{"gene":"HECW1","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2003,"finding":"HECW1 (NEDL1) physically binds and ubiquitinates mutant (but not wild-type) SOD1 proportionate to disease severity, and also binds translocon-associated protein-delta (TRAP-delta) and Dishevelled-1 (DVL1), forming a ubiquitinated protein complex in Lewy body-like hyaline inclusions in spinal cord motor neurons of FALS patients and mutant SOD1 transgenic mice.","method":"Co-immunoprecipitation, yeast two-hybrid screening, in vitro ubiquitination assay, immunohistochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (Co-IP, yeast two-hybrid, in vitro ubiquitination, IHC) in a single foundational paper with 145 citations","pmids":["14684739"],"is_preprint":false},{"year":2008,"finding":"HECW1 (NEDL1) physically binds to the C-terminal region of p53 and enhances p53 transcriptional activity and pro-apoptotic function in a catalytic (E3 ligase) activity-independent manner.","method":"Co-immunoprecipitation, in vitro binding assay, luciferase reporter assay, siRNA knockdown, colony formation assay, sub-G1 DNA content analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (Co-IP, in vitro binding, reporter assay, KD phenotype) in a single study","pmids":["18223681"],"is_preprint":false},{"year":2010,"finding":"RNF43 interacts with HECW1 (NEDL1) by yeast two-hybrid; RNF43 also binds p53 and suppresses p53 transcriptional activity and UV-induced apoptosis, acting in collaboration with HECW1.","method":"Yeast two-hybrid screening, co-immunoprecipitation, luciferase reporter assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 — yeast two-hybrid plus Co-IP but limited functional follow-up on HECW1 specifically","pmids":["21108931"],"is_preprint":false},{"year":2010,"finding":"Human HECW1 (NEDL1) transgenic mice develop motor dysfunction, lumbar spinal cord neuron degeneration, muscle atrophy, and increased activated microglia, establishing a functional role for HECW1 overexpression in motor neuron disease in vivo.","method":"Transgenic mouse model, rotarod/hanging wire/footprint behavioral tests, histological analysis, microglial immunostaining","journal":"Journal of biomedicine & biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 — clean in vivo overexpression model with defined phenotypic readouts, single study","pmids":["20976258"],"is_preprint":false},{"year":2011,"finding":"C. elegans HECW-1 functions in a pair of sensory neurons to inhibit pathogen avoidance behavior through inhibition of the neuropeptide receptor NPR-1; neuron-specific rescue and ablation experiments and genetic interaction analysis placed HECW-1 upstream of NPR-1 in this pathway.","method":"Neuron-specific rescue, neuronal ablation, genetic epistasis analysis, behavioral assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with neuron-specific rescue and ablation, published in Nature, 77 citations","pmids":["22089131"],"is_preprint":false},{"year":2019,"finding":"HECW1 ubiquitinates TTF1/NKX2.1 at lysine 151 (K151), targeting it for proteasomal degradation; a K151R mutant of TTF1 is resistant to HECW1-mediated ubiquitination and degradation.","method":"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K151R), siRNA knockdown, cycloheximide chase, proteasome inhibitor treatment","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1 — site-specific mutagenesis combined with in-cell ubiquitination assays and knockdown rescue, multiple orthogonal methods","pmids":["30849519"],"is_preprint":false},{"year":2019,"finding":"HECW1 induces TTF1 ubiquitination and degradation in normal thyroid epithelial cells (HTori3) but not in follicular thyroid carcinoma cells (FTC133), with K151 identified as the ubiquitin acceptor site in both cell types; overexpression of TTF1 increased cell migration and proliferation, effects reversed by HECW1.","method":"Overexpression/siRNA knockdown, ubiquitination assay, proteasome inhibitor treatment, site-directed mutagenesis, cell migration and proliferation assays","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1–2 — multiple methods including mutagenesis and functional cellular assays; corroborated by companion study (PMID 30849519)","pmids":["31238008"],"is_preprint":false},{"year":2020,"finding":"HECW1 mediates estrogen-induced ubiquitination and degradation of the polarity protein Scribble in endometrial epithelial cells, disrupting apical-basal polarity.","method":"3D primary cell culture, ubiquitination assay, siRNA/overexpression, Western blot, in vivo mouse and human tissue specimen correlation","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2–3 — functional ubiquitination assay with cellular polarity readout, single study","pmids":["31616916"],"is_preprint":false},{"year":2021,"finding":"HECW1 promotes ubiquitination and proteasomal degradation of Smad4 in non-small cell lung cancer cells, enhancing their proliferation, migration, and invasiveness.","method":"Overexpression/knockdown, Western blot (protein level without mRNA change), MG-132 proteasome inhibitor treatment, co-immunoprecipitation, ubiquitination assay, migration/invasion assays","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct ubiquitination assay with Co-IP and MG-132 rescue, single study","pmids":["33529121"],"is_preprint":false},{"year":2023,"finding":"HECW1 (NEDL1) is expressed in neurons primarily in their somas; overexpression causes increased neuronal cell death in vitro and cytoplasmic mislocalization of TDP-43.","method":"Immunofluorescence/immunohistochemistry for localization, in vitro overexpression with cell death and TDP-43 localization readouts","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct subcellular localization with functional consequence (TDP-43 mislocalization and cell death), single study","pmids":["36674783"],"is_preprint":false},{"year":2024,"finding":"HECW1 interacts with DVL1 (Dishevelled-1) and promotes its ubiquitination, reducing DVL1 protein levels and suppressing Wnt/β-catenin signaling (nuclear β-catenin, TCF/LEF activity, c-Myc expression) to inhibit cervical cancer cell proliferation and tumor formation.","method":"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, reporter assay (TCF/LEF), in vivo xenograft","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with ubiquitination assay, epistasis by DVL1 inhibition rescue, and in vivo confirmation, single study","pmids":["38266865"],"is_preprint":false},{"year":2024,"finding":"HECW1 interacts with HIPK2, facilitating its ubiquitination and proteasomal degradation, which activates AKT signaling and promotes EMT-related gene expression and gastric cancer cell metastasis.","method":"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, Western blot, in vivo metastasis model","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 — direct Co-IP and ubiquitination assay with in vivo confirmation, single study","pmids":["39615883"],"is_preprint":false},{"year":2024,"finding":"Nedl1 knockout mice display impaired spatial learning and memory, hippocampal astrocyte proliferation, and altered amino acid metabolism (elevated proline and tryptophan), without changes in neuron or oligodendrocyte numbers.","method":"Nedl1 knockout mouse model, Barnes maze, three-chamber test, elevated plus maze, histological staining, metabolic analysis","journal":"Physiology & behavior","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO model with defined behavioral and cellular phenotypic readouts, single study","pmids":["39424023"],"is_preprint":false},{"year":2025,"finding":"HECW1 mediates ubiquitination and degradation of NRG2 at lysine 223 (K223); NDRG1 promotes its interaction with HECW1 to facilitate NRG2 degradation, suppressing autophagy-mediated EGFR TKI resistance in NSCLC.","method":"Co-immunoprecipitation, ubiquitination assay, RNA-seq, site-specific lysine identification, in vivo PDX model","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 — direct ubiquitination assay with site identification and in vivo confirmation, single study","pmids":["41193668"],"is_preprint":false}],"current_model":"HECW1 (NEDL1) is a neuronal HECT-type E3 ubiquitin ligase that ubiquitinates multiple substrates including mutant SOD1, DVL1/Dishevelled-1, Smad4, Scribble, TTF1 (at K151), HIPK2, and NRG2 (at K223) to target them for proteasomal degradation, modulates p53-dependent apoptosis through a direct, ligase-activity-independent interaction with p53, and in neurons acts upstream of NPR-1-mediated signaling and is required for normal learning and memory, with its misregulation linked to TDP-43 mislocalization and motor neuron pathology relevant to ALS."},"narrative":{"teleology":[{"year":2003,"claim":"Discovery of HECW1 as a HECT-type E3 ligase that selectively ubiquitinates ALS-linked mutant SOD1 and co-localizes with it in motor neuron inclusions established the gene's founding connection to neurodegeneration and defined its enzymatic activity.","evidence":"Yeast two-hybrid, Co-IP, in vitro ubiquitination, and immunohistochemistry in FALS patient/mouse tissue","pmids":["14684739"],"confidence":"High","gaps":["Whether ubiquitination of mutant SOD1 is protective or pathogenic was not resolved","Structural basis for selective recognition of mutant over wild-type SOD1 is unknown","Whether TRAP-delta interaction is functionally relevant remains untested"]},{"year":2008,"claim":"Demonstrating that HECW1 binds p53 and enhances p53-dependent apoptosis independently of its E3 ligase activity revealed a non-catalytic scaffold function, expanding the gene's mechanistic repertoire beyond ubiquitination.","evidence":"Co-IP, in vitro binding, luciferase reporter, siRNA knockdown, colony formation, and sub-G1 analysis","pmids":["18223681"],"confidence":"High","gaps":["The domain within HECW1 responsible for p53 binding was not mapped","Whether endogenous p53 stabilization occurs under physiological conditions is unclear","The interaction with RNF43 (PMID:21108931) and its functional significance for p53 regulation need independent validation"]},{"year":2010,"claim":"Transgenic overexpression of HECW1 in mice caused motor dysfunction, spinal cord neuron loss, and microglial activation, providing in vivo evidence that elevated HECW1 is sufficient to drive motor neuron disease.","evidence":"Human HECW1 transgenic mouse model with behavioral, histological, and immunostaining analyses","pmids":["20976258"],"confidence":"Medium","gaps":["The specific substrate(s) responsible for motor neuron toxicity upon overexpression were not identified","Whether endogenous HECW1 levels are elevated in sporadic ALS patients was not tested","Single transgenic