexpression in muscle, conditional NT-3 deletion from motor neurons, Schwann cell counting at NMJ The Journal of comparative neurology Medium 17278135
2009 Trypanosoma cruzi trans-sialidase/PDNF binds TrkC (as shown by co-immunoprecipitation and competition with NT-3), activates TrkC-dependent MAPK signaling and promotes neurite outgrowth and survival of neuronal (PC12) and glial (Schwann) cells in a TrkC-dependent manner. Co-immunoprecipitation, NT-3 competition binding assay, TrkC-engineered PC12 cells, MAPK signaling assay, neurite outgrowth and cell survival assays Infection and immunity Medium 19179422
2011 TrkC functions as a host cell entry receptor for T. cruzi. Overexpression of human TrkC (but not TrkB) in a T. cruzi-resistant neuronal cell line (PC12-NNR5) and in CHO cells greatly increases permissiveness to T. cruzi infection. NT-3 and PDNF block infection of TrkC-expressing cells. Inhibitors of Trk autophosphorylation (K252a, AG879) and TrkC-induced MAPK/Erk and Akt signaling block TrkC-mediated cell invasion. Anti-TrkC antibody reduces cutaneous infection in a mouse model. TrkC transfection gain-of-function, pharmacological inhibition (K252a, AG879, U0126, LY294002), neutralizing antibody, in vivo mouse infection model, NT-3 competition Infection and immunity Medium 21788388
2014 Missense mutations in NTRK3 identified in human congenital heart disease (ventricular septal defects) reduce TrkC autophosphorylation in response to NT-3 and decrease phosphorylation of downstream target proteins. Three of four mutant TrkC-expressing cell lines show altered growth under low-serum conditions without NT-3. NTRK3 mutation functional analysis in neuroblastoma cell lines, autophosphorylation assay, downstream signaling (Western blotting), cell growth assay Human mutation Medium 25196463
2020 ETV6-NTRK3 and MYO5A-NTRK3 fusions have distinct subcellular localizations in melanocytes: ETV6-NTRK3 localizes to the nucleus and diffusely in the cytoplasm, causing epithelioid cytomorphology; MYO5A-NTRK3 is excluded from the nucleus, localizes to dendrites, and results in a highly dendritic cytomorphology. Expression of ETV6-NTRK3 and MYO5A-NTRK3 in immortalized melanocytes, immunofluorescence subcellular localization, cell morphology analysis Modern pathology Medium 32968185
2021 HERV-K(HML-2) transcriptional activation leads to hyperactivation of NTRK3 expression in cortical neurons, disrupting cortical patterning and neuronal differentiation. Direct CRISPR-based activation of NTRK3 phenocopies HERV-K(HML-2) induction effects, and reducing NTRK3 levels in the context of HERV-K(HML-2) induction restores cortical neuron differentiation. CRISPR activation/repression of HERV-K(HML-2), CRISPR activation of NTRK3, NTRK3 knockdown epistasis, human iPSC-derived cortical neuron differentiation, forebrain organoid cortical layer analysis Cell stem cell Medium 33951478
2022 NT-3 activates TrkC at lower concentrations than BDNF activates TrkB in human neurons co-expressing both receptors, explaining NT-3/TrkC selectivity. At high NT-3 concentrations, TrkB is also activated and TrkC is downregulated. TrkC activation induces gene expression changes similar to TrkB activation (including synaptic plasticity genes). Low neurotrophin concentrations preserve receptor selectivity and allow reactivation. Human ESC-derived neurons with and without TrkB knockout (CRISPR engineering), Trk activation assays (Western blotting, phosphorylation), transcriptome analysis (gene expression changes), receptor downregulation assays Journal of neurochemistry High 35536742
2024 NT-3 upregulated in DRG neurons after paclitaxel activates TrkC, which increases CCL2 (C-C chemokine ligand 2) mRNA and protein in DRG neurons, contributing to chemotherapy-induced neuropathic pain. Blocking NT-3 upregulation attenuates paclitaxel-induced nociceptive hypersensitivities; mimicking NT-3 increase produces pain hypersensitivity in naive mice. NT3 mRNA co-expresses with TrkC and CCL2 mRNAs in DRG neurons. In vivo paclitaxel mouse model, NT-3 blockade and mimicry experiments (behavioral nociceptive assays), TrkC activation assay, CCL2 mRNA/protein quantification in DRG EMBO reports Medium 38594391

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer cell 693 12450792
1998 A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nature genetics 629 9462753
1994 Disruption of the neurotrophin-3 receptor gene trkC eliminates la muscle afferents and results in abnormal movements. Nature 550 8145824
1993 Alternative forms of rat TrkC with different functional capabilities. Neuron 380 8494647
1998 ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma. Cancer research 297 9823307
