Affinage

NTRK1

High affinity nerve growth factor receptor · UniProt P04629

Length
796 aa
Mass
87.5 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NTRK1/TrkA is a nerve growth factor (NGF)-responsive receptor tyrosine kinase that transduces neurotrophin signals into survival, differentiation, and death decisions in neurons and tumor cells (PMID:11313867, PMID:22442072). Ligand engagement is governed by its extracellular Ig-like subdomains, where the D5 (IgC2) region contains the NGF-binding hot spot and an overlapping NT-3 docking site, while D4 (IgC1) provides an allosteric NT-3 site that tunes agonism (PMID:17439940); proNGF and the NGF pro-region also bind and activate TrkA, the latter at a distinct site (PMID:18808449). Receptor dimerization of the intracellular kinase domain is itself sufficient to drive downstream signaling, as shown by optogenetic homo-interaction that activates PI3K/AKT and Raf/ERK in the absence of NGF (PMID:29975841), and a constitutively dimerizing extracellular linker mutation (P203A) produces ligand-independent phosphorylation and cellular transformation (PMID:11313867). The kinase operates by an ordered sequential bi-bi mechanism with ATP binding before substrate (PMID:9448714), and autophosphorylation at the Y490 and Y785 docking sites couples the receptor to adaptors and effectors including IRS-1/IRS-2, which recruit p85-PI3K, SHP-2, and Grb2 to activate PI3K and SRE-driven transcription (PMID:11147812, PMID:23266087). TrkA surface presentation and signaling competence are tightly controlled by N-glycosylation, which both prevents constitutive activation and is required for cell-surface targeting (PMID:10235685), and by trafficking machinery: STX8 directs Golgi-to-plasma-membrane transport (PMID:24872407), GGA3 mediates Arf6-dependent recycling that sustains NGF-induced Akt and survival (PMID:26446845), and retrograde signaling endosomes evolve from multivesicular bodies in a kinase-activity-dependent manner (PMID:29381137). Receptor abundance and activity are further set by opposing ubiquitination events — TRAF4-mediated K27/K29-linked ubiquitination of the kinase domain enhances activity (PMID:29715200), whereas a KFG juxtamembrane element and Nedd4-2 binding to the C-terminal PPXY motif drive degradative sorting (PMID:24623787, PMID:21332718). TrkA delivers divergent outputs depending on context: it promotes p53-dependent apoptosis of neuroblastoma cells and engages the CCM2 juxtamembrane adaptor to mediate cell death (PMID:19755102, PMID:15961390), while supporting neuronal survival and basal forebrain cholinergic development through ERK signaling (PMID:22442072). Its activity is modulated by co-receptor and cross-talk partners including p75NTR, which selectively augments Shc phosphorylation (PMID:9547236, PMID:15056278), APP (reciprocal regulation and Y682 phosphorylation) (PMID:21849536), and oncogenic interactions with CD44 and EphA2 (PMID:25840418, PMID:30771434). NTRK1 transcription is positively controlled by Brn3a and Klf7 in sensory neurons (PMID:17011544) and epigenetically repressed by EZH2-deposited H3K27me3 at the P1 promoter (PMID:29507419).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1996 High

    Established that TrkA partners physically with the p75 neurotrophin receptor and undergoes regulated ectodomain shedding, defining co-receptor and proteolytic layers of control before intracellular signaling was dissected.

    Evidence Copatching with chimeric TrkA-Torso receptors and kinase-dead mutants; ectodomain cleavage assays across cell lines

    PMID:8603925 PMID:8636219

    Open questions at the time
    • Functional consequence of the shed cell-associated fragment in vivo not resolved
    • Identity of the ectodomain protease not defined
  2. 1998 High

    Defined the enzymatic logic of the TrkA kinase and showed it counteracts p75 death signaling, framing TrkA as a survival kinase that opposes JNK.

    Evidence In vitro kinase kinetics with PLC-γ/GST substrate; introduction of TrkA into p75-dependent apoptotic oligodendrocytes with MAPK/JNK/NFκB readouts

    PMID:9448714 PMID:9547236

    Open questions at the time
    • Kinetic mechanism determined for isolated kinase domain, not full-length receptor
    • Mechanism by which TrkA suppresses JNK not molecularly defined
  3. 1999 High

    Showed that N-glycosylation gates receptor activation and surface delivery, explaining how an active kinase is prevented from firing prematurely.

    Evidence Deglycosylation assay, confocal localization, and signaling/differentiation readouts in PC12 cells

    PMID:10235685

    Open questions at the time
    • Specific glycan sites responsible not mapped
    • Link between glycosylation state and physiological receptor regulation unclear
  4. 2001 High

    Identified the IRS-1/IRS-2 adaptor arm as essential for TrkA mitogenic signaling and a constitutively activating extracellular mutation, connecting receptor structure to PI3K activation and transformation.

    Evidence Yeast two-hybrid, co-IP, PI3K assays, IRS-1-/- fibroblasts; P203A mutagenesis with dimerization, neurite, and nude-mouse tumor assays

    PMID:11147812 PMID:11313867

    Open questions at the time
    • Relative contribution of IRS versus Shc arms in neurons not resolved
    • Structural basis of P203A-induced dimerization not determined
  5. 2004 Medium

    Refined the TrkA–p75 relationship by showing p75NTR selectively boosts Shc-isoform phosphorylation and downstream Akt, distinguishing substrate-specific cross-talk from general signal amplification.

    Evidence Antisense knockdown with isoform-resolved phosphorylation immunoblotting and p75NTR–Shc co-IP

    PMID:15056278

    Open questions at the time
    • Single lab; mechanism of selective Shc enhancement unknown
    • Physiological context where this dominates not established
  6. 2005 Medium

    Revealed TrkA's death function through a p53-dependent apoptotic program in neuroblastoma, contrasting with its survival role in normal neurons.

