{"gene":"NTSR1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2020,"finding":"SBI-553 acts as a β-arrestin-biased allosteric modulator of NTSR1: it functions as a β-arrestin-biased agonist at NTSR1 and simultaneously antagonizes G protein signaling by the endogenous ligand neurotensin, demonstrating that NTSR1 G protein and β-arrestin activation produce discrete, separable physiological effects. SBI-553 showed efficacy in animal models of psychostimulant (cocaine) abuse without the side effects of balanced NTSR1 agonism.","method":"Pharmacological characterization of NTSR1 signaling bias in cell-based assays; animal models of cocaine self-administration; comparison of G protein vs. β-arrestin pathway activation","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (receptor signaling assays, biased agonism characterization, in vivo behavioral pharmacology) in a single rigorous study published in a high-impact journal","pmids":["32470395"],"is_preprint":false},{"year":2004,"finding":"Ntsr1-deficient mice show no significant alteration in thermal nociception (hot plate jump latency, tail flick, hind paw licking) compared to wild-type controls, indicating that NTSR1 does not play a major role in NT-mediated thermal nociception, whereas Ntsr2-deficient mice show significantly altered jump latency. NTSR1 and NTSR2 mRNA expression was mapped in brain regions involved in nociception (PAG, RVM), with NTSR2 predominating.","method":"Genetic knockout mice (Ntsr1-deficient and Ntsr2-deficient); hot plate test, tail flick, hind paw licking; in situ hybridization for receptor mRNA distribution","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined behavioral phenotype, but finding for NTSR1 is a negative result (no thermal nociception phenotype); single lab","pmids":["14725975"],"is_preprint":false},{"year":2006,"finding":"Neurotensin (NT) at threshold concentrations counteracts D2 receptor agonist-induced inhibition of striatal dopamine release and pallidal GABA release via antagonistic intramembrane NTR1/D2 receptor interactions in the basal ganglia; these effects are blocked by the NTSR1 antagonist SR48692, demonstrating functional receptor-receptor crosstalk between NTSR1 and D2 receptors at striatal dopamine terminals and striato-pallidal GABA neurons.","method":"In vivo mono and dual-probe microdialysis in freely moving rats; pharmacological blockade with NTSR1 antagonist SR48692","journal":"Journal of neural transmission","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo microdialysis with receptor antagonist validation, single lab","pmids":["16983483"],"is_preprint":false},{"year":2014,"finding":"NTS/NTSR1 signaling causes overexpression and autocrine/paracrine activation of EGFR, HER2, and HER3 in lung tumor cells. The EGFR and HER3 autocrine activation is mediated by MMP1 activation and release of EGF-like ligands (HB-EGF, Neuregulin 1). Establishment of an NTS autocrine loop modulates tumor growth and confers responsiveness to erlotinib.","method":"Cell-based assays with NTS/NTSR1-expressing lung cancer lines; siRNA knockdown; autocrine loop characterization; xenograft tumor models with erlotinib treatment; measurement of MMP1 activation and EGF-like ligand release","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cellular and in vivo methods in single lab; mechanistic pathway placed (NTSR1→MMP1→HB-EGF/NRG1→EGFR/HER3)","pmids":["25249545"],"is_preprint":false},{"year":2017,"finding":"NTS/NTSR1 signaling in glioblastoma cells activates the MAPK and NF-κB pathways, which promotes expression of Wnt ligands (Wnt1, Wnt3a, Wnt5a). Reciprocally, Wnt3a increases NTSR1 mRNA and protein expression while the Wnt inhibitor iCRT3 decreases it, establishing a positive feedback loop between NTS/NTSR1 and Wnt/β-catenin signaling that contributes to tumor growth.","method":"Genetic silencing (siRNA), pharmacological inhibition, gain-of-function studies in glioblastoma cell lines; in vivo xenograft tumor models; bioinformatic analysis; western blotting and qPCR","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KD, inhibitors, OE, in vivo), single lab","pmids":["29065410"],"is_preprint":false},{"year":2018,"finding":"NTSR1 knockdown in glioblastoma cells reduces invasion by downregulating Jun expression; Jun transcriptionally activates miR-494 by binding to its promoter (confirmed by ChIP assay); miR-494 directly suppresses SOCS6 expression (confirmed by dual-luciferase reporter); the resulting NTSR1→Jun→miR-494→SOCS6 axis mediates NTSR1-induced glioblastoma invasion in vitro and in vivo.","method":"siRNA knockdown of NTSR1; transwell/wound-healing invasion assays; chromatin