1993 trkC, a receptor for neurotrophin-3, is widely expressed in the developing nervous system and in non-neuronal tissues. Development (Cambridge, England) 276 8223273
1994 Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastoma. Proceedings of the National Academy of Sciences of the United States of America 209 7809137
1998 TrkB and TrkC signaling are required for maturation and synaptogenesis of hippocampal connections. The Journal of neuroscience : the official journal of the Society for Neuroscience 207 9736654
1996 TrkB and TrkC neurotrophin receptors cooperate in promoting survival of hippocampal and cerebellar granule neurons. Genes & development 196 8918886
2016 FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors. Journal of translational medicine 185 27974047
2016 ALK, ROS1 and NTRK3 gene rearrangements in inflammatory myofibroblastic tumours. Histopathology 181 26647767
1994 Developmental expression of trkC, the neurotrophin-3 receptor, in the mammalian nervous system. The Journal of neuroscience : the official journal of the Society for Neuroscience 181 8283230
2000 TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 179 10694553
1997 Targeted deletion of all isoforms of the trkC gene suggests the use of alternate receptors by its ligand neurotrophin-3 in neuronal development and implicates trkC in normal cardiogenesis. Proceedings of the National Academy of Sciences of the United States of America 172 9405689
2011 Postsynaptic TrkC and presynaptic PTPσ function as a bidirectional excitatory synaptic organizing complex. Neuron 170 21262467
2010 Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not. Nature 167 20811452
2016 Transcriptome sequencing identifies ETV6-NTRK3 as a gene fusion involved in GIST. The Journal of pathology 157 26606880
1993 trkC encodes multiple neurotrophin-3 receptors with distinct biological properties and substrate specificities. The EMBO journal 155 8344249
1998 Development of bone morphogenetic protein receptors in the nervous system and possible roles in regulating trkC expression. The Journal of neuroscience : the official journal of the Society for Neuroscience 137 9547239
2016 NTRK3 kinase fusions in Spitz tumours. The Journal of pathology 127 27477320
1999 Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastomas. Cancer research 125 9973222
2017 Recurrent EML4-NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 124 29099503
2003 Neurotrophin 3 activation of TrkC induces Schwann cell migration through the c-Jun N-terminal kinase pathway. Proceedings of the National Academy of Sciences of the United States of America 124 14614136
1997 Expression of TrkA, TrkB and TrkC in human neuroblastomas. Journal of neuro-oncology 120 9049830
1999 Expression of trkB and trkC mRNAs by adult midbrain dopamine neurons: a double-label in situ hybridization study. The Journal of comparative neurology 119 9886032
2005 ETV6-NTRK3: a chimeric protein tyrosine kinase with transformation activity in multiple cell lineages. Seminars in cancer biology 116 15826836
2014 Neurotrophin signaling via TrkB and TrkC receptors promotes the growth of brain tumor-initiating cells. The Journal of biological chemistry 115 25538243
2000 The ETV6-NTRK3 gene fusion encodes a chimeric protein tyrosine kinase that transforms NIH3T3 cells. Oncogene 110 10702799
2001 The chimeric protein tyrosine kinase ETV6-NTRK3 requires both Ras-Erk1/2 and PI3-kinase-Akt signaling for fibroblast transformation. Cancer research 103 11751416
1999 Expression of TrkB and TrkC but not BDNF mRNA in neurochemically identified interneurons in rat visual cortex in vivo and in organotypic cultures. The European journal of neuroscience 100 10103114
2019 The histologic spectrum of soft tissue spindle cell tumors with NTRK3 gene rearrangements. Genes, chromosomes & cancer 99 31112350
2013 NTRK3 is a potential tumor suppressor gene commonly inactivated by epigenetic mechanisms in colorectal cancer. PLoS genetics 85 23874207
1999 Mice lacking NT-3, and its receptor TrkC, exhibit profound deficiencies in CNS glial cells. Glia 78 10384880
2003 Voluntary exercise increases neurotrophin-3 and its receptor TrkC in the spinal cord. Brain research 75 14499950
2005 Haploinsufficiency for trkB and trkC receptors induces cell loss and accumulation of alpha-synuclein in the substantia nigra. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 74 16037097
2006 A kinase-deficient TrkC receptor isoform activates Arf6-Rac1 signaling through the scaffold protein tamalin. The Journal of cell biology 73 16636148
2002 Distinct requirements for TrkB and TrkC signaling in target innervation by sensory neurons. Genes & development 73 11877382