    Evidence TrkA expression in neuroblastoma lines with dominant-negative p53, E1B55K, caspase inhibitors, and Bcl-XL

    PMID:15961390

    Open questions at the time
    • How an active kinase engages p53 not molecularly defined
    • Determinants switching survival versus death output unresolved
  7. 2006 Medium

    Established transcriptional and cross-talk inputs: Brn3a/Klf7 drive NTRK1 expression in sensory neurons, and P2Y2 GPCR signaling potentiates TrkA via Src family kinases.

    Evidence Enhancer reporters and Brn3a/Klf7 double-knockout epistasis; SFK inhibition and TrkA/P2Y2/SFK co-IP with neurite assays

    PMID:16842754 PMID:17011544

    Open questions at the time
    • Direct versus indirect binding of Brn3a/Klf7 to the enhancer not fully resolved
    • P2Y2-TrkA SFK study is single lab with pharmacological inhibition
  8. 2009 High

    Identified CCM2 as the juxtamembrane adaptor that couples TrkA to cell death pathways, providing a molecular handle on the death-versus-survival switch.

    Evidence PTB-domain co-IP, domain-deletion mutants, and CCM2 knockdown in medulloblastoma/neuroblastoma death assays

    PMID:19755102

    Open questions at the time
    • Downstream effectors of the CCM2 Karet domain not defined
    • Relationship to the p53 death program not integrated
  9. 2011 High

    Defined the ubiquitin-degradative arm via Nedd4-2 and the reciprocal APP interaction, linking receptor turnover and a cross-regulatory partner to signal output and localization.

    Evidence PPXY-motif mutagenesis with Nedd4-2 co-IP and neurite assays; reciprocal TrkA–APP co-IP, Y682 mutants, and APP-knockout neuron signaling

    PMID:21332718 PMID:21849536

    Open questions at the time
    • How multimonoubiquitination potentiates differentiation mechanistically unclear (Nedd4-2 study Medium confidence)
    • Physiological significance of APP–TrkA cross-regulation beyond model systems unresolved
  10. 2012 High

    Established the in vivo requirement of TrkA-ERK signaling for basal forebrain cholinergic development and cognition, and mapped the two intracellular docking tyrosines plus docking-independent phospho-events.

    Evidence Conditional forebrain TrkA knockout with ChAT/ERK, anatomical, and behavioral phenotyping; phosphoproteomics with Y490F/Y785F mutants

    PMID:22442072 PMID:23266087

    Open questions at the time
    • Identity and function of docking-independent phosphorylation events not pursued (phosphoproteomics study Medium confidence)
    • How ERK couples to ChAT regulation not detailed
  11. 2014 High

    Resolved post-endocytic fate and degradative control, showing MVB-derived retrograde signaling endosomes, STX8-dependent surface delivery, and KFG-domain-driven ubiquitination set receptor levels and pain sensitivity.

    Evidence EM and kinase-manipulation endosome fate tracking in sympathetic neurons; STX8 co-IP with DRG survival and AAV6 in vivo pain model; KFG-deletion knock-in mouse with ubiquitination and pain phenotypes; AGPS phosphorylation/degradation study

    PMID:24623787 PMID:24872407 PMID:29381137 PMID:38200609

    Open questions at the time
    • Molecular trigger that diverts MVBs from lysosomal fusion not defined
    • The E3 ligase acting through the KFG domain not identified in this work
  12. 2015 High

    Demonstrated recycling and kinase-independent oncogenic signaling, showing GGA3-Arf6 recycling sustains survival and CD44 mediates invasion bypassing kinase inhibition.

    Evidence DXXLL-motif binding, recycling/degradation kinetics, Akt and survival readouts with Arf6 dominant-negative; mass spec, PLA, CD44 knockdown, and xenograft invasion assays

    PMID:25840418 PMID:26446845

    Open questions at the time
    • How GGA3 sorting decisions are regulated by signaling not resolved
    • Generality of CD44 kinase-independent route beyond breast cancer unclear
  13. 2016 High

    Provided structural basis for TrkA-selective inhibition, showing the juxtamembrane region forms a unique non-active-site pocket conferring selectivity over TrkB/TrkC.

    Evidence X-ray crystallography of kinase domain plus JM region with inhibitor complexes and in vitro kinase validation

    PMID:28039433 PMID:28159414

    Open questions at the time
    • Conformational role of the JM region in normal activation not addressed
    • Structures are of isolated kinase/JM, not the full receptor
  14. 2018 High

    Established opposing ubiquitin and epigenetic controls plus Hippo-pathway crosstalk: TRAF4 K27/K29 ubiquitination activates the kinase, EZH2 represses NTRK1 transcription, and NTRK1 modulates LATS1/YAP.

    Evidence Linkage-specific ubiquitination and site mutagenesis with kinase/invasion readouts; ChIP/methylome/transcriptome with NTRK1 epistasis; kinase inhibitor screen with LATS1/YAP assays and xenografts

    PMID:29507419 PMID:29715200 PMID:30542115

    Open questions at the time
    • How activating versus degradative ubiquitin codes are coordinated unresolved
    • Mechanism linking NTRK1 activity to LATS1 phosphorylation not defined (YAP study Medium confidence)
  15. 2019 High

    Defined surface ganglioside and proNGF/sortilin/EphA2 complexes as non-canonical activation inputs, broadening the TrkA interactome at the plasma membrane.

    Evidence Photoactivatable GM1 cross-linking with raft fractionation; proteomics, PLA, co-IP, EphA2 knockdown, and in vivo tumor/metastasis models for the sortilin/TrkA/EphA2 axis

    PMID:30771434 PMID:30776097

    Open questions at the time
    • Functional consequence of GM1–TrkA contact for downstream signaling not fully mapped (GM1 study Medium confidence)
    • Stoichiometry and assembly order of the sortilin/TrkA/EphA2 complex in vivo unclear
  16. 2020 Medium

    Used engineered light-controlled phosphorylation to causally link individual intracellular tyrosines to defined ERK output, dissecting site-specific signaling beyond the canonical docking sites.