immunoprecipitation (ChIP); dual-luciferase reporter assay; western blotting; qRT-PCR; orthotopic xenograft mouse model","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, reporter assay, KD, in vivo) establishing a defined pathway; single lab","pmids":["30261490"],"is_preprint":false},{"year":2023,"finding":"The transcription factor TOX4 binds to the NTSR1 promoter and transcriptionally activates NTSR1 expression in lung cancer cells. The lncRNA SLCO4A1-AS1 acts as a decoy for TOX4 by direct interaction, preventing TOX4 from binding the NTSR1 promoter and thereby suppressing NTSR1 transcription and downstream cancer cell migration and invasion via cytoskeletal remodeling.","method":"RNA pull-down; RNA immunoprecipitation (RIP); chromatin immunoprecipitation (ChIP); dual-luciferase reporter assay; transwell migration/invasion assays; RNA-seq; western blotting; tail vein injection mouse model","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, RIP, pull-down, reporter assay, in vivo) in single lab identifying TOX4 as a transcriptional activator of NTSR1","pmids":["37726723"],"is_preprint":false},{"year":2012,"finding":"NTSR1 and NTSR2 are expressed in human B cell lines and normal human B lymphocytes. Neurotensin is functional in B cell lines, inducing proliferation and inhibiting apoptosis from serum deprivation or Fas activation. In B cell leukemia patient cells, NTSR1 expression is decreased while NTSR2 is overexpressed.","method":"RT-PCR and western blotting for receptor expression; functional assays of neurotensin-induced proliferation and apoptosis inhibition in B cell lines","journal":"Journal of immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, primarily expression characterization with limited mechanistic follow-up on NTSR1 specifically","pmids":["23109725"],"is_preprint":false}],"current_model":"NTSR1 is a G protein-coupled receptor for neurotensin that signals through both canonical G protein pathways and β-arrestin-mediated pathways to produce distinct physiological effects; at the cellular level, NTSR1 activates MAPK and NF-κB signaling, engages MMP1-mediated transactivation of EGFR/HER family receptors, and forms a positive feedback loop with Wnt/β-catenin signaling, while in the basal ganglia it engages in antagonistic receptor-receptor interactions with dopamine D2 receptors; its transcription is directly activated by the TOX4 transcription factor, and biased allosteric modulation of NTSR1 toward β-arrestin versus G protein signaling produces separable behavioral outcomes including selective attenuation of addictive behaviors."},"narrative":{"mechanistic_narrative":"NTSR1 is a G protein-coupled receptor for neurotensin whose distinct downstream effects can be separated by biasing signaling toward β-arrestin versus G protein pathways: the allosteric modulator SBI-553 acts as a β-arrestin-biased agonist while antagonizing neurotensin-driven G protein signaling, and this bias is sufficient to attenuate psychostimulant (cocaine) self-administration without the side effects of balanced agonism [PMID:32470395]. In the basal ganglia, NTSR1 engages in antagonistic intramembrane receptor-receptor interactions with dopamine D2 receptors, with threshold neurotensin counteracting D2 agonist-induced inhibition of striatal dopamine and pallidal GABA release [PMID:16983483]. In tumor contexts, NTS/NTSR1 signaling activates MAPK and NF-κB pathways and drives oncogenic programs: it triggers MMP1-mediated release of EGF-like ligands (HB-EGF, Neuregulin 1) that transactivate EGFR, HER2, and HER3 in lung cancer cells [PMID:25249545], forms a positive feedback loop with Wnt/β-catenin signaling in glioblastoma [PMID:29065410], and promotes invasion through a Jun→miR-494→SOCS6 axis [PMID:30261490]. NTSR1 transcription is directly activated by the transcription factor TOX4, which is itself sequestered by the lncRNA SLCO4A1-AS1 [PMID:37726723]. Genetic knockout studies indicate NTSR1 does not contribute substantially to neurotensin-mediated thermal nociception, a role instead attributable to NTSR2 [PMID:14725975].","teleology":[{"year":2004,"claim":"To define whether NTSR1 versus NTSR2 mediates neurotensin's antinociceptive effects, knockout mice resolved that NTSR1 is dispensable for thermal nociception, assigning that role to NTSR2.","evidence":"Ntsr1- and Ntsr2-deficient mice in hot plate, tail flick, and hind paw licking tests with in situ hybridization mapping","pmids":["14725975"],"confidence":"Medium","gaps":["Negative result for NTSR1 does not exclude roles in non-thermal pain modalities","Does not address NTSR1 signaling mechanism in any