2002 Expression of trkA, trkB, and trkC in injured and regenerating retinal ganglion cells of adult rats. Investigative ophthalmology & visual science 66 12037005
2020 NTRK3 overexpression in undifferentiated sarcomas with YWHAE and BCOR genetic alterations. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 65 32034283
1999 trkA, trkB, and trkC messenger RNA expression by bulbospinal cells of the rat. Neuroscience 65 10426534
2019 Novel NTRK3 Fusions in Fibrosarcomas of Adults. The American journal of surgical pathology 62 30520818
1994 Expression of trkC receptor mRNA during development of the avian nervous system. Journal of neurobiology 59 8071661
2013 Dependence receptor TrkC is a putative colon cancer tumor suppressor. Proceedings of the National Academy of Sciences of the United States of America 57 23341610
1993 Molecular cloning and cellular localization of trkC in the chicken embryo. Brain research. Developmental brain research 57 8261614
2016 LINC00052 regulates the expression of NTRK3 by miR-128 and miR-485-3p to strengthen HCC cells invasion and migration. Oncotarget 53 27351280
2003 A highly conserved NTRK3 C-terminal sequence in the ETV6-NTRK3 oncoprotein binds the phosphotyrosine binding domain of insulin receptor substrate-1: an essential interaction for transformation. The Journal of biological chemistry 51 14668342
2015 Congenital mesoblastic nephroma: a study of 19 cases using immunohistochemistry and ETV6-NTRK3 fusion gene rearrangement. Pathology 50 27020209
1999 Differential expression of trkB.T1 and trkB.T2, truncated trkC, and p75(NGFR) in the cochlea prior to hearing function. The Journal of comparative neurology 49 10494076
2010 ETV6-NTRK3-mediated breast epithelial cell transformation is blocked by targeting the IGF1R signaling pathway. Cancer research 48 21148487
2017 ETV6-NTRK3 and STRN-ALK kinase fusions are recurrent events in papillary thyroid cancer of adult population. European journal of endocrinology 47 29046324
2019 Pan-Trk immunohistochemistry reliably identifies ETV6-NTRK3 fusion in secretory carcinoma of the salivary gland. Virchows Archiv : an international journal of pathology 45 31423558
1997 trkA and trkC expression is increased in human diabetic skin. Neuroscience letters 43 9197281
1996 Decreased expression of TrkB and TrkC mRNAs in spinal motoneurons of aged rats. The European journal of neuroscience 41 8963440
2003 Neural crest stem cell and cardiac endothelium defects in the TrkC null mouse. Molecular and cellular neurosciences 40 14550777
2017 Identification of NTRK3 Fusions in Childhood Melanocytic Neoplasms. The Journal of molecular diagnostics : JMD 39 28433076
2007 Localization of TrkC to Schwann cells and effects of neurotrophin-3 signaling at neuromuscular synapses. The Journal of comparative neurology 38 17278135
2000 Neurotrophin receptor TrkC predicts good clinical outcome in medulloblastoma and other primitive neuroectodermal brain tumors. Klinische Padiatrie 37 10994550
1999 Expression of p75(NTR), trkB and trkC in nonmanipulated and axotomized motoneurons of aged rats. Brain research. Molecular brain research 37 10350634
2021 Activation of HERV-K(HML-2) disrupts cortical patterning and neuronal differentiation by increasing NTRK3. Cell stem cell 36 33951478
1998 Differential expression of TrkC catalytic and noncatalytic isoforms suggests that they act independently or in association. The Journal of comparative neurology 36 9802700
2016 A small molecule TrkB/TrkC neurotrophin receptor co-activator with distinctive effects on neuronal survival and process outgrowth. Neuropharmacology 35 27334657
2016 Dysregulated JAK2 expression by TrkC promotes metastasis potential, and EMT program of metastatic breast cancer. Scientific reports 35 27654855
1997 Mapping of the tyrosine kinase receptors trkA (NTRK1), trkB (NTRK2) and trkC(NTRK3) to human chromosomes 1q22, 9q22 and 15q25 by fluorescence in situ hybridization. European journal of human genetics : EJHG 35 9195161
1994 Molecular cloning of the cDNA for human TrkC (NTRK3), chromosomal assignment, and evidence for a splice variant. Genomics 35 7806211
2020 Fusion partners of NTRK3 affect subcellular localization of the fusion kinase and cytomorphology of melanocytes. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 33 32968185
2019 TrkC-Targeted Kinase Inhibitors And PROTACs. Molecular pharmaceutics 33 31512882
2004 TrkC kinase expression in distinct subsets of cutaneous trigeminal innervation and nonneuronal cells. The Journal of comparative neurology 33 15558783
2008 Linkage disequilibrium mapping of a chromosome 15q25-26 major depression linkage region and sequencing of NTRK3. Biological psychiatry 32 18367154