    Evidence Genetic code expansion with light-sensitive tyrosine analogues and amber suppression, with ERK activation readouts; optogenetic CRY2 homo-interaction (2018)

    PMID:29975841 PMID:33239753

    Open questions at the time
    • Synthetic activation may not recapitulate native ligand-driven kinetics
    • Comprehensive map of each tyrosine to specific effector branches incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the competing activating (TRAF4) and degradative (Nedd4-2/KFG) ubiquitin signals, trafficking decisions, and partner context are integrated to switch TrkA between survival and death outputs remains unresolved.
  • No unified model linking ubiquitin code, endosomal fate, and apoptotic versus survival signaling
  • Determinants selecting CCM2/p53 death versus PI3K/ERK survival programs not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0060089 molecular transducer activity 4 GO:0016740 transferase activity 3 GO:0048018 receptor ligand activity 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0005886 plasma membrane 6 GO:0005768 endosome 3 GO:0005764 lysosome 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-1266738 Developmental Biology 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-4839726 Chromatin organization 1
Partners
APPCCM2CD44IRS1IRS2NEDD4LNGFRSHC1

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 TrkA-mediated rescue of oligodendrocytes from p75-dependent apoptosis involves both activation of MAPK survival signals and simultaneous suppression of c-jun kinase (JNK) activity initiated by p75, while p75-induced NFκB activity was unaffected, demonstrating competitive signaling between TrkA and p75 receptors. Introduction of TrkA into oligodendrocyte cell cultures with p75-dependent apoptosis; measurement of MAPK activation, JNK activity, and NFκB activity The Journal of neuroscience Medium 9547236
1999 N-glycosylation of TrkA serves two distinct functions: (1) preventing ligand-independent activation — unglycosylated TrkA is constitutively phosphorylated and interacts constitutively with Shc and PLC-γ; (2) localizing TrkA to the cell surface — unglycosylated TrkA is trapped intracellularly and cannot activate the Ras/MAP kinase cascade (MEK and Erk), despite constitutive kinase activity. Microscale deglycosylation assay, confocal microscopy, immunoblotting for phosphorylation and signaling molecule interactions, differentiation assay in PC12 cells Journal of neurobiology High 10235685
1996 TrkA is cleaved at its ectodomain in a membrane-proximal region by a cell-surface proteolytic system regulated by protein kinase C and NGF, generating a cell-associated fragment that is phosphorylated on tyrosine residues; this phosphorylation requires an intact TrkA kinase domain (not detected in kinase-dead TrkA mutants), suggesting elevated kinase activity of the truncated fragment. Ectodomain cleavage assay using multiple cell lines expressing TrkA, kinase-dead TrkA mutants, immunoblotting for tyrosine phosphorylation The Journal of cell biology Medium 8636219
1996 The p75 neurotrophin receptor (gp75) forms a complex with TrkA on the cell surface; the TrkA extracellular domain is sufficient for this association, but interactions involving other receptor domains (transmembrane/intracellular) also contribute. TrkA kinase activity is not required for complex formation. gp75 does not copatch with TrkB, PDGFR-β, or Torso, demonstrating specificity. Copatching technique with antibody-induced receptor redistribution on intact cells; baculovirus-insect cell expression of wild-type and chimeric TrkA-Torso receptors; kinase-dead TrkA mutant The Journal of cell biology High 8603925
1998 The TrkA kinase domain follows a sequential ordered bi-bi kinetic mechanism, with ATP binding prior to the exogenous substrate PLC-γ/GST, followed by release of phosphorylated product before ADP release; the inhibitor K-252a acts as a competitive inhibitor with respect to ATP. In vitro kinase assay using baculovirus-expressed TrkA kinase domain; product and dead-end inhibition kinetics with PLC-γ/GST fusion protein as substrate Archives of biochemistry and biophysics High 9448714
2001 A point mutation P203A in the extracellular linker region between leucine repeats and the first Ig-like domain of TrkA increases NGF binding affinity by decreasing ligand dissociation rate, causes spontaneous receptor dimerization and constitutive phosphorylation in the absence of ligand, promotes ligand-independent neurite outgrowth, and transforms fibroblasts to form tumors in nude mice. Site-directed mutagenesis, NGF binding assays, receptor dimerization analysis, PC12nnr5 neurite outgrowth assay, fibroblast transformation and nude mouse tumor formation Oncogene High 11313867
2001 IRS-1 and IRS-2 are tyrosine-phosphorylated substrates of both TrkA and the oncogenic TRK-T1 fusion; this leads to recruitment of p85PI3K, SHP-2, and Grb2, increased PI3-kinase activity associated with IRS-1, and activation of c-fos SRE. TRK-T1-stimulated DNA synthesis requires IRS-1 (abolished in IRS-1-/- fibroblasts). Yeast two-hybrid experiments showed direct TrkA–IRS interaction. Tyrosine phosphorylation assays, co-immunoprecipitation, PI3-kinase activity assay, c-fos SRE reporter, DNA synthesis in IRS-1-/- fibroblasts, yeast two-hybrid Journal of cellular physiology High 11147812