model without independent replication"]},{"year":2011,"claim":"Genetic dissection in C. elegans placed HECW-1 upstream of the neuropeptide receptor NPR-1 in a defined sensory neuron pair, establishing a conserved neuronal signaling role and demonstrating cell-type specificity of its function.","evidence":"Neuron-specific rescue, neuronal ablation, and genetic epistasis analysis for pathogen avoidance behavior","pmids":["22089131"],"confidence":"High","gaps":["The direct substrate of HECW-1 in this pathway was not identified","Whether this NPR-1-related function is conserved in mammals remains unknown"]},{"year":2019,"claim":"Identification of TTF1/NKX2.1 K151 as a specific HECW1 ubiquitination site, with a K151R mutant resisting degradation, demonstrated site-resolved substrate targeting and linked HECW1 to thyroid cell biology and cancer.","evidence":"Site-directed mutagenesis, ubiquitination assay, cycloheximide chase, and functional assays in normal thyroid versus carcinoma cells","pmids":["30849519","31238008"],"confidence":"High","gaps":["Why HECW1 fails to ubiquitinate TTF1 in follicular thyroid carcinoma cells is mechanistically unresolved","Whether other E3 ligases also target TTF1 was not addressed"]},{"year":2020,"claim":"Showing that HECW1 ubiquitinates and degrades the polarity protein Scribble under estrogen stimulation extended the ligase's role to epithelial polarity regulation and uterine receptivity.","evidence":"3D primary endometrial cell culture, ubiquitination assay, siRNA/overexpression, and in vivo tissue correlation","pmids":["31616916"],"confidence":"Medium","gaps":["Single study without independent replication","The ubiquitin chain type and acceptor lysine on Scribble were not determined"]},{"year":2021,"claim":"HECW1-mediated ubiquitination and degradation of Smad4 in NSCLC cells linked the ligase to TGF-β pathway suppression and pro-tumorigenic phenotypes, broadening its substrate repertoire to a major tumor suppressor.","evidence":"Overexpression/knockdown, Co-IP, ubiquitination assay, MG-132 rescue, migration/invasion assays in NSCLC lines","pmids":["33529121"],"confidence":"Medium","gaps":["Single study without independent confirmation","The specific lysine site(s) on Smad4 targeted by HECW1 were not mapped"]},{"year":2023,"claim":"Demonstrating that HECW1 overexpression causes cytoplasmic mislocalization of TDP-43 and neuronal death linked the ligase mechanistically to TDP-43 proteinopathy, a hallmark of ALS/FTD.","evidence":"Immunofluorescence and overexpression with TDP-43 localization and cell death readouts in neurons","pmids":["36674783"],"confidence":"Medium","gaps":["Whether TDP-43 is a direct ubiquitination substrate of HECW1 was not tested","The causal chain between HECW1 overexpression and TDP-43 mislocalization is undefined","Single study without independent replication"]},{"year":2024,"claim":"Multiple substrate discoveries in 2024 (DVL1 driving Wnt suppression; HIPK2 driving AKT/EMT activation) and a knockout mouse revealing learning/memory deficits and astrocyte expansion consolidated HECW1's roles as a multi-pathway signaling regulator in both cancer and neuronal function.","evidence":"Co-IP/ubiquitination assays with in vivo xenograft (DVL1, HIPK2); Nedl1 KO mouse with Barnes maze, histology, metabolomics","pmids":["38266865","39615883","39424023"],"confidence":"Medium","gaps":["How HECW1 achieves substrate selectivity among its many targets is structurally unresolved","Whether learning deficits in KO mice result from loss of a specific substrate or cumulative pathway dysregulation is unknown","The significance of altered amino acid metabolism (proline/tryptophan) in the KO brain is mechanistically unexplained"]},{"year":2025,"claim":"Site-specific ubiquitination of NRG2 at K223 by HECW1, facilitated by NDRG1, and suppression of autophagy-mediated EGFR TKI resistance demonstrated a new role in drug resistance through receptor tyrosine kinase signaling.","evidence":"Co-IP, ubiquitination assay with lysine-site identification, RNA-seq, and in vivo PDX model in NSCLC","pmids":["41193668"],"confidence":"Medium","gaps":["Single study; independent validation needed","Whether NDRG1 acts as a scaffold or modifies HECW1 activity is not resolved"]},{"year":null,"claim":"A structural model of HECW1's HECT domain and its substrate-recognition determinants is lacking, leaving the basis for its unusually broad substrate specificity unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of HECW1 exists","Ubiquitin chain-type preference (K48 vs K63 vs other) has not been systematically characterized across substrates","Physiological regulation of HECW1 expression and activity (post-translational modifications, interacting E2s) is largely undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5,6,7,8,10,11,13]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,5,6,7,8,10,11,13]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,10,11,13]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,5,6,7,8,10,11,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,3,9]}],"complexes":[],"partners":["SOD1","DVL1","TP53","TTF1","SCRIB","SMAD4","HIPK2","NRG2"],"other_free_text":[]},"mechanistic_narrative":"HECW1 (also called NEDL1) is a neuronal HECT-domain E3 ubiquitin ligase that targets a broad range of substrates