pathway"]},{"year":2006,"claim":"To test whether NTSR1 functionally modulates dopaminergic circuits, in vivo microdialysis showed NTSR1 antagonizes D2 receptor signaling through intramembrane receptor-receptor crosstalk at striatal terminals.","evidence":"Mono/dual-probe microdialysis in freely moving rats with NTSR1 antagonist SR48692","pmids":["16983483"],"confidence":"Medium","gaps":["Molecular basis of the NTSR1/D2 heteromer not structurally defined","Single lab, pharmacological inference"]},{"year":2012,"claim":"To explore NTSR1 outside the nervous system, expression and functional assays placed NTSR1 in B lymphocytes where neurotensin promotes proliferation and survival.","evidence":"RT-PCR, western blot, and proliferation/apoptosis assays in human B cell lines and leukemia patient cells","pmids":["23109725"],"confidence":"Low","gaps":["Primarily expression characterization with limited NTSR1-specific mechanistic follow-up","Causal role of NTSR1 versus NTSR2 in B cell effects not disentangled"]},{"year":2014,"claim":"To establish how NTSR1 drives epithelial tumor growth, lung cancer studies showed it transactivates EGFR/HER family receptors via MMP1-mediated EGF-like ligand release.","evidence":"siRNA knockdown, autocrine loop characterization, and erlotinib xenograft models in NTS/NTSR1-expressing lung cancer cells","pmids":["25249545"],"confidence":"Medium","gaps":["Direct link between NTSR1 proximal signaling and MMP1 activation not detailed","Single lab"]},{"year":2017,"claim":"To connect NTSR1 to developmental signaling in tumors, glioblastoma work identified a MAPK/NF-κB-driven positive feedback loop with Wnt/β-catenin.","evidence":"siRNA, pharmacological inhibition, gain-of-function, and xenograft assays with western blot/qPCR in glioblastoma lines","pmids":["29065410"],"confidence":"Medium","gaps":["Mechanism linking NTSR1 to Wnt ligand induction not fully resolved","Single lab"]},{"year":2018,"claim":"To define how NTSR1 promotes invasion, a defined NTSR1→Jun→miR-494→SOCS6 transcriptional/microRNA axis was mapped in glioblastoma.","evidence":"siRNA knockdown, ChIP, dual-luciferase reporter, invasion assays, and orthotopic xenografts","pmids":["30261490"],"confidence":"Medium","gaps":["Proximal NTSR1 signaling events upstream of Jun not specified","Single lab"]},{"year":2023,"claim":"To identify upstream control of NTSR1 expression, TOX4 was shown to be a direct transcriptional activator antagonized by the lncRNA SLCO4A1-AS1.","evidence":"RNA pull-down, RIP, ChIP, dual-luciferase reporter, migration/invasion assays, and tail vein metastasis model in lung cancer","pmids":["37726723"],"confidence":"Medium","gaps":["Whether TOX4 regulation of NTSR1 operates outside lung cancer is unknown","Single lab"]},{"year":2020,"claim":"To demonstrate that NTSR1 signaling pathways are pharmacologically separable, SBI-553 was characterized as a β-arrestin-biased modulator producing therapeutic effects on cocaine abuse distinct from balanced agonism.","evidence":"Biased agonism cell-based signaling assays and cocaine self-administration animal models","pmids":["32470395"],"confidence":"High","gaps":["Structural basis of biased allosteric modulation not resolved here","In vivo target engagement beyond cocaine models not addressed"]},{"year":null,"claim":"How NTSR1's discrete G protein versus β-arrestin signaling branches map onto its diverse downstream effectors (D2 crosstalk, MMP1/EGFR transactivation, Wnt feedback, Jun/miR-494 axis) across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking signaling bias to specific oncogenic pathways","Receptor-receptor heteromer structure undefined","Tissue-specificity of TOX4-driven NTSR1 expression unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,3,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,5,6]}],"complexes":[],"partners":["DRD2","TOX4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P30989","full_name":"Neurotensin receptor type 1","aliases":["High-affinity levocabastine-insensitive neurotensin receptor","NTRH"],"length_aa":418,"mass_kda":46.3,"function":"G-protein coupled receptor for the tridecapeptide neurotensin (NTS) (PubMed:21725197, PubMed:23140271, PubMed:8381365). Signaling is effected via G proteins that activate a phosphatidylinositol-calcium second messenger system. Signaling leads to the activation of downstream MAP kinases and protects cells against apoptosis (PubMed:21725197)","subcellular_location":"Cell membrane; Membrane raft","url":"https://www.uniprot.org/uniprotkb/P30989/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NTSR1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NTSR1","total_profiled":1310},"omim":[{"mim_id":"619628","title":"AFTIPHILIN; AFTPH","url":"https://www.omim.org/entry/619628"},{"mim_id":"610255","title":"MICRO