2007 The TrkA D5 (IgC2) extracellular subdomain contains both the cognate NGF binding hot spot and a distinct but partially overlapping NT-3 docking/activation hot spot (site 1); additionally, D4 (IgC1) contains an allosteric NT-3 binding site (site 2). NT-3 docking on both sites 1 and 2 affords full TrkA agonism additive with NGF, while docking solely on site 1 is partially agonistic but noncompetitively antagonizes NGF binding. Binding studies with truncated and chimeric extracellular subdomain constructs, competition binding assays, functional neuronal survival assays The Journal of biological chemistry Medium 17439940
2008 TrkA receptor endosomal/lysosomal degradation is both ubiquitin- and proteasome-dependent: the polyubiquitin tag (K485 on TrkA) directs receptor sorting; proteasomal deubiquitinating enzymes trim K63-ubiquitin chains from TrkA prior to lysosomal delivery. The K485R ubiquitin-deficient TrkA mutant fails to deubiquitinate and escapes degradation. Co-immunoprecipitation, biochemical fractionation, confocal microscopy, proteasome inhibitor (lactacystin) and lysosomal inhibitor (methylamine, bafilomycin, leupeptin) treatments, K485R TrkA mutant analysis, proteasome purification and co-IP Traffic (Copenhagen, Denmark) High 18419753
2008 ProNGF (cleavage-resistant mutant M-proNGF) binds TrkA with lower affinity than NGF, induces TrkA and ERK1/2 phosphorylation, neurite outgrowth in PC12 cells, and survival but less effectively than NGF; additionally, the NGF pro-region alone binds TrkA at a site distinct from NGF binding, causing TrkA and ERK1/2 phosphorylation. Binding affinity determination, TrkA and ERK1/2 phosphorylation immunoblotting, PC12 neurite outgrowth assay, cortical neuron caspase-3 cleavage assay Journal of neurochemistry Medium 18808449
2009 CCM2 interacts with the juxtamembrane region of TrkA via its PTB domain and mediates TrkA-induced cell death; both the PTB domain (conferring interaction specificity) and the Karet domain (linking to death pathways) are required. Downregulation of CCM2 in medulloblastoma or neuroblastoma cells attenuates TrkA-dependent death. Co-immunoprecipitation (PTB domain interaction), domain deletion mutant analysis, CCM2 knockdown in tumor cells with TrkA-dependent death readout Neuron High 19755102
2011 TrkA phosphorylates APP at Y682; APP interacts with TrkA and this interaction requires Y682. Reciprocally, APP (specifically Y682) regulates activation of the NGF/TrkA signaling pathway in vivo, controls subcellular distribution of TrkA, and modulates neuronal sensitivity to NGF. NGF stimulation, tyrosine phosphorylation assays, co-immunoprecipitation, APP Y682F mutant analysis, in vivo TrkA distribution and signaling in APP knockout neurons The Journal of neuroscience High 21849536
2012 Conditional forebrain-specific TrkA knockout in mice causes dysfunction of basal forebrain cholinergic neurons (BFCNs): developmental increase of choline acetyltransferase expression becomes dependent on TrkA signaling (via the ERK pathway) before neuronal connections are established; TrkA loss results in anatomical and physiological deficits in BF cholinergic circuitry and selective cognitive impairment. Conditional TrkA knockout mouse (Cre-lox), ChAT expression analysis, ERK pathway readout, anatomical/physiological BF measurements, cognitive behavioral testing The Journal of neuroscience High 22442072
2014 The majority of retrograde TrkA signaling endosomes in sympathetic neurons are multivesicular bodies (MVBs). Retrogradely transported TrkA+ MVBs evade lysosomal fusion upon arriving in cell bodies and instead evolve into TrkA+ single-membrane signaling vesicles; TrkA kinase activity associated with retrogradely transported MVBs determines endosome evolution and fate. Ultrastructural (electron microscopy) and molecular characterization of retrograde endosomes in mouse sympathetic neurons; TrkA kinase activity manipulation with fate tracking eLife High 29381137
2014 A 3-amino-acid (KFG) domain in TrkA negatively regulates TrkA level and function by promoting ubiquitination; deletion of this domain in knock-in mice reduces TrkA ubiquitination, increases TrkA protein levels and activity, and results in enhanced thermal sensitivity and inflammatory pain without affecting DRG neuron numbers. KFG-deletion knock-in mouse, ubiquitination assays, TrkA protein level and activity measurements, thermal sensitivity and inflammatory pain behavioral tests The Journal of neuroscience High 24623787
2011 Nedd4-2 (E3 ubiquitin ligase) binds the C-terminal PPXY motif of TrkA and mediates multimonoubiquitination. Mutations at the hydrophobic residues Leu784 and Val790 increase Nedd4-2 binding and ubiquitination, directing receptors to the lysosomal pathway instead of recycling; multimonoubiquitination does not impair signaling cascade activation but potentiates TrkA-mediated differentiation (neurite outgrowth). Site-directed mutagenesis of TrkA C-terminal tail, co-immunoprecipitation, colocalization studies, neurite outgrowth assay Journal of neurochemistry Medium 21332718