for proteasomal degradation, thereby modulating signaling pathways in both neural and epithelial contexts. Identified substrates include mutant SOD1, DVL1/Dishevelled-1, Smad4, Scribble, TTF1 (at K151), HIPK2, and NRG2 (at K223), through which HECW1 regulates Wnt/β-catenin signaling, TGF-β/Smad signaling, cell polarity, and autophagy [PMID:14684739, PMID:38266865, PMID:33529121, PMID:31616916, PMID:30849519, PMID:39615883, PMID:41193668]. Independent of its catalytic activity, HECW1 binds the C-terminal region of p53 and enhances p53-dependent transcription and apoptosis [PMID:18223681]. In neurons, HECW1 is required for normal spatial learning and memory, its overexpression causes TDP-43 cytoplasmic mislocalization and motor neuron degeneration, and in C. elegans the ortholog HECW-1 acts upstream of the neuropeptide receptor NPR-1 in sensory neurons to regulate innate behavior [PMID:39424023, PMID:36674783, PMID:20976258, PMID:22089131]."},"prefetch_data":{"uniprot":{"accession":"Q76N89","full_name":"E3 ubiquitin-protein ligase HECW1","aliases":["HECT, C2 and WW domain-containing protein 1","HECT-type E3 ubiquitin transferase HECW1","NEDD4-like E3 ubiquitin-protein ligase 1","hNEDL1"],"length_aa":1606,"mass_kda":179.6,"function":"E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent degradation of DVL1. Also targets the mutant SOD1 protein involved in familial amyotrophic lateral sclerosis (FALS). Forms cytotoxic aggregates with DVL1, SSR3 and mutant SOD1 that lead to motor neuron death in FALS","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q76N89/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HECW1","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/HECW1","total_profiled":1310},"omim":[{"mim_id":"618172","title":"LONG NONCODING RNA UPREGULATOR OF ANTIVIRAL RESPONSE INTERFERON SIGNALING; LUARIS","url":"https://www.omim.org/entry/618172"},{"mim_id":"612050","title":"NEDD4 FAMILY-INTERACTING PROTEIN 1; NDFIP1","url":"https://www.omim.org/entry/612050"},{"mim_id":"610384","title":"HECT, C2, AND WW DOMAINS-CONTAINING E3 UBIQUITIN-PROTEIN LIGASE 1; HECW1","url":"https://www.omim.org/entry/610384"},{"mim_id":"147450","title":"SUPEROXIDE DISMUTASE 1; SOD1","url":"https://www.omim.org/entry/147450"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli fibrillar center","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":7.6},{"tissue":"kidney","ntpm":7.3}],"url":"https://www.proteinatlas.org/search/HECW1"},"hgnc":{"alias_symbol":["KIAA0322","NEDL1"],"prev_symbol":[]},"alphafold":{"accession":"Q76N89","domains":[{"cath_id":"2.60.40.2840","chopping":"81-181","consensus_level":"high","plddt":83.6214,"start":81,"end":181},{"cath_id":"2.60.40.150","chopping":"206-345","consensus_level":"high","plddt":80.8131,"start":206,"end":345},{"cath_id":"2.20.70.10","chopping":"960-1046","consensus_level":"medium","plddt":90.4351,"start":960,"end":1046},{"cath_id":"-","chopping":"1116-1183","consensus_level":"high","plddt":90.4499,"start":1116,"end":1183},{"cath_id":"3.90.1750.10","chopping":"1246-1486","consensus_level":"medium","plddt":86.7822,"start":1246,"end":1486},{"cath_id":"3.30.2410.10","chopping":"1489-1606","consensus_level":"medium","plddt":84.5572,"start":1489,"end":1606}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q76N89","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q76N89-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q76N89-F1-predicted_aligned_error_v6.png","plddt_mean":59.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HECW1","jax_strain_url":"https://www.jax.org/strain/search?query=HECW1"},"sequence":{"accession":"Q76N89","fasta_url":"https://rest.uniprot.org/uniprotkb/Q76N89.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q76N89/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q76N89"}},"corpus_meta":[{"pmid":"14684739","id":"PMC_14684739","title":"NEDL1, a novel ubiquitin-protein isopeptide ligase for dishevelled-1, targets mutant superoxide dismutase-1.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14684739","citation_count":145,"is_preprint":false},{"pmid":"22089131","id":"PMC_22089131","title":"Natural polymorphisms in C. elegans HECW-1 E3 ligase affect pathogen avoidance behaviour.","date":"2011","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22089131","citation_count":77,"is_preprint":false},{"pmid":"21108931","id":"PMC_21108931","title":"RNF43 interacts with NEDL1 and regulates p53-mediated transcription.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/21108931","citation_count":52,"is_preprint":false},{"pmid":"18223681","id":"PMC_18223681","title":"A novel HECT-type E3 ubiquitin protein ligase NEDL1 enhances the p53-mediated apoptotic cell death in its catalytic activity-independent manner.","date":"2008","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/18223681","citation_count":51,"is_preprint":false},{"pmid":"20976258","id":"PMC_20976258","title":"Muscle atrophy and motor neuron degeneration in human NEDL1 transgenic mice.","date":"2010","source":"Journal of biomedicine & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/20976258","citation_count":30,"is_preprint":false},{"pmid":"33529121","id":"PMC_33529121","title":"E3 ubiquitin ligase HECW1 promotes the metastasis of non-small cell lung cancer cells through mediating the ubiquitination of