RNA 133A2; MIR133A2","url":"https://www.omim.org/entry/610255"},{"mim_id":"610254","title":"MICRO RNA 133A1; MIR133A1","url":"https://www.omim.org/entry/610254"},{"mim_id":"605538","title":"NEUROTENSIN RECEPTOR 2; NTSR2","url":"https://www.omim.org/entry/605538"},{"mim_id":"162651","title":"NEUROTENSIN RECEPTOR 1; NTSR1","url":"https://www.omim.org/entry/162651"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"intestine","ntpm":9.8}],"url":"https://www.proteinatlas.org/search/NTSR1"},"hgnc":{"alias_symbol":["NTR"],"prev_symbol":[]},"alphafold":{"accession":"P30989","domains":[{"cath_id":"1.20.1070.10","chopping":"57-275_292-384","consensus_level":"medium","plddt":91.3084,"start":57,"end":384}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P30989","model_url":"https://alphafold.ebi.ac.uk/files/AF-P30989-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P30989-F1-predicted_aligned_error_v6.png","plddt_mean":79.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NTSR1","jax_strain_url":"https://www.jax.org/strain/search?query=NTSR1"},"sequence":{"accession":"P30989","fasta_url":"https://rest.uniprot.org/uniprotkb/P30989.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P30989/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P30989"}},"corpus_meta":[{"pmid":"12404007","id":"PMC_12404007","title":"The 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Focus on NTR/D2 interactions in the basal ganglia.","date":"2006","source":"Journal of neural transmission (Vienna, Austria : 1996)","url":"https://pubmed.ncbi.nlm.nih.gov/16983483","citation_count":21,"is_preprint":false},{"pmid":"27038014","id":"PMC_27038014","title":"Comparison of P75 NTR-positive and -negative etcomesenchymal stem cell odontogenic differentiation through epithelial-mesenchymal interaction.","date":"2016","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/27038014","citation_count":21,"is_preprint":false},{"pmid":"37726723","id":"PMC_37726723","title":"LncRNA SLCO4A1-AS1 suppresses lung cancer progression by sequestering the TOX4-NTSR1 signaling axis.","date":"2023","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/37726723","citation_count":19,"is_preprint":false},{"pmid":"25642700","id":"PMC_25642700","title":"The unphosphorylated EIIA(Ntr) protein represses the synthesis of alkylresorcinols in Azotobacter vinelandii.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25642700","citation_count":19,"is_preprint":false},{"pmid":"14662858","id":"PMC_14662858","title":"Expression and characterization of the C345C/NTR domains of complement components C3 and C5.","date":"2003","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/14662858","citation_count":19,"is_preprint":false},{"pmid":"34655688","id":"PMC_34655688","title":"Bisphenol A single and repeated treatment increases HDAC2, leading to cholinergic neurotransmission dysfunction and SN56 cholinergic apoptotic cell death through AChE variants overexpression and NGF/TrkA/P75NTR signaling disruption.","date":"2021","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/34655688","citation_count":19,"is_preprint":false},{"pmid":"31514753","id":"PMC_31514753","title":"The p75NTR neurotrophin receptor is required to organize the mature neuromuscular synapse by regulating synaptic vesicle availability.","date":"2019","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/31514753","citation_count":19,"is_preprint":false},{"pmid":"26057084","id":"PMC_26057084","title":"Merlin status regulates p75(NTR) expression and apoptotic signaling in Schwann cells following nerve injury.","date":"2015","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/26057084","citation_count":18,"is_preprint":false},{"pmid":"29065410","id":"PMC_29065410","title":"A Novel Positive Feedback Loop Between NTSR1 and Wnt/β-Catenin Contributes to Tumor Growth of Glioblastoma.","date":"2017","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29065410","citation_count":18,"is_preprint":false},{"pmid":"35457078","id":"PMC_35457078","title":"Expression of NGF/proNGF and Their Receptors TrkA, p75NTR and Sortilin in Melanoma.