{"gene":"NEURL1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2007,"finding":"NEURL1 (mouse Neurl1) functions as an E3 ubiquitin ligase that monoubiquitinates Jagged1 in vitro, leading to decreased Jagged1 levels in cells and blocking Notch signaling from Jagged1-expressing cells to neighboring Notch-expressing cells.","method":"In vitro ubiquitination assay, cell-based signaling assay, point mutations abolishing ubiquitin ligase activity","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of ubiquitination combined with cell-based functional assay and loss-of-function point mutations, single lab but multiple orthogonal methods","pmids":["18077452"],"is_preprint":false},{"year":2007,"finding":"Neurl1 is N-myristoylated at its N-terminus, which targets it to the plasma membrane; point mutations abolishing myristoylation prevent plasma membrane localization and impair Neurl1's ability to down-regulate Jagged1 expression and block Notch signaling.","method":"N-myristoylation site point mutagenesis, subcellular fractionation/localization, cell-based signaling assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence, multiple orthogonal methods (mutagenesis + fractionation + signaling readout), single lab","pmids":["18077452"],"is_preprint":false},{"year":2019,"finding":"NEURL1 directly interacts with PDE9A (a cGMP-hydrolyzing phosphodiesterase) via both of its Neuralized Homology Repeat (NHR) domains, and promotes polyubiquitination of PDE9A, leading to its proteasome-mediated degradation primarily via ubiquitin lysine residue K27.","method":"Yeast two-hybrid screen, co-immunoprecipitation, domain mapping (NHR1 and NHR2), ubiquitination assay, proteasome inhibitor rescue","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP confirming interaction, domain mapping, functional ubiquitination assay with mechanistic detail (K27 linkage), single lab with multiple orthogonal methods","pmids":["31068605"],"is_preprint":false},{"year":2025,"finding":"NEURL1 promotes ubiquitination and proteasomal degradation of PDE9A in bladder cancer cells in a RING-domain-dependent manner; overexpression of NEURL1 inhibits cell growth and increases apoptosis, while RING-deleted NEURL1 loses these effects.","method":"Stable overexpression of full-length and RING-deleted NEURL1, proteasome inhibitor (MG-132) rescue, cell viability and apoptosis assays","journal":"In vitro cellular & developmental biology. Animal","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RING domain deletion mutagenesis with functional readout and MG-132 rescue confirm mechanism, but single lab and single study with no independent replication","pmids":["40442542"],"is_preprint":false},{"year":2002,"finding":"Mouse Neurl encodes a polypeptide associated with the plasma membrane (also detected in cytoplasm), and is expressed from early embryonic stages in neural tissues, limbs, and organs undergoing epithelial-mesenchymal interactions.","method":"Subcellular fractionation, expression analysis in embryonic tissues","journal":"Biochimica et biophysica acta","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single fractionation experiment establishing membrane association, no functional consequence linked","pmids":["11997106"],"is_preprint":false},{"year":2016,"finding":"Rat NEURL1 mRNA is dendritically localized in hippocampal neurons; both long and short 3'UTR isoforms mediate transport of reporter mRNAs into dendrites, with the dendritic targeting element (DTE) of the short splice variant mapped to nucleotides 1–148 and 416–914 of the full-length 3'UTR.","method":"Reporter mRNA localization assay in primary hippocampal neurons, deletion mapping of 3'UTR regions","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization experiment in neurons with systematic deletion mapping of DTE, but single lab and limited to mRNA transport mechanism","pmids":["27780737"],"is_preprint":false}],"current_model":"NEURL1 is a RING-type E3 ubiquitin ligase that is targeted to the plasma membrane via N-myristoylation, where it directly ubiquitinates Notch ligand Jagged1 (via monoubiquitination) to promote its turnover and suppress Notch signaling, and also targets PDE9A for K27-linked polyubiquitination and proteasomal degradation through its two Neuralized Homology Repeat domains."