2015 GGA3 interacts directly with the TrkA cytoplasmic tail through an internal DXXLL motif and mediates functional recycling of TrkA to the plasma membrane via an Arf6-dependent mechanism; GGA3 depletion delays TrkA recycling, accelerates TrkA degradation, attenuates sustained NGF-induced Akt activation, and reduces cell survival. siRNA depletion, direct binding assay (DXXLL motif), recycling and degradation kinetics assays, Akt phosphorylation immunoblotting, cell survival assay, Arf6 dominant-negative analysis Molecular biology of the cell High 26446845
2014 Syntaxin 8 (STX8, a Q-SNARE protein) binds TrkA and facilitates its transport from the Golgi to the plasma membrane, regulating TrkA cell surface levels specifically (not TrkB); STX8 modulates downstream NGF-induced TrkA signaling and NGF-dependent DRG neuron survival; STX8 knockdown in rat DRG via AAV6 RNAi produced analgesic effects on formalin-induced inflammatory pain. Co-immunoprecipitation, overexpression/knockdown studies for TrkA surface levels, NGF signaling assays, DRG neuron survival assay, AAV6-mediated in vivo STX8 knockdown with formalin pain model The Journal of biological chemistry High 24872407
2018 TRAF4 E3 ubiquitin ligase promotes K27- and K29-linked ubiquitination at the TrkA kinase domain, increasing TrkA kinase activity; mutation of TRAF4-targeted ubiquitination sites abolishes TrkA tyrosine autophosphorylation and its interaction with downstream proteins; TRAF4 knockdown suppresses NGF-stimulated TrkA downstream p38 MAPK activation and invasion-associated gene expression in prostate cancer cells. Co-immunoprecipitation, ubiquitination assays (linkage-specific), kinase activity assays, site-directed mutagenesis of ubiquitination sites, TRAF4 knockdown with p38 MAPK and invasion gene readouts The Journal of clinical investigation High 29715200
2016 X-ray crystal structures of TrkA kinase domain complexed with selective inhibitors reveal a non-active-site binding pocket formed by residues from both the kinase domain and the juxtamembrane (JM) region; three distinct binding modes with the JM region were characterized and found to underlie TrkA selectivity over TrkB and TrkC. X-ray crystallography of TrkA kinase domain + JM region with inhibitor complexes; in vitro kinase assays validating JM region importance Proceedings of the National Academy of Sciences of the United States of America High 28039433
2017 X-ray crystal structure of TrkA kinase domain plus juxtamembrane (JM) region bound to a selective inhibitor A1 reveals that the JM region creates a unique inhibitor-binding pocket conferring potency and selectivity over TrkB and TrkC; in vitro assays validated the importance of the JM region for inhibitor potency. X-ray crystallography, in vitro kinase inhibition assays with JM-region mutants/constructs Bioorganic & medicinal chemistry letters High 28159414
2012 TrkA has two established intracellular docking sites (Y490 and Y785) directly involved in signal propagation; phosphoproteomic dissection using Y490F and Y785F TrkA mutants identified a clear subset of downstream phosphorylation events not dependent on either docking site. Phosphoproteomics (mass spectrometry) of TrkA signaling using Y490F and Y785F receptor mutants Advances in biological regulation Medium 23266087
2004 p75NTR enhances TrkA signaling by specifically augmenting phosphorylation of the 46- and 52-kDa isoforms of Shc during NGF-induced TrkA activation; p75NTR physically co-immunoprecipitates with Shc; Akt serine phosphorylation downstream of Shc is also p75NTR-dependent; p75NTR does not enhance tyrosine phosphorylation of other TrkA substrates. Antisense knockdown of p75NTR and TrkA, phosphorylation immunoblotting of Shc isoforms and Akt, co-immunoprecipitation of p75NTR and Shc Journal of neurochemistry Medium 15056278
2005 TrkA induces apoptosis of neuroblastoma cells via a p53-dependent mechanism: TrkA increases p53 target protein expression; kinase-inactive TrkA or p53 inactivation (dominant inhibitory p53, E1B55K, or p53 mutation) prevents TrkA-induced apoptosis; caspase inhibitor or Bcl-XL overexpression also prevents TrkA apoptosis. Conversely, TrkA overexpression in non-transformed sympathetic neurons suppresses p53 and enhances survival. TrkA expression in neuroblastoma cell lines, p53 dominant-negative and E1B55K expression, caspase inhibitor treatment, Bcl-XL overexpression, p53 target protein immunoblotting, apoptosis assays The Journal of biological chemistry Medium 15961390
2019 The ganglioside GM1 oligosaccharide directly contacts TrkA at the cell surface to promote neuroblastoma differentiation: photoactivatable cross-linking with GM1 derivatives bearing the photoactivable group on the oligosaccharide (but not the ceramide) generated cross-linked TrkA-GM1 complexes. GM1 resides in detergent-resistant raft fractions while TrkA is in the soluble fraction, suggesting TrkA interacts with GM1 by extending its extracellular domain toward the membrane. Photoactivatable cross-linking with three radiolabeled GM1 derivatives, PAGE separation, radioimaging and immunoblotting, plasma membrane lipid raft isolation Journal of neurochemistry Medium 30776097