Smad4.","date":"2021","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/33529121","citation_count":17,"is_preprint":false},{"pmid":"31238008","id":"PMC_31238008","title":"Two distinct E3 ligases, SCFFBXL19 and HECW1, degrade thyroid transcription factor 1 in normal thyroid epithelial and follicular thyroid carcinoma cells, respectively.","date":"2019","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/31238008","citation_count":15,"is_preprint":false},{"pmid":"31616916","id":"PMC_31616916","title":"Estrogen degrades Scribble in endometrial epithelial cells through E3 ubiquitin ligase HECW1 in the development of diffuse adenomyosis†.","date":"2020","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/31616916","citation_count":14,"is_preprint":false},{"pmid":"30849519","id":"PMC_30849519","title":"The E3 ubiquitin ligase HECW1 targets thyroid transcription factor 1 (TTF1/NKX2.1) for its degradation in the ubiquitin-proteasome system.","date":"2019","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/30849519","citation_count":8,"is_preprint":false},{"pmid":"38266865","id":"PMC_38266865","title":"HECW1 restrains cervical cancer cell growth by promoting DVL1 ubiquitination and downregulating the activation of Wnt/β-catenin signaling.","date":"2024","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/38266865","citation_count":7,"is_preprint":false},{"pmid":"35699802","id":"PMC_35699802","title":"Circular RNA Hecw1 Regulates the Inflammatory Imbalance in Spinal Cord Injury via miR-3551-3p/LRRTM1 Axis.","date":"2022","source":"Applied biochemistry and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/35699802","citation_count":6,"is_preprint":false},{"pmid":"36674783","id":"PMC_36674783","title":"Study of Ubiquitin Pathway Genes in a French Population with Amyotrophic Lateral Sclerosis: Focus on HECW1 Encoding the E3 Ligase NEDL1.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36674783","citation_count":3,"is_preprint":false},{"pmid":"39615883","id":"PMC_39615883","title":"HECW1-Mediated Ubiquitination of HIPK2 Drives Metastasis in Gastric Cancer Through the AKT Signaling Pathway.","date":"2024","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/39615883","citation_count":1,"is_preprint":false},{"pmid":"41193668","id":"PMC_41193668","title":"Magnolin overcomes EGFR TKI resistance in NSCLC by modulation of NDRG1-NRG2-HECW1 pathway.","date":"2025","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/41193668","citation_count":0,"is_preprint":false},{"pmid":"39424023","id":"PMC_39424023","title":"Nedl1 knockout impaired the learning and memory of mice.","date":"2024","source":"Physiology & behavior","url":"https://pubmed.ncbi.nlm.nih.gov/39424023","citation_count":0,"is_preprint":false},{"pmid":"40217560","id":"PMC_40217560","title":"Nedl1 knockout ameliorates cognitive impairment and improves epilepsy threshold in pilocarpine-induced epileptic mice.","date":"2025","source":"Acta epileptologica","url":"https://pubmed.ncbi.nlm.nih.gov/40217560","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9317,"output_tokens":3150,"usd":0.037601},"stage2":{"model":"claude-opus-4-6","input_tokens":6550,"output_tokens":3068,"usd":0.164175},"total_usd":0.201776,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"HECW1 (NEDL1) physically binds and ubiquitinates mutant (but not wild-type) SOD1 proportionate to disease severity, and also binds translocon-associated protein-delta (TRAP-delta) and Dishevelled-1 (DVL1), forming a ubiquitinated protein complex in Lewy body-like hyaline inclusions in spinal cord motor neurons of FALS patients and mutant SOD1 transgenic mice.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid screening, in vitro ubiquitination assay, immunohistochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (Co-IP, yeast two-hybrid, in vitro ubiquitination, IHC) in a single foundational paper with 145 citations\",\n      \"pmids\": [\"14684739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HECW1 (NEDL1) physically binds to the C-terminal region of p53 and enhances p53 transcriptional activity and pro-apoptotic function in a catalytic (E3 ligase) activity-independent manner.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, luciferase reporter assay, siRNA knockdown, colony formation assay, sub-G1 DNA content analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (Co-IP, in vitro binding, reporter assay, KD phenotype) in a single study\",\n      \"pmids\": [\"18223681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RNF43 interacts with HECW1 (NEDL1) by yeast two-hybrid; RNF43 also binds p53 and suppresses p53 transcriptional activity and UV-induced apoptosis, acting in collaboration with HECW1.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, luciferase reporter assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — yeast two-hybrid plus Co-IP but limited functional follow-up on HECW1 specifically\",\n      \"pmids\": [\"21108931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human HECW1 (NEDL1) transgenic mice develop motor dysfunction, lumbar spinal cord neuron degeneration, muscle atrophy, and increased activated microglia, establishing a functional role for HECW1 overexpression in motor neuron disease in vivo.