},"narrative":{"mechanistic_narrative":"NEURL1 is a RING-type E3 ubiquitin ligase that regulates intercellular signaling and protein turnover by targeting specific substrates for ubiquitination [PMID:18077452, PMID:31068605]. It monoubiquitinates the Notch ligand Jagged1 in vitro, reducing cellular Jagged1 levels and blocking Notch signaling from ligand-presenting cells to neighboring Notch-expressing cells; this activity depends on its ubiquitin ligase function [PMID:18077452]. NEURL1 is N-myristoylated at its N-terminus, which targets it to the plasma membrane, and this localization is required for its down-regulation of Jagged1 and suppression of Notch signaling [PMID:18077452]. Through both of its Neuralized Homology Repeat (NHR) domains, NEURL1 also directly binds the cGMP-hydrolyzing phosphodiesterase PDE9A and promotes its K27-linked polyubiquitination and proteasomal degradation [PMID:31068605]; in bladder cancer cells this RING-domain-dependent degradation of PDE9A is accompanied by inhibited cell growth and increased apoptosis [PMID:40442542]. Beyond its ligase activity and substrate targeting, NEURL1 mRNA is itself subject to dendritic transport in neurons via 3'UTR targeting elements [PMID:27780737].","teleology":[{"year":2007,"claim":"Established NEURL1 as an enzymatically active E3 ubiquitin ligase with a defined substrate, resolving how it intersects the Notch pathway by acting on the ligand rather than the receptor.","evidence":"In vitro ubiquitination assay, cell-based Notch signaling assay, and ligase-dead point mutations in mouse Neurl1","pmids":["18077452"],"confidence":"High","gaps":["Monoubiquitination linkage type and the lysine residues on Jagged1 not defined","Whether endogenous Jagged1 turnover depends on NEURL1 in vivo untested"]},{"year":2007,"claim":"Showed that NEURL1 activity toward Jagged1 requires correct subcellular targeting, linking N-myristoylation-driven plasma membrane localization to its signaling function.","evidence":"Myristoylation-site mutagenesis, subcellular fractionation, and signaling readout","pmids":["18077452"],"confidence":"High","gaps":["Whether membrane targeting also governs non-Jagged1 substrates not addressed"]},{"year":2019,"claim":"Identified a second, mechanistically distinct substrate, demonstrating that NEURL1 uses its NHR domains to bind PDE9A and direct an atypical K27-linked polyubiquitin signal for proteasomal degradation.","evidence":"Yeast two-hybrid, reciprocal co-IP, NHR domain mapping, ubiquitination assay, and proteasome inhibitor rescue","pmids":["31068605"],"confidence":"High","gaps":["Physiological context of PDE9A regulation by NEURL1 not established","Functional consequence of cGMP signaling changes not measured"]},{"year":2025,"claim":"Placed the NEURL1-PDE9A axis in a disease context, showing RING-dependent PDE9A degradation correlates with tumor-suppressive cellular phenotypes.","evidence":"Stable full-length vs RING-deleted NEURL1 overexpression, MG-132 rescue, viability and apoptosis assays in bladder cancer cells","pmids":["40442542"],"confidence":"Medium","gaps":["Single study without independent replication","Causal link between PDE9A degradation and apoptosis not formally separated from other NEURL1 effects"]},{"year":2016,"claim":"Revealed a layer of post-transcriptional control over NEURL1 itself by mapping 3'UTR elements that drive dendritic mRNA localization in neurons.","evidence":"Reporter mRNA localization in primary hippocampal neurons with systematic 3'UTR deletion mapping","pmids":["27780737"],"confidence":"Medium","gaps":["Trans-acting factors binding the dendritic targeting element not identified","Functional consequence of local NEURL1 translation in dendrites untested"]},{"year":null,"claim":"How NEURL1 substrate selection (Jagged1 vs PDE9A), ubiquitin linkage choice (mono- vs K27-linked), and tissue-specific roles are coordinated remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of NEURL1 RING or NHR domains engaging substrates","Determinants of mono- vs poly- and K27-linkage specificity unknown","In vivo physiological substrates and phenotypes not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]}],"complexes":[],"partners":["JAG1","PDE9A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O76050","full_name":"E3 ubiquitin-protein ligase NEURL1","aliases":["Neuralized-like protein 1A","h-neu","h-neuralized 1","RING finger protein 67","RING-type E3 ubiquitin transferase NEURL1"],"length_aa":574,"mass_kda":61.9,"function":"Plays a role in hippocampal-dependent synaptic plasticity, learning and memory. Involved in the formation of spines and functional synaptic contacts by modulating the translational activity of the cytoplasmic polyadenylation element-binding protein CPEB3. Promotes ubiquitination of CPEB3, and hence induces CPEB3-dependent mRNA translation activation of glutamate receptor GRIA1 and GRIA2. Can function as an E3 ubiquitin-protein ligase to activate monoubiquitination of JAG1 (in vitro), thereby regulating the Notch pathway. Acts as a tumor suppressor; inhibits malignant cell transformation of medulloblastoma (MB) cells by inhibiting the Notch signaling pathway","subcellular_location":"Cytoplasm, perinuclear region; Cell membrane; Perikaryon; Cell projection, dendrite; Postsynaptic density","url":"https://www.uniprot.org/uniprotkb/O76050/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NEURL1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NEURL1","total_profiled":1310},"omim":[{"mim_id":"617206","title":"NEURALIZED