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35457078","citation_count":17,"is_preprint":false},{"pmid":"33258176","id":"PMC_33258176","title":"Inactive variants of death receptor p75NTR reduce Alzheimer's neuropathology by interfering with APP internalization.","date":"2020","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/33258176","citation_count":17,"is_preprint":false},{"pmid":"19429059","id":"PMC_19429059","title":"Immunohistochemical localization of sortilin and p75(NTR) in normal and ischemic rat retina.","date":"2009","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/19429059","citation_count":17,"is_preprint":false},{"pmid":"31608921","id":"PMC_31608921","title":"A fluorescent probe for simultaneously sensing NTR and hNQO1 and distinguishing cancer cells.","date":"2019","source":"Journal of materials chemistry. B","url":"https://pubmed.ncbi.nlm.nih.gov/31608921","citation_count":17,"is_preprint":false},{"pmid":"28979360","id":"PMC_28979360","title":"Implication of the neurotrophin receptor p75NTR in vascular diseases: beyond the eye.","date":"2016","source":"Expert review of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/28979360","citation_count":17,"is_preprint":false},{"pmid":"17394529","id":"PMC_17394529","title":"Antagonistic effects of TrkB and p75(NTR) on NMDA receptor currents in post-synaptic densities transplanted into Xenopus oocytes.","date":"2007","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17394529","citation_count":17,"is_preprint":false},{"pmid":"30261490","id":"PMC_30261490","title":"Interference with NTSR1 Expression Exerts an Anti-Invasion Effect via the Jun/miR-494/SOCS6 Axis of Glioblastoma Cells.","date":"2018","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30261490","citation_count":16,"is_preprint":false},{"pmid":"27388253","id":"PMC_27388253","title":"Copy number and expression analysis of FOSL1, GSTP1, NTSR1, FADD and CCND1 genes in primary breast tumors with axillary lymph node metastasis.","date":"2016","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27388253","citation_count":16,"is_preprint":false},{"pmid":"23110888","id":"PMC_23110888","title":"The NTSR1 gene modulates the association between hippocampal structure and working memory performance.","date":"2012","source":"NeuroImage","url":"https://pubmed.ncbi.nlm.nih.gov/23110888","citation_count":15,"is_preprint":false},{"pmid":"25748048","id":"PMC_25748048","title":"Association of p75(NTR) and α9β1 integrin modulates NGF-dependent cellular responses.","date":"2015","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/25748048","citation_count":15,"is_preprint":false},{"pmid":"32699962","id":"PMC_32699962","title":"Antagonism of proNGF or its receptor p75NTR reverses remodelling and improves bladder function in a mouse model of diabetic voiding dysfunction.","date":"2020","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/32699962","citation_count":15,"is_preprint":false},{"pmid":"12106693","id":"PMC_12106693","title":"Expression of p75(NTR) in photoreceptor cells of dystrophic rat retinas.","date":"2002","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/12106693","citation_count":15,"is_preprint":false},{"pmid":"35393432","id":"PMC_35393432","title":"SorCS3 promotes the internalization of p75NTR to inhibit GBM progression.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35393432","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50803,"output_tokens":3081,"usd":0.099312,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9658,"output_tokens":2885,"usd":0.060207,"stage2_stop_reason":"end_turn"},"total_usd":0.159519,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify which papers are about the canonical NTSR1 (neurotensin receptor 1, high-affinity neurotensin receptor) versus p75NTR (the neurotrophin receptor, NGFR). \n\nThe HGNC aliases provided are \"NTR\" — but examining the corpus, the vast majority of papers are about p75NTR (the neurotrophin receptor, gene symbol NGFR), not NTSR1 (neurotensin receptor 1). The query gene is NTSR1 (neurotensin receptor 1).\n\nPapers clearly about NTSR1 (neurotensin receptor 1):\n- PMID 32470395 (SBI-553, β-arrestin-biased NTSR1 modulator)\n- PMID 14725975 (Ntsr1-deficient mice, thermal nociception)\n- PMID 23109725 (NTSR1 in B lymphocytes)\n- PMID 11032391 (NTSR1 gene, schizophrenia)\n- PMID 21394204 (NTSR1 polymorphism, working memory)\n- PMID 16983483 (NTR1 antagonist SR48692, receptor-receptor interactions)\n- PMID 26334593 (NTSR1 epigenetic silencing in colorectal cancer)\n- PMID 29065410 (NTSR1 and Wnt/β-Catenin in glioblastoma)\n- PMID 30261490 (NTSR1 and Jun/miR-494/SOCS6 in glioblastoma)\n- PMID 37726723 (SLCO4A1-AS1/TOX4/NTSR1 axis - lncRNA, but describes NTSR1 mechanism)\n- PMID 25249545 (NTS/NTSR1 causing EGFR/HER2/HER3 activation)\n- PMID 23110888 (NTSR1 gene modulates hippocampal structure/WM)\n- PMID 27388253 (copy number/expression, breast cancer - mostly correlative)\n\nPapers about p75NTR (NGFR) should be excluded as they are about a different gene (NGFR/p75NTR), not NTSR1. The alias \"NTR\" in this context appears to refer to the neurotensin receptor, but p75NTR is a completely different protein. I will extract only NTSR1 mechanistic findings.