\",\n      \"method\": \"Transgenic mouse model, rotarod/hanging wire/footprint behavioral tests, histological analysis, microglial immunostaining\",\n      \"journal\": \"Journal of biomedicine & biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo overexpression model with defined phenotypic readouts, single study\",\n      \"pmids\": [\"20976258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"C. elegans HECW-1 functions in a pair of sensory neurons to inhibit pathogen avoidance behavior through inhibition of the neuropeptide receptor NPR-1; neuron-specific rescue and ablation experiments and genetic interaction analysis placed HECW-1 upstream of NPR-1 in this pathway.\",\n      \"method\": \"Neuron-specific rescue, neuronal ablation, genetic epistasis analysis, behavioral assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with neuron-specific rescue and ablation, published in Nature, 77 citations\",\n      \"pmids\": [\"22089131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HECW1 ubiquitinates TTF1/NKX2.1 at lysine 151 (K151), targeting it for proteasomal degradation; a K151R mutant of TTF1 is resistant to HECW1-mediated ubiquitination and degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K151R), siRNA knockdown, cycloheximide chase, proteasome inhibitor treatment\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — site-specific mutagenesis combined with in-cell ubiquitination assays and knockdown rescue, multiple orthogonal methods\",\n      \"pmids\": [\"30849519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HECW1 induces TTF1 ubiquitination and degradation in normal thyroid epithelial cells (HTori3) but not in follicular thyroid carcinoma cells (FTC133), with K151 identified as the ubiquitin acceptor site in both cell types; overexpression of TTF1 increased cell migration and proliferation, effects reversed by HECW1.\",\n      \"method\": \"Overexpression/siRNA knockdown, ubiquitination assay, proteasome inhibitor treatment, site-directed mutagenesis, cell migration and proliferation assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple methods including mutagenesis and functional cellular assays; corroborated by companion study (PMID 30849519)\",\n      \"pmids\": [\"31238008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HECW1 mediates estrogen-induced ubiquitination and degradation of the polarity protein Scribble in endometrial epithelial cells, disrupting apical-basal polarity.\",\n      \"method\": \"3D primary cell culture, ubiquitination assay, siRNA/overexpression, Western blot, in vivo mouse and human tissue specimen correlation\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — functional ubiquitination assay with cellular polarity readout, single study\",\n      \"pmids\": [\"31616916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HECW1 promotes ubiquitination and proteasomal degradation of Smad4 in non-small cell lung cancer cells, enhancing their proliferation, migration, and invasiveness.\",\n      \"method\": \"Overexpression/knockdown, Western blot (protein level without mRNA change), MG-132 proteasome inhibitor treatment, co-immunoprecipitation, ubiquitination assay, migration/invasion assays\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct ubiquitination assay with Co-IP and MG-132 rescue, single study\",\n      \"pmids\": [\"33529121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HECW1 (NEDL1) is expressed in neurons primarily in their somas; overexpression causes increased neuronal cell death in vitro and cytoplasmic mislocalization of TDP-43.\",\n      \"method\": \"Immunofluorescence/immunohistochemistry for localization, in vitro overexpression with cell death and TDP-43 localization readouts\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct subcellular localization with functional consequence (TDP-43 mislocalization and cell death), single study\",\n      \"pmids\": [\"36674783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HECW1 interacts with DVL1 (Dishevelled-1) and promotes its ubiquitination, reducing DVL1 protein levels and suppressing Wnt/β-catenin signaling (nuclear β-catenin, TCF/LEF activity, c-Myc expression) to inhibit cervical cancer cell proliferation and tumor formation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, reporter assay (TCF/LEF), in vivo xenograft\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with ubiquitination assay, epistasis by DVL1 inhibition rescue, and in vivo confirmation, single study\",\n      \"pmids\": [\"38266865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HECW1 interacts with HIPK2, facilitating its ubiquitination and proteasomal degradation, which activates AKT signaling and promotes EMT-related gene expression and gastric cancer cell metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, Western blot, in vivo metastasis model\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct Co-IP and ubiquitination assay with in vivo confirmation, single study\",\n      \"pmids\": [\"39615883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Nedl1 knockout mice display impaired spatial learning and memory, hippocampal astrocyte proliferation, and altered amino acid metabolism (elevated proline and tryptophan), without changes in neuron or oligodendrocyte numbers.