E3 UBIQUITIN PROTEIN LIGASE 3; NEURL3","url":"https://www.omim.org/entry/617206"},{"mim_id":"615893","title":"NEURALIZED E3 UBIQUITIN PROTEIN LIGASE 1B; NEURL1B","url":"https://www.omim.org/entry/615893"},{"mim_id":"603804","title":"NEURALIZED E3 UBIQUITIN PROTEIN LIGASE 1; NEURL1","url":"https://www.omim.org/entry/603804"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":63.3},{"tissue":"skeletal muscle","ntpm":136.2},{"tissue":"tongue","ntpm":55.8}],"url":"https://www.proteinatlas.org/search/NEURL1"},"hgnc":{"alias_symbol":["h-neu","RNF67","neu-1"],"prev_symbol":["NEURL"]},"alphafold":{"accession":"O76050","domains":[{"cath_id":"2.60.120.920","chopping":"64-221","consensus_level":"high","plddt":88.7572,"start":64,"end":221},{"cath_id":"2.60.120.920","chopping":"288-449","consensus_level":"high","plddt":80.6171,"start":288,"end":449},{"cath_id":"3.30.40.10","chopping":"519-574","consensus_level":"medium","plddt":86.6861,"start":519,"end":574}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O76050","model_url":"https://alphafold.ebi.ac.uk/files/AF-O76050-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O76050-F1-predicted_aligned_error_v6.png","plddt_mean":70.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NEURL1","jax_strain_url":"https://www.jax.org/strain/search?query=NEURL1"},"sequence":{"accession":"O76050","fasta_url":"https://rest.uniprot.org/uniprotkb/O76050.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O76050/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O76050"}},"corpus_meta":[{"pmid":"17327233","id":"PMC_17327233","title":"The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17327233","citation_count":106,"is_preprint":false},{"pmid":"18077452","id":"PMC_18077452","title":"Neuralized-like 1 (Neurl1) targeted to the plasma membrane by N-myristoylation regulates the Notch ligand Jagged1.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18077452","citation_count":69,"is_preprint":false},{"pmid":"9425240","id":"PMC_9425240","title":"A point mutation in the neu-1 locus causes the neuraminidase defect in the SM/J mouse.","date":"1998","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9425240","citation_count":58,"is_preprint":false},{"pmid":"7119440","id":"PMC_7119440","title":"Evidence for placing the Neu-1 locus within the mouse H-2 complex.","date":"1982","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/7119440","citation_count":56,"is_preprint":false},{"pmid":"27756787","id":"PMC_27756787","title":"A Four-Gene Promoter Methylation Marker Panel Consisting of GREM1, NEURL, LAD1, and NEFH Predicts Survival of Clear Cell Renal Cell Cancer Patients.","date":"2016","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/27756787","citation_count":45,"is_preprint":false},{"pmid":"19769716","id":"PMC_19769716","title":"Role of the elastin receptor complex (S-Gal/Cath-A/Neu-1) in skin repair and regeneration.","date":"2009","source":"Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society","url":"https://pubmed.ncbi.nlm.nih.gov/19769716","citation_count":29,"is_preprint":false},{"pmid":"11997106","id":"PMC_11997106","title":"Cloning, chromosomal organization and expression analysis of Neurl, the mouse homolog of Drosophila melanogaster neuralized gene.","date":"2002","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/11997106","citation_count":14,"is_preprint":false},{"pmid":"3745925","id":"PMC_3745925","title":"Electrophoretic analysis of liver neuraminidase-1 variation in mice and additional evidence concerning the location of NEU-1.","date":"1986","source":"Journal of immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/3745925","citation_count":13,"is_preprint":false},{"pmid":"31068605","id":"PMC_31068605","title":"Neuralized family member NEURL1 is a ubiquitin ligase for the cGMP-specific phosphodiesterase 9A.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31068605","citation_count":12,"is_preprint":false},{"pmid":"27203392","id":"PMC_27203392","title":"NEURL rs6584555 and CAND2 rs4642101 contribute to postoperative atrial fibrillation: a prospective study among Chinese population.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27203392","citation_count":11,"is_preprint":false},{"pmid":"3770467","id":"PMC_3770467","title":"Genetic analysis of liver neuraminidase isozymes in Rattus norvegicus: independent control of NEU-1 and NEU-2 phenotypes.","date":"1986","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/3770467","citation_count":5,"is_preprint":false},{"pmid":"27780737","id":"PMC_27780737","title":"Rat NEURL1 3'UTR is alternatively spliced and targets mRNA to dendrites.","date":"2016","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/27780737","citation_count":4,"is_preprint":false},{"pmid":"29414417","id":"PMC_29414417","title":"Generation of novel induced pluripotent stem cell (iPSC) line from a 16-year-old sialidosis patient with NEU-1 gene