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"SBI-553 acts as a β-arrestin-biased allosteric modulator of NTSR1: it functions as a β-arrestin-biased agonist at NTSR1 and simultaneously antagonizes G protein signaling by the endogenous ligand neurotensin, demonstrating that NTSR1 G protein and β-arrestin activation produce discrete, separable physiological effects. SBI-553 showed efficacy in animal models of psychostimulant (cocaine) abuse without the side effects of balanced NTSR1 agonism.\",\n      \"method\": \"Pharmacological characterization of NTSR1 signaling bias in cell-based assays; animal models of cocaine self-administration; comparison of G protein vs. β-arrestin pathway activation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (receptor signaling assays, biased agonism characterization, in vivo behavioral pharmacology) in a single rigorous study published in a high-impact journal\",\n      \"pmids\": [\"32470395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Ntsr1-deficient mice show no significant alteration in thermal nociception (hot plate jump latency, tail flick, hind paw licking) compared to wild-type controls, indicating that NTSR1 does not play a major role in NT-mediated thermal nociception, whereas Ntsr2-deficient mice show significantly altered jump latency. NTSR1 and NTSR2 mRNA expression was mapped in brain regions involved in nociception (PAG, RVM), with NTSR2 predominating.\",\n      \"method\": \"Genetic knockout mice (Ntsr1-deficient and Ntsr2-deficient); hot plate test, tail flick, hind paw licking; in situ hybridization for receptor mRNA distribution\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined behavioral phenotype, but finding for NTSR1 is a negative result (no thermal nociception phenotype); single lab\",\n      \"pmids\": [\"14725975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Neurotensin (NT) at threshold concentrations counteracts D2 receptor agonist-induced inhibition of striatal dopamine release and pallidal GABA release via antagonistic intramembrane NTR1/D2 receptor interactions in the basal ganglia; these effects are blocked by the NTSR1 antagonist SR48692, demonstrating functional receptor-receptor crosstalk between NTSR1 and D2 receptors at striatal dopamine terminals and striato-pallidal GABA neurons.\",\n      \"method\": \"In vivo mono and dual-probe microdialysis in freely moving rats; pharmacological blockade with NTSR1 antagonist SR48692\",\n      \"journal\": \"Journal of neural transmission\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo microdialysis with receptor antagonist validation, single lab\",\n      \"pmids\": [\"16983483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NTS/NTSR1 signaling causes overexpression and autocrine/paracrine activation of EGFR, HER2, and HER3 in lung tumor cells. The EGFR and HER3 autocrine activation is mediated by MMP1 activation and release of EGF-like ligands (HB-EGF, Neuregulin 1). Establishment of an NTS autocrine loop modulates tumor growth and confers responsiveness to erlotinib.\",\n      \"method\": \"Cell-based assays with NTS/NTSR1-expressing lung cancer lines; siRNA knockdown; autocrine loop characterization; xenograft tumor models with erlotinib treatment; measurement of MMP1 activation and EGF-like ligand release\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cellular and in vivo methods in single lab; mechanistic pathway placed (NTSR1→MMP1→HB-EGF/NRG1→EGFR/HER3)\",\n      \"pmids\": [\"25249545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NTS/NTSR1 signaling in glioblastoma cells activates the MAPK and NF-κB pathways, which promotes expression of Wnt ligands (Wnt1, Wnt3a, Wnt5a). Reciprocally, Wnt3a increases NTSR1 mRNA and protein expression while the Wnt inhibitor iCRT3 decreases it, establishing a positive feedback loop between NTS/NTSR1 and Wnt/β-catenin signaling that contributes to tumor growth.