2007 TrkC binds to the bone morphogenetic protein type II receptor to suppress bone morphogenetic protein signaling. Cancer research 32 17942918
2020 Roles of TrkC Signaling in the Regulation of Tumorigenicity and Metastasis of Cancer. Cancers 31 31936239
2011 DNA methylation-dependent regulation of TrkA, TrkB, and TrkC genes in human hepatocellular carcinoma. Biochemical and biophysical research communications 31 21295543
2003 Differential cross-regulation of TrkA and TrkC tyrosine kinase receptors with p75. Oncogene 31 12944916
2003 Functional expression of the TrkC gene, encoding a high affinity receptor for NT-3, in antigen-specific T helper type 2 (Th2) cells. Immunology letters 29 12941481
2007 c-Src is required for tropomyosin receptor kinase C (TrkC)-induced activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. The Journal of biological chemistry 28 17991742
2020 Therapeutic Potential of NTRK3 Inhibition in Desmoplastic Small Round Cell Tumor. Clinical cancer research : an official journal of the American Association for Cancer Research 26 33229458
2005 Discordant changes in cortical TrkC mRNA and protein during the human lifespan. The European journal of neuroscience 26 15932601
1985 Roles of the trkB and trkC gene products of Escherichia coli in K+ transport. Biochimie 26 3888294
2017 Autophagy and TrkC/NT-3 signaling joined forces boost the hypoxic glioblastoma cell survival. Carcinogenesis 25 28402394
1999 Expression of neurotrophin receptors trkB and trkC and their ligands in rat adrenal gland and the intermediolateral column of the spinal cord. Cell and tissue research 25 10382271
1994 Gene regulation of trkB and trkC in the chick retina by light/darkness exposure. Oncogene 25 8208527
1993 Molecular cloning and expression of a novel truncated form of chicken trkC. FEBS letters 25 8394830
2016 Emerging roles of the neurotrophin receptor TrkC in synapse organization. Neuroscience research 24 27697534
2014 Asymmetrical expression of BDNF and NTRK3 genes in frontoparietal cortex of stress-resilient rats in an animal model of depression. Synapse (New York, N.Y.) 24 24753016
2013 TrkC promotes survival and growth of leukemia cells through Akt-mTOR-dependent up-regulation of PLK-1 and Twist-1. Molecules and cells 23 23832765
2011 Neurotrophin receptor TrkC is an entry receptor for Trypanosoma cruzi in neural, glial, and epithelial cells. Infection and immunity 23 21788388
2009 Trypanosoma cruzi promotes neuronal and glial cell survival through the neurotrophic receptor TrkC. Infection and immunity 23 19179422
2006 Dok5 is substrate of TrkB and TrkC receptors and involved in neurotrophin induced MAPK activation. Cellular signalling 23 16647839
2001 Differences in early and late responses between neurotrophin-stimulated trkA- and trkC-transfected SH-SY5Y neuroblastoma cells. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 23 11205744
2008 Expression of trkB and trkC receptors and their ligands brain-derived neurotrophic factor and neurotrophin-3 in the murine amygdala. Journal of neuroscience research 21 17828769
2022 Selective activation and down-regulation of Trk receptors by neurotrophins in human neurons co-expressing TrkB and TrkC. Journal of neurochemistry 20 35536742
2013 The dependence receptor TrkC triggers mitochondria-dependent apoptosis upon Cobra-1 recruitment. Molecular cell 20 24034695
2011 A tripartite complex composed of ETV6-NTRK3, IRS1 and IGF1R is required for ETV6-NTRK3-mediated membrane localization and transformation. Oncogene 20 21804605
1994 Expression of trkC in a mouse osteoblastic cell line and its response to neurotrophin-3. Biochemical and biophysical research communications 20 8093043
2024 Construction of functional neural network tissue combining CBD-NT3-modified linear-ordered collagen scaffold and TrkC-modified iPSC-derived neural stem cells for spinal cord injury repair. Bioactive materials 18 38333615
2024 NT-3 contributes to chemotherapy-induced neuropathic pain through TrkC-mediated CCL2 elevation in DRG neurons. EMBO reports 18 38594391
2022 EML4-NTRK3 Fusion Cervical Sarcoma: A Case Report and Literature Review. Frontiers in medicine 18 35572973
2014 Mutations in NTRK3 suggest a novel signaling pathway in human congenital heart disease. Human mutation 18 25196463
2021 Circular RNA hsa_circ_0009172 suppresses gastric cancer by regulation of microRNA-485-3p-mediated NTRK3. Cancer gene therapy 17 33531648
2021 NT3/TrkC Pathway Modulates the Expression of UCP-1 and Adipocyte Size in Human and Rodent Adipose Tissue. Frontiers in endocrinology 17 33815288
2005 Heparanase, TrkC and p75NTR: their functional involvement in human medulloblastoma cell invasion. International journal of oncology 17 16077909

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