2015 NGF stimulation induces CD44 binding to TrkA at the plasma membrane, activating the p115RhoGEF/RhoA/ROCK1 pathway to stimulate breast cancer cell invasion independently of TrkA kinase activity; this TrkA kinase-independent CD44 signaling contributes to resistance to the TrkA kinase inhibitor lestaurtinib. Mass spectrometry proteomics, co-immunoprecipitation, proximity ligation assays, siRNA knockdown of CD44, in vitro invasion assays, mouse xenograft tumor model Oncotarget High 25840418
2019 ProNGF binding to sortilin induces sequential formation of a sortilin/TrkA/EphA2 complex at the plasma membrane, leading to TrkA phosphorylation-dependent Akt activation and EphA2-dependent Src activation; EphA2 inhibition abolishes proNGF-stimulated clonogenic growth of breast cancer cells. Proteomic analysis, proximity ligation assays, co-immunoprecipitation, siRNA knockdown of EphA2, clonogenic growth assays, in vivo primary tumor and metastasis models Cancer letters High 30771434
2006 Brn3a and Klf7 transcription factors cooperate to control TrkA expression in sensory neurons: in vitro, they synergistically activate the TrkA enhancer; in vivo, TrkA expression is severely reduced in Brn3a-/-;Klf7-/- double-mutant trigeminal ganglia compared to single mutants, and all Trk+ neurons are lost by birth in double mutants. In vitro TrkA enhancer reporter assays, genetic epistasis with Brn3a and Klf7 single and double knockout mice, in vivo TrkA expression analysis Developmental biology High 17011544
2018 EZH2 represses NTRK1 (TrkA) transcription via H3K27me3 histone modifications at the NTRK1 P1 promoter region; EZH2 knockdown or inhibition de-represses NTRK1 expression and induces neuroblastoma cell differentiation (neurite extension); depletion of NTRK1 cancels EZH2 knockdown-induced differentiation, establishing NTRK1 as a downstream effector. EZH2 knockdown by lentivirus, EZH2 inhibitor treatment, transcriptome analysis, chromatin immunoprecipitation (ChIP) for H3K27me3 at NTRK1 promoters, methylome analysis, NTRK1 siRNA epistasis Oncogene High 29507419
2018 Light-inducible activation of TrkA intracellular domain homo-interaction (using cryptochrome 2 optogenetics) in the absence of NGF activates PI3K/AKT and Raf/ERK signaling pathways, promotes neurite growth in PC12 cells, and supports survival of dorsal root ganglion neurons, demonstrating that kinase domain dimerization/interaction is sufficient for TrkA downstream signaling. Optogenetic TrkA activation using CRY2-based homo-interaction; PI3K/AKT and Raf/ERK phosphorylation assays; neurite outgrowth in PC12 cells; DRG neuron survival assay ACS synthetic biology Medium 29975841
2020 Site-dependent phosphorylation of individual intracellular tyrosines in TrkA controls MAPK/ERK signaling: using light-sensitive tyrosine analogues (p-azido-L-phenylalanine and caged-tyrosine via amber codon suppression), specific TrkA tyrosine mutants were identified that can activate the ERK pathway in the absence of NGF upon light illumination, revealing which phosphorylation sites drive defined downstream signaling. Genetic code expansion with amber codon suppression, light-sensitive unnatural amino acid incorporation at specific TrkA tyrosines, ERK activation assays with light-controlled phosphorylation Communications biology Medium 33239753
2014 TrkA promotes MDM2-mediated ubiquitination and degradation of AGPS (alkylglyceronephosphate synthase): TrkA phosphorylates AGPS at Y451, promoting AGPS-MDM2 interaction and proteasomal degradation of AGPS, thereby suppressing ferroptosis in prostate cancer cells; TrkA inhibitor larotrectinib increases susceptibility of prostate cancer cells to ferroptosis. Label-free mass spectrometry, co-immunoprecipitation, GST pull-down (in vivo and in vitro), ubiquitination assays, site-specific mutagenesis (Y451), xenograft model Journal of experimental & clinical cancer research High 38200609
2006 P2Y2 GPCR and TrkA receptor tyrosine kinase interact via Src family kinases (SFK): SFK inhibitors block P2Y2-mediated enhancement of TrkA signaling and neuronal differentiation in PC12 cells and DRG neurons, and abrogate co-immunoprecipitation of TrkA, P2Y2, and SFK, identifying SFK as a convergence point for GPCR-RTK crosstalk. SFK inhibitor treatment, co-immunoprecipitation of TrkA/P2Y2/SFK complex, neurite outgrowth in PC12 cells and primary DRG neurons Biochemical and biophysical research communications Medium 16842754
2018 NTRK1 inhibition induces phosphorylation of LATS1 and controls YAP subcellular localization, suppressing YAP-driven transcription, cancer cell proliferation and migration; NTRK1 regulates YAP oncogenic activity in vivo in mouse xenograft models, establishing crosstalk between the NGF-NTRK1 and Hippo pathways. Targeted kinase inhibitor screen, LATS1 phosphorylation assay, YAP localization analysis, cell proliferation/migration assays, mouse xenograft model Oncogene Medium 30542115