\",\n      \"method\": \"Genetic silencing (siRNA), pharmacological inhibition, gain-of-function studies in glioblastoma cell lines; in vivo xenograft tumor models; bioinformatic analysis; western blotting and qPCR\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KD, inhibitors, OE, in vivo), single lab\",\n      \"pmids\": [\"29065410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NTSR1 knockdown in glioblastoma cells reduces invasion by downregulating Jun expression; Jun transcriptionally activates miR-494 by binding to its promoter (confirmed by ChIP assay); miR-494 directly suppresses SOCS6 expression (confirmed by dual-luciferase reporter); the resulting NTSR1→Jun→miR-494→SOCS6 axis mediates NTSR1-induced glioblastoma invasion in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown of NTSR1; transwell/wound-healing invasion assays; chromatin immunoprecipitation (ChIP); dual-luciferase reporter assay; western blotting; qRT-PCR; orthotopic xenograft mouse model\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, reporter assay, KD, in vivo) establishing a defined pathway; single lab\",\n      \"pmids\": [\"30261490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The transcription factor TOX4 binds to the NTSR1 promoter and transcriptionally activates NTSR1 expression in lung cancer cells. The lncRNA SLCO4A1-AS1 acts as a decoy for TOX4 by direct interaction, preventing TOX4 from binding the NTSR1 promoter and thereby suppressing NTSR1 transcription and downstream cancer cell migration and invasion via cytoskeletal remodeling.\",\n      \"method\": \"RNA pull-down; RNA immunoprecipitation (RIP); chromatin immunoprecipitation (ChIP); dual-luciferase reporter assay; transwell migration/invasion assays; RNA-seq; western blotting; tail vein injection mouse model\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, RIP, pull-down, reporter assay, in vivo) in single lab identifying TOX4 as a transcriptional activator of NTSR1\",\n      \"pmids\": [\"37726723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NTSR1 and NTSR2 are expressed in human B cell lines and normal human B lymphocytes. Neurotensin is functional in B cell lines, inducing proliferation and inhibiting apoptosis from serum deprivation or Fas activation. In B cell leukemia patient cells, NTSR1 expression is decreased while NTSR2 is overexpressed.\",\n      \"method\": \"RT-PCR and western blotting for receptor expression; functional assays of neurotensin-induced proliferation and apoptosis inhibition in B cell lines\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, primarily expression characterization with limited mechanistic follow-up on NTSR1 specifically\",\n      \"pmids\": [\"23109725\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NTSR1 is a G protein-coupled receptor for neurotensin that signals through both canonical G protein pathways and β-arrestin-mediated pathways to produce distinct physiological effects; at the cellular level, NTSR1 activates MAPK and NF-κB signaling, engages MMP1-mediated transactivation of EGFR/HER family receptors, and forms a positive feedback loop with Wnt/β-catenin signaling, while in the basal ganglia it engages in antagonistic receptor-receptor interactions with dopamine D2 receptors; its transcription is directly activated by the TOX4 transcription factor, and biased allosteric modulation of NTSR1 toward β-arrestin versus G protein signaling produces separable behavioral outcomes including selective attenuation of addictive behaviors.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NTSR1 is a G protein-coupled receptor for neurotensin whose distinct downstream effects can be separated by biasing signaling toward β-arrestin versus G protein pathways: the allosteric modulator SBI-553 acts as a β-arrestin-biased agonist while antagonizing neurotensin-driven G protein signaling, and this bias is sufficient to attenuate psychostimulant (cocaine) self-administration without the side effects of balanced agonism [#0]. In the basal ganglia, NTSR1 engages in antagonistic intramembrane receptor-receptor interactions with dopamine D2 receptors, with threshold neurotensin counteracting D2 agonist-induced inhibition of striatal dopamine and pallidal GABA release [#2]. In tumor contexts, NTS/NTSR1 signaling activates MAPK and NF-κB pathways and drives oncogenic programs: it triggers MMP1-mediated release of EGF-like ligands (HB-EGF, Neuregulin 1) that transactivate EGFR, HER2, and HER3 in lung cancer cells [#3], forms a positive feedback loop with Wnt/β-catenin signaling in glioblastoma [#4], and promotes invasion through a Jun→miR-494→SOCS6 axis [#5]. NTSR1 transcription is directly activated by the transcription factor TOX4, which is itself sequestered by the lncRNA SLCO4A1-AS1 [#6]. Genetic knockout studies indicate NTSR1 does not contribute substantially to neurotensin-mediated thermal nociception, a role instead attributable to NTSR2 [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"To define whether NTSR1 versus NTSR2 mediates neurotensin's antinociceptive effects, knockout mice resolved that NTSR1 is dispensable for thermal nociception, assigning that role to NTSR2.