mutation.","date":"2018","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/29414417","citation_count":4,"is_preprint":false},{"pmid":"31039368","id":"PMC_31039368","title":"PITX2 and NEURL1 SNP polymorphisms in Hungarian atrial fibrillation patients determined by quantitative real-time PCR and melting curve analysis.","date":"2019","source":"Journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/31039368","citation_count":1,"is_preprint":false},{"pmid":"40442542","id":"PMC_40442542","title":"NEURL1 acts as a candidate suppressor in bladder cancer by down-regulating PDE9A.","date":"2025","source":"In vitro cellular & developmental biology. Animal","url":"https://pubmed.ncbi.nlm.nih.gov/40442542","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9365,"output_tokens":1467,"usd":0.02505,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8182,"output_tokens":2124,"usd":0.047005,"stage2_stop_reason":"end_turn"},"total_usd":0.072055,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"NEURL1 (mouse Neurl1) functions as an E3 ubiquitin ligase that monoubiquitinates Jagged1 in vitro, leading to decreased Jagged1 levels in cells and blocking Notch signaling from Jagged1-expressing cells to neighboring Notch-expressing cells.\",\n      \"method\": \"In vitro ubiquitination assay, cell-based signaling assay, point mutations abolishing ubiquitin ligase activity\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of ubiquitination combined with cell-based functional assay and loss-of-function point mutations, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"18077452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Neurl1 is N-myristoylated at its N-terminus, which targets it to the plasma membrane; point mutations abolishing myristoylation prevent plasma membrane localization and impair Neurl1's ability to down-regulate Jagged1 expression and block Notch signaling.\",\n      \"method\": \"N-myristoylation site point mutagenesis, subcellular fractionation/localization, cell-based signaling assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence, multiple orthogonal methods (mutagenesis + fractionation + signaling readout), single lab\",\n      \"pmids\": [\"18077452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NEURL1 directly interacts with PDE9A (a cGMP-hydrolyzing phosphodiesterase) via both of its Neuralized Homology Repeat (NHR) domains, and promotes polyubiquitination of PDE9A, leading to its proteasome-mediated degradation primarily via ubiquitin lysine residue K27.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, domain mapping (NHR1 and NHR2), ubiquitination assay, proteasome inhibitor rescue\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP confirming interaction, domain mapping, functional ubiquitination assay with mechanistic detail (K27 linkage), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31068605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NEURL1 promotes ubiquitination and proteasomal degradation of PDE9A in bladder cancer cells in a RING-domain-dependent manner; overexpression of NEURL1 inhibits cell growth and increases apoptosis, while RING-deleted NEURL1 loses these effects.\",\n      \"method\": \"Stable overexpression of full-length and RING-deleted NEURL1, proteasome inhibitor (MG-132) rescue, cell viability and apoptosis assays\",\n      \"journal\": \"In vitro cellular & developmental biology. Animal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RING domain deletion mutagenesis with functional readout and MG-132 rescue confirm mechanism, but single lab and single study with no independent replication\",\n      \"pmids\": [\"40442542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mouse Neurl encodes a polypeptide associated with the plasma membrane (also detected in cytoplasm), and is expressed from early embryonic stages in neural tissues, limbs, and organs undergoing epithelial-mesenchymal interactions.\",\n      \"method\": \"Subcellular fractionation, expression analysis in embryonic tissues\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single fractionation experiment establishing membrane association, no functional consequence linked\",\n      \"pmids\": [\"11997106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Rat NEURL1 mRNA is dendritically localized in hippocampal neurons; both long and short 3'UTR isoforms mediate transport of reporter mRNAs into dendrites, with the dendritic targeting element (DTE) of the short splice variant mapped to nucleotides 1–148 and 416–914 of the full-length 3'UTR.