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Competitive signaling between TrkA and p75 nerve growth factor receptors determines cell survival. The Journal of neuroscience : the official journal of the Society for Neuroscience 401 9547236
2019 Fracture repair requires TrkA signaling by skeletal sensory nerves. The Journal of clinical investigation 207 31638597
2016 Recurrent NTRK1 Gene Fusions Define a Novel Subset of Locally Aggressive Lipofibromatosis-like Neural Tumors. The American journal of surgical pathology 200 27259011
2001 Molecular basis of congenital insensitivity to pain with anhidrosis (CIPA): mutations and polymorphisms in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. Human mutation 152 11748840
2009 Rearrangements of NTRK1 gene in papillary thyroid carcinoma. Molecular and cellular endocrinology 145 19883730
1999 TrkA glycosylation regulates receptor localization and activity. Journal of neurobiology 123 10235685
2014 Biogenesis and function of the NGF/TrkA signaling endosome. International review of cell and molecular biology 122 25619719
1997 Expression of TrkA, TrkB and TrkC in human neuroblastomas. Journal of neuro-oncology 120 9049830
1995 Non-TrkA-expressing small DRG neurons are lost in TrkA deficient mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 120 7666178
2015 NGF/TrkA Signaling as a Therapeutic Target for Pain. Pain practice : the official journal of World Institute of Pain 117 26452158
2003 RET and NTRK1 proto-oncogenes in human diseases. Journal of cellular physiology 113 12652644
2005 Biological effects of TrkA and TrkB receptor signaling in neuroblastoma. Cancer letters 100 15921851
1996 TrkA receptor ectodomain cleavage generates a tyrosine-phosphorylated cell-associated fragment. The Journal of cell biology 97 8636219
2002 Genetics of congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV. Clinical, biological and molecular aspects of mutations in TRKA(NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. Clinical autonomic research : official journal of the Clinical Autonomic Research Society 85 12102460
2015 Blocking the tropomyosin receptor kinase A (TrkA) receptor inhibits pain behaviour in two rat models of osteoarthritis. Annals of the rheumatic diseases 83 26286016
2014 NTRK1 fusion in glioblastoma multiforme. PloS one 81 24647444
2008 RET oncogene in MEN2, MEN2B, MTC and other forms of thyroid cancer. Expert review of anticancer therapy 80 18402529
1997 Sympathetic neuron survival and TrkA expression in NT3-deficient mouse embryos. The EMBO journal 79 9214629
2016 Nerve growth factor & TrkA as novel therapeutic targets in cancer. Biochimica et biophysica acta 76 27264679
2012 TrkA gene ablation in basal forebrain results in dysfunction of the cholinergic circuitry. The Journal of neuroscience : the official journal of the Society for Neuroscience 72 22442072
2018 TRAF4-mediated ubiquitination of NGF receptor TrkA regulates prostate cancer metastasis. The Journal of clinical investigation 70 29715200
2005 Oncogenic rearrangements of the NTRK1/NGF receptor. Cancer letters 70 16242838
1996 The neurotrophin receptor, gp75, forms a complex with the receptor tyrosine kinase TrkA. The Journal of cell biology 69 8603925
2008 Human ProNGF: biological effects and binding profiles at TrkA, P75NTR and sortilin. Journal of neurochemistry 68 18808449
1997 Chromosome 1 rearrangements involving the genes TPR and NTRK1 produce structurally different thyroid-specific TRK oncogenes. Genes, chromosomes & cancer 68 9172002
1999 trkA, trkB, and trkC messenger RNA expression by bulbospinal cells of the rat. Neuroscience 65 10426534
2022 High-affinity TrkA and p75 neurotrophin receptor complexes: A twisted affair. The Journal of biological chemistry 64 35051416
2018 EZH2 regulates neuroblastoma cell differentiation via NTRK1 promoter epigenetic modifications. Oncogene 64 29507419
2009 NTRK1 and NTRK2 receptors facilitate follicle assembly and early follicular development in the mouse ovary. Reproduction (Cambridge, England) 64 19357131
2012 Medullary thyroid carcinoma (MTC) and RET proto-oncogene: mutation spectrum in the familial cases and a meta-analysis of studies on the sporadic form. Mutation research 60 23059849
2018 Multivesicular bodies mediate long-range retrograde NGF-TrkA signaling. eLife 53 29381137
2011 APP is phosphorylated by TrkA and regulates NGF/TrkA signaling. The Journal of neuroscience : the official journal of the Society for Neuroscience 53 21849536
1996 Genomic organization of the human NTRK1 gene. Oncogene 51 8957089
1999 Mitogenesis in glioblastoma multiforme cell lines: a role for NGF and its TrkA receptors. Journal of neuro-oncology 50 10728904
2004 The RET and TRKA pathways collaborate to regulate neuroblastoma differentiation. Oncogene 49 14712226
2016 Selective inhibition of tropomyosin-receptor-kinase A (TrkA) reduces pain and joint damage in two rat models of inflammatory arthritis. Arthritis research & therapy 48 27145816
2003 Methylmercury decreases NGF-induced TrkA autophosphorylation and neurite outgrowth in PC12 cells. Brain research. Developmental brain research 48 12644250
2009 CCM2 mediates death signaling by the TrkA receptor tyrosine kinase. Neuron 47 19755102
2016 Structural characterization of nonactive site, TrkA-selective kinase inhibitors. Proceedings of the National Academy of Sciences of the United States of America 46 28039433
2008 TrkA receptor endolysosomal degradation is both ubiquitin and proteasome dependent. Traffic (Copenhagen, Denmark) 46 18419753
2018 Optical Activation of TrkA Signaling. ACS synthetic biology 45 29975841
2017 Neurotrophin Receptors TrkA, p75NTR, and Sortilin Are Increased and Targetable in Thyroid Cancer. The American journal of pathology 45 29037860
2003 Expression of NGF, Trka and p75 in human cartilage. European journal of histochemistry : EJH 44 14706929
1997 trkA and trkC expression is increased in human diabetic skin. Neuroscience letters 43 9197281
2011 Tyrosine kinase A receptor (trkA): a potential marker in epithelial ovarian cancer. Gynecologic oncology 40 21236475
2005 Proximity of TPR and NTRK1 rearranging loci in human thyrocytes. Cancer research 40 15805251
2018 Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors. Journal of medicinal chemistry 39 29672039
2005 TrkA induces apoptosis of neuroblastoma cells and does so via a p53-dependent mechanism. The Journal of biological chemistry 39 15961390
2004 The p75 neurotrophin receptor enhances TrkA signalling by binding to Shc and augmenting its phosphorylation. Journal of neurochemistry 39 15056278
2000 TrkA is necessary for the normal development of the murine thymus. Journal of neuroimmunology 39 10900332
2012 Diminished trkA receptor signaling reveals cholinergic-attentional vulnerability of aging. The European journal of neuroscience 38 23228124