\",\n      \"evidence\": \"Ntsr1- and Ntsr2-deficient mice in hot plate, tail flick, and hind paw licking tests with in situ hybridization mapping\",\n      \"pmids\": [\"14725975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result for NTSR1 does not exclude roles in non-thermal pain modalities\", \"Does not address NTSR1 signaling mechanism in any pathway\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"To test whether NTSR1 functionally modulates dopaminergic circuits, in vivo microdialysis showed NTSR1 antagonizes D2 receptor signaling through intramembrane receptor-receptor crosstalk at striatal terminals.\",\n      \"evidence\": \"Mono/dual-probe microdialysis in freely moving rats with NTSR1 antagonist SR48692\",\n      \"pmids\": [\"16983483\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the NTSR1/D2 heteromer not structurally defined\", \"Single lab, pharmacological inference\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"To explore NTSR1 outside the nervous system, expression and functional assays placed NTSR1 in B lymphocytes where neurotensin promotes proliferation and survival.\",\n      \"evidence\": \"RT-PCR, western blot, and proliferation/apoptosis assays in human B cell lines and leukemia patient cells\",\n      \"pmids\": [\"23109725\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Primarily expression characterization with limited NTSR1-specific mechanistic follow-up\", \"Causal role of NTSR1 versus NTSR2 in B cell effects not disentangled\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"To establish how NTSR1 drives epithelial tumor growth, lung cancer studies showed it transactivates EGFR/HER family receptors via MMP1-mediated EGF-like ligand release.\",\n      \"evidence\": \"siRNA knockdown, autocrine loop characterization, and erlotinib xenograft models in NTS/NTSR1-expressing lung cancer cells\",\n      \"pmids\": [\"25249545\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link between NTSR1 proximal signaling and MMP1 activation not detailed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"To connect NTSR1 to developmental signaling in tumors, glioblastoma work identified a MAPK/NF-κB-driven positive feedback loop with Wnt/β-catenin.\",\n      \"evidence\": \"siRNA, pharmacological inhibition, gain-of-function, and xenograft assays with western blot/qPCR in glioblastoma lines\",\n      \"pmids\": [\"29065410\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking NTSR1 to Wnt ligand induction not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"To define how NTSR1 promotes invasion, a defined NTSR1→Jun→miR-494→SOCS6 transcriptional/microRNA axis was mapped in glioblastoma.\",\n      \"evidence\": \"siRNA knockdown, ChIP, dual-luciferase reporter, invasion assays, and orthotopic xenografts\",\n      \"pmids\": [\"30261490\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Proximal NTSR1 signaling events upstream of Jun not specified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"To identify upstream control of NTSR1 expression, TOX4 was shown to be a direct transcriptional activator antagonized by the lncRNA SLCO4A1-AS1.\",\n      \"evidence\": \"RNA pull-down, RIP, ChIP, dual-luciferase reporter, migration/invasion assays, and tail vein metastasis model in lung cancer\",\n      \"pmids\": [\"37726723\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TOX4 regulation of NTSR1 operates outside lung cancer is unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"To demonstrate that NTSR1 signaling pathways are pharmacologically separable, SBI-553 was characterized as a β-arrestin-biased modulator producing therapeutic effects on cocaine abuse distinct from balanced agonism.\",\n      \"evidence\": \"Biased agonism cell-based signaling assays and cocaine self-administration animal models\",\n      \"pmids\": [\"32470395\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of biased allosteric modulation not resolved here\", \"In vivo target engagement beyond cocaine models not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NTSR1's discrete G protein versus β-arrestin signaling branches map onto its diverse downstream effectors (D2 crosstalk, MMP1/EGFR transactivation, Wnt feedback, Jun/miR-494 axis) across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking signaling bias to specific oncogenic pathways\", \"Receptor-receptor heteromer structure undefined\", \"Tissue-specificity of TOX4-driven NTSR1 expression unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 5, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"DRD2\",\n      \"TOX4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}