\",\n      \"method\": \"Reporter mRNA localization assay in primary hippocampal neurons, deletion mapping of 3'UTR regions\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization experiment in neurons with systematic deletion mapping of DTE, but single lab and limited to mRNA transport mechanism\",\n      \"pmids\": [\"27780737\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NEURL1 is a RING-type E3 ubiquitin ligase that is targeted to the plasma membrane via N-myristoylation, where it directly ubiquitinates Notch ligand Jagged1 (via monoubiquitination) to promote its turnover and suppress Notch signaling, and also targets PDE9A for K27-linked polyubiquitination and proteasomal degradation through its two Neuralized Homology Repeat domains.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NEURL1 is a RING-type E3 ubiquitin ligase that regulates intercellular signaling and protein turnover by targeting specific substrates for ubiquitination [#0, #2]. It monoubiquitinates the Notch ligand Jagged1 in vitro, reducing cellular Jagged1 levels and blocking Notch signaling from ligand-presenting cells to neighboring Notch-expressing cells; this activity depends on its ubiquitin ligase function [#0]. NEURL1 is N-myristoylated at its N-terminus, which targets it to the plasma membrane, and this localization is required for its down-regulation of Jagged1 and suppression of Notch signaling [#1]. Through both of its Neuralized Homology Repeat (NHR) domains, NEURL1 also directly binds the cGMP-hydrolyzing phosphodiesterase PDE9A and promotes its K27-linked polyubiquitination and proteasomal degradation [#2]; in bladder cancer cells this RING-domain-dependent degradation of PDE9A is accompanied by inhibited cell growth and increased apoptosis [#3]. Beyond its ligase activity and substrate targeting, NEURL1 mRNA is itself subject to dendritic transport in neurons via 3'UTR targeting elements [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established NEURL1 as an enzymatically active E3 ubiquitin ligase with a defined substrate, resolving how it intersects the Notch pathway by acting on the ligand rather than the receptor.\",\n      \"evidence\": \"In vitro ubiquitination assay, cell-based Notch signaling assay, and ligase-dead point mutations in mouse Neurl1\",\n      \"pmids\": [\"18077452\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Monoubiquitination linkage type and the lysine residues on Jagged1 not defined\", \"Whether endogenous Jagged1 turnover depends on NEURL1 in vivo untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed that NEURL1 activity toward Jagged1 requires correct subcellular targeting, linking N-myristoylation-driven plasma membrane localization to its signaling function.\",\n      \"evidence\": \"Myristoylation-site mutagenesis, subcellular fractionation, and signaling readout\",\n      \"pmids\": [\"18077452\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether membrane targeting also governs non-Jagged1 substrates not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a second, mechanistically distinct substrate, demonstrating that NEURL1 uses its NHR domains to bind PDE9A and direct an atypical K27-linked polyubiquitin signal for proteasomal degradation.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP, NHR domain mapping, ubiquitination assay, and proteasome inhibitor rescue\",\n      \"pmids\": [\"31068605\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological context of PDE9A regulation by NEURL1 not established\", \"Functional consequence of cGMP signaling changes not measured\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed the NEURL1-PDE9A axis in a disease context, showing RING-dependent PDE9A degradation correlates with tumor-suppressive cellular phenotypes.\",\n      \"evidence\": \"Stable full-length vs RING-deleted NEURL1 overexpression, MG-132 rescue, viability and apoptosis assays in bladder cancer cells\",\n      \"pmids\": [\"40442542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study without independent replication\", \"Causal link between PDE9A degradation and apoptosis not formally separated from other NEURL1 effects\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a layer of post-transcriptional control over NEURL1 itself by mapping 3'UTR elements that drive dendritic mRNA localization in neurons.\",\n      \"evidence\": \"Reporter mRNA localization in primary hippocampal neurons with systematic 3'UTR deletion mapping\",\n      \"pmids\": [\"27780737\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trans-acting factors binding the dendritic targeting element not identified\", \"Functional consequence of local NEURL1 translation in dendrites untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NEURL1 substrate selection (Jagged1 vs PDE9A), ubiquitin linkage choice (mono- vs K27-linked), and tissue-specific roles are coordinated remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of NEURL1 RING or NHR domains engaging substrates\", \"Determinants of mono- vs poly- and K27-linkage specificity unknown\", \"In vivo physiological substrates and phenotypes not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"JAG1\", \"PDE9A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}