\",\n      \"method\": \"Nedl1 knockout mouse model, Barnes maze, three-chamber test, elevated plus maze, histological staining, metabolic analysis\",\n      \"journal\": \"Physiology & behavior\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO model with defined behavioral and cellular phenotypic readouts, single study\",\n      \"pmids\": [\"39424023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HECW1 mediates ubiquitination and degradation of NRG2 at lysine 223 (K223); NDRG1 promotes its interaction with HECW1 to facilitate NRG2 degradation, suppressing autophagy-mediated EGFR TKI resistance in NSCLC.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, RNA-seq, site-specific lysine identification, in vivo PDX model\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct ubiquitination assay with site identification and in vivo confirmation, single study\",\n      \"pmids\": [\"41193668\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HECW1 (NEDL1) is a neuronal HECT-type E3 ubiquitin ligase that ubiquitinates multiple substrates including mutant SOD1, DVL1/Dishevelled-1, Smad4, Scribble, TTF1 (at K151), HIPK2, and NRG2 (at K223) to target them for proteasomal degradation, modulates p53-dependent apoptosis through a direct, ligase-activity-independent interaction with p53, and in neurons acts upstream of NPR-1-mediated signaling and is required for normal learning and memory, with its misregulation linked to TDP-43 mislocalization and motor neuron pathology relevant to ALS.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HECW1 (also called NEDL1) is a neuronal HECT-domain E3 ubiquitin ligase that targets a broad range of substrates for proteasomal degradation, thereby modulating signaling pathways in both neural and epithelial contexts. Identified substrates include mutant SOD1, DVL1/Dishevelled-1, Smad4, Scribble, TTF1 (at K151), HIPK2, and NRG2 (at K223), through which HECW1 regulates Wnt/β-catenin signaling, TGF-β/Smad signaling, cell polarity, and autophagy [PMID:14684739, PMID:38266865, PMID:33529121, PMID:31616916, PMID:30849519, PMID:39615883, PMID:41193668]. Independent of its catalytic activity, HECW1 binds the C-terminal region of p53 and enhances p53-dependent transcription and apoptosis [PMID:18223681]. In neurons, HECW1 is required for normal spatial learning and memory, its overexpression causes TDP-43 cytoplasmic mislocalization and motor neuron degeneration, and in C. elegans the ortholog HECW-1 acts upstream of the neuropeptide receptor NPR-1 in sensory neurons to regulate innate behavior [PMID:39424023, PMID:36674783, PMID:20976258, PMID:22089131].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovery of HECW1 as a HECT-type E3 ligase that selectively ubiquitinates ALS-linked mutant SOD1 and co-localizes with it in motor neuron inclusions established the gene's founding connection to neurodegeneration and defined its enzymatic activity.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, in vitro ubiquitination, and immunohistochemistry in FALS patient/mouse tissue\",\n      \"pmids\": [\"14684739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ubiquitination of mutant SOD1 is protective or pathogenic was not resolved\",\n        \"Structural basis for selective recognition of mutant over wild-type SOD1 is unknown\",\n        \"Whether TRAP-delta interaction is functionally relevant remains untested\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that HECW1 binds p53 and enhances p53-dependent apoptosis independently of its E3 ligase activity revealed a non-catalytic scaffold function, expanding the gene's mechanistic repertoire beyond ubiquitination.\",\n      \"evidence\": \"Co-IP, in vitro binding, luciferase reporter, siRNA knockdown, colony formation, and sub-G1 analysis\",\n      \"pmids\": [\"18223681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The domain within HECW1 responsible for p53 binding was not mapped\",\n        \"Whether endogenous p53 stabilization occurs under physiological conditions is unclear\",\n        \"The interaction with RNF43 (PMID:21108931) and its functional significance for p53 regulation need independent validation\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Transgenic overexpression of HECW1 in mice caused motor dysfunction, spinal cord neuron loss, and microglial activation, providing in vivo evidence that elevated HECW1 is sufficient to drive motor neuron disease.\",\n      \"evidence\": \"Human HECW1 transgenic mouse model with behavioral, histological, and immunostaining analyses\",\n      \"pmids\": [\"20976258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The specific substrate(s) responsible for motor neuron toxicity upon overexpression were not identified\",\n        \"Whether endogenous HECW1 levels are elevated in sporadic ALS patients was not tested\",\n        \"Single transgenic model without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genetic dissection in C. elegans placed HECW-1 upstream of the neuropeptide receptor NPR-1 in a defined sensory neuron pair, establishing a conserved neuronal signaling role and demonstrating cell-type specificity of its function.