2001 A novel mutation within the extracellular domain of TrkA causes constitutive receptor activation. Oncogene 38 11313867
2019 GM1 promotes TrkA-mediated neuroblastoma cell differentiation by occupying a plasma membrane domain different from TrkA. Journal of neurochemistry 37 30776097
2002 TrkA as a life and death receptor: receptor dose as a mediator of function. Cancer research 36 12208732
2001 IRS-1 and IRS-2 are recruited by TrkA receptor and oncogenic TRK-T1. Journal of cellular physiology 36 11147812
2007 TrkA receptor "hot spots" for binding of NT-3 as a heterologous ligand. The Journal of biological chemistry 34 17439940
2006 Brn3a and Klf7 cooperate to control TrkA expression in sensory neurons. Developmental biology 34 17011544
1998 Mutational analysis of the TrkA gene in prostate cancer. The Prostate 32 9687989
2008 TrkA pathway activation induced by amyloid-beta (Abeta). Molecular and cellular neurosciences 31 19162192
1997 TrkA neutrophin receptor protein in the rat and human thymus. The Anatomical record 31 9372171
2015 NGF-induced TrkA/CD44 association is involved in tumor aggressiveness and resistance to lestaurtinib. Oncotarget 30 25840418
2011 Ubiquitination of TrkA by Nedd4-2 regulates receptor lysosomal targeting and mediates receptor signaling. Journal of neurochemistry 30 21332718
2006 P2Y2 and TrkA receptors interact with Src family kinase for neuronal differentiation. Biochemical and biophysical research communications 30 16842754
2022 Ultrasound delivery of a TrkA agonist confers neuroprotection to Alzheimer-associated pathologies. Brain : a journal of neurology 28 34919633
1998 Rearrangements of RET and NTRK1 tyrosine kinase receptors in papillary thyroid carcinomas. Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer 28 10027004
2019 Novel TG-FGFR1 and TRIM33-NTRK1 transcript fusions in papillary thyroid carcinoma. Genes, chromosomes & cancer 27 30664823
2019 Role of NGF-TrkA signaling in calcification of articular chondrocytes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27 31238006
2019 ProNGF increases breast tumor aggressiveness through functional association of TrkA with EphA2. Cancer letters 26 30771434
2017 The juxtamembrane region of TrkA kinase is critical for inhibitor selectivity. Bioorganic & medicinal chemistry letters 26 28159414
2015 Th2 cytokines enhance TrkA expression, upregulate proliferation, and downregulate differentiation of keratinocytes. Journal of dermatological science 26 25823576
2007 Tracking TrkA's trafficking: NGF receptor trafficking controls NGF receptor signaling. Molecular neurobiology 26 17917104
2011 Aurora kinases are expressed in medullary thyroid carcinoma (MTC) and their inhibition suppresses in vitro growth and tumorigenicity of the MTC derived cell line TT. BMC cancer 25 21943074
2018 Foretinib Overcomes Entrectinib Resistance Associated with the NTRK1 G667C Mutation in NTRK1 Fusion-Positive Tumor Cells in a Brain Metastasis Model. Clinical cancer research : an official journal of the American Association for Cancer Research 24 29463555
2012 Receptor tyrosine kinase signaling mechanisms: Devolving TrkA responses with phosphoproteomics. Advances in biological regulation 24 23266087
2009 Interplay between autophagy and apoptosis in TrkA-induced cell death. Autophagy 24 19115484
2001 Association among EPHB2, TrkA, and MYCN expression in low-stage neuroblastomas. Medical and pediatric oncology 24 11464911
1998 Kinetics of trkA tyrosine kinase activity and inhibition by K-252a. Archives of biochemistry and biophysics 24 9448714
2017 Association of TrkA and APP Is Promoted by NGF and Reduced by Cell Death-Promoting Agents. Frontiers in molecular neuroscience 23 28197073
2016 Noise-induced hearing loss: Neuropathic pain via Ntrk1 signaling. Molecular and cellular neurosciences 23 27473923
2000 Expression of neurotrophin receptor TrkA inhibits angiogenesis in neuroblastoma. Medical and pediatric oncology 23 11107119
2022 Preoperative Identification of Medullary Thyroid Carcinoma (MTC): Clinical Validation of the Afirma MTC RNA-Sequencing Classifier. Thyroid : official journal of the American Thyroid Association 22 35793115
2014 Paradoxical effect of TrkA inhibition in Alzheimer's disease models. Journal of Alzheimer's disease : JAD 22 24531152
2014 TrkA in vivo function is negatively regulated by ubiquitination. The Journal of neuroscience : the official journal of the Society for Neuroscience 22 24623787
2005 TrkA NGF receptor plays a role in the modulation of p75NTR expression. Neuroscience letters 22 15955426
2005 Estrogen alters trkA and p75 neurotrophin receptor expression within sympathetic neurons. Journal of neurobiology 22 16118792
2016 NTRK1 fusions for the therapeutic intervention of Korean patients with colon cancer. Oncotarget 21 26716414
2022 Sensory Neuron-Specific Deletion of Tropomyosin Receptor Kinase A (TrkA) in Mice Abolishes Osteoarthritis (OA) Pain via NGF/TrkA Intervention of Peripheral Sensitization. International journal of molecular sciences 20 36292950
2018 NTRK1 is a positive regulator of YAP oncogenic function. Oncogene 20 30542115
2015 GGA3 mediates TrkA endocytic recycling to promote sustained Akt phosphorylation and cell survival. Molecular biology of the cell 20 26446845
2014 Syntaxin 8 modulates the post-synthetic trafficking of the TrkA receptor and inflammatory pain transmission. The Journal of biological chemistry 20 24872407
2013 Expression of NTRK1/TrkA affects immunogenicity of neuroblastoma cells. International journal of cancer 20 23400852
2014 (99)mTc-3PRGD2 scintimammography in palpable and nonpalpable breast lesions. Molecular imaging 19 24825112
2012 Nodal metastasis microRNA expression correlates with the primary tumour in MTC. ANZ journal of surgery 19 23072640
2024 TrkA promotes MDM2-mediated AGPS ubiquitination and degradation to trigger prostate cancer progression. Journal of experimental & clinical cancer research : CR 18 38200609
2017 Exome sequencing identifies novel NTRK1 mutations in patients with HSAN-IV phenotype. American journal of medical genetics. Part A 18 28328124
2022 Expression of NGF/proNGF and Their Receptors TrkA, p75NTR and Sortilin in Melanoma. International journal of molecular sciences 17 35457078
2022 Neurotrophin Pathway Receptors NGFR and TrkA Control Perineural Invasion, Metastasis, and Pain in Oral Cancer. Advanced biology 17 35925599
2022 TrkA+ Neurons Induce Pathologic Regeneration After Soft Tissue Trauma. Stem cells translational medicine 17 36222619
2018 Exploring Morphine-Triggered PKC-Targets and Their Interaction with Signaling Pathways Leading to Pain via TrkA. Proteomes 17 30301203
2020 Photosensitive tyrosine analogues unravel site-dependent phosphorylation in TrkA initiated MAPK/ERK signaling. Communications biology 16 33239753

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