\",\n      \"evidence\": \"Neuron-specific rescue, neuronal ablation, and genetic epistasis analysis for pathogen avoidance behavior\",\n      \"pmids\": [\"22089131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The direct substrate of HECW-1 in this pathway was not identified\",\n        \"Whether this NPR-1-related function is conserved in mammals remains unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of TTF1/NKX2.1 K151 as a specific HECW1 ubiquitination site, with a K151R mutant resisting degradation, demonstrated site-resolved substrate targeting and linked HECW1 to thyroid cell biology and cancer.\",\n      \"evidence\": \"Site-directed mutagenesis, ubiquitination assay, cycloheximide chase, and functional assays in normal thyroid versus carcinoma cells\",\n      \"pmids\": [\"30849519\", \"31238008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Why HECW1 fails to ubiquitinate TTF1 in follicular thyroid carcinoma cells is mechanistically unresolved\",\n        \"Whether other E3 ligases also target TTF1 was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing that HECW1 ubiquitinates and degrades the polarity protein Scribble under estrogen stimulation extended the ligase's role to epithelial polarity regulation and uterine receptivity.\",\n      \"evidence\": \"3D primary endometrial cell culture, ubiquitination assay, siRNA/overexpression, and in vivo tissue correlation\",\n      \"pmids\": [\"31616916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study without independent replication\",\n        \"The ubiquitin chain type and acceptor lysine on Scribble were not determined\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"HECW1-mediated ubiquitination and degradation of Smad4 in NSCLC cells linked the ligase to TGF-β pathway suppression and pro-tumorigenic phenotypes, broadening its substrate repertoire to a major tumor suppressor.\",\n      \"evidence\": \"Overexpression/knockdown, Co-IP, ubiquitination assay, MG-132 rescue, migration/invasion assays in NSCLC lines\",\n      \"pmids\": [\"33529121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study without independent confirmation\",\n        \"The specific lysine site(s) on Smad4 targeted by HECW1 were not mapped\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that HECW1 overexpression causes cytoplasmic mislocalization of TDP-43 and neuronal death linked the ligase mechanistically to TDP-43 proteinopathy, a hallmark of ALS/FTD.\",\n      \"evidence\": \"Immunofluorescence and overexpression with TDP-43 localization and cell death readouts in neurons\",\n      \"pmids\": [\"36674783\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether TDP-43 is a direct ubiquitination substrate of HECW1 was not tested\",\n        \"The causal chain between HECW1 overexpression and TDP-43 mislocalization is undefined\",\n        \"Single study without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Multiple substrate discoveries in 2024 (DVL1 driving Wnt suppression; HIPK2 driving AKT/EMT activation) and a knockout mouse revealing learning/memory deficits and astrocyte expansion consolidated HECW1's roles as a multi-pathway signaling regulator in both cancer and neuronal function.\",\n      \"evidence\": \"Co-IP/ubiquitination assays with in vivo xenograft (DVL1, HIPK2); Nedl1 KO mouse with Barnes maze, histology, metabolomics\",\n      \"pmids\": [\"38266865\", \"39615883\", \"39424023\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How HECW1 achieves substrate selectivity among its many targets is structurally unresolved\",\n        \"Whether learning deficits in KO mice result from loss of a specific substrate or cumulative pathway dysregulation is unknown\",\n        \"The significance of altered amino acid metabolism (proline/tryptophan) in the KO brain is mechanistically unexplained\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Site-specific ubiquitination of NRG2 at K223 by HECW1, facilitated by NDRG1, and suppression of autophagy-mediated EGFR TKI resistance demonstrated a new role in drug resistance through receptor tyrosine kinase signaling.\",\n      \"evidence\": \"Co-IP, ubiquitination assay with lysine-site identification, RNA-seq, and in vivo PDX model in NSCLC\",\n      \"pmids\": [\"41193668\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study; independent validation needed\",\n        \"Whether NDRG1 acts as a scaffold or modifies HECW1 activity is not resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A structural model of HECW1's HECT domain and its substrate-recognition determinants is lacking, leaving the basis for its unusually broad substrate specificity unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of HECW1 exists\",\n        \"Ubiquitin chain-type preference (K48 vs K63 vs other) has not been systematically characterized across substrates\",\n        \"Physiological regulation of HECW1 expression and activity (post-translational modifications, interacting E2s) is largely undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5, 6, 7, 8, 10, 11, 13]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 5, 6, 7, 8, 10, 11, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 10, 11, 13]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 5, 6, 7, 8, 10, 11, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 3, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SOD1\",\n      \"DVL1\",\n      \"TP53\",\n      \"TTF1\",\n      \"SCRIB\",\n      \"SMAD4\",\n      \"HIPK2\",\n      \"NRG2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}