{"gene":"HECW1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2003,"finding":"NEDL1 (HECW1) physically binds translocon-associated protein-delta (TRAP-delta) and binds and ubiquitinates mutant (but not wild-type) SOD1, with ubiquitination proportional to disease severity caused by that mutant. NEDL1 also binds Dishevelled-1 (DVL1), a Wnt signaling transducer, via two-hybrid screening. Mutant SOD1 interacted with DVL1 in the presence of NEDL1, causing DVL1 dysfunction.","method":"Co-immunoprecipitation, ubiquitination assay, yeast two-hybrid screening, immunohistochemistry","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and ubiquitination assay in single lab, two orthogonal methods, but no in vitro reconstitution or mutagenesis","pmids":["14684739"],"is_preprint":false},{"year":2008,"finding":"NEDL1 (HECW1) binds to the C-terminal region of p53 and enhances p53 transcriptional activity and p53-mediated apoptosis in a catalytic activity-independent manner. NEDL1 knockdown conferred resistance to adriamycin-induced apoptosis in p53 wild-type cells.","method":"Co-immunoprecipitation, in vitro binding assay, luciferase reporter assay, siRNA knockdown, colony formation assay, flow cytometry","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus in vitro binding plus reporter assay, single lab, multiple orthogonal methods","pmids":["18223681"],"is_preprint":false},{"year":2010,"finding":"RNF43 binds NEDL1 (HECW1) as identified by yeast two-hybrid screening. RNF43 also interacts with p53 and suppresses p53 transcriptional activity, attenuating UV-induced apoptosis, in collaboration with NEDL1.","method":"Yeast two-hybrid screening, co-immunoprecipitation, luciferase reporter assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid plus co-IP but mechanistic role of HECW1 in the RNF43-p53 axis not directly demonstrated by experiment on HECW1 itself","pmids":["21108931"],"is_preprint":false},{"year":2010,"finding":"Overexpression of human NEDL1 (HECW1) in transgenic mice caused motor neuron degeneration, muscle atrophy, and microglial activation in the spinal cord, establishing a gain-of-function neurodegeneration phenotype in vivo.","method":"Transgenic mouse model, rotarod/hanging wire/footprint behavioral tests, histology, microglia immunostaining","journal":"Journal of biomedicine & biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined in vivo loss-of-function-like phenotype via transgenic overexpression with multiple behavioral and histological readouts, single lab","pmids":["20976258"],"is_preprint":false},{"year":2011,"finding":"C. elegans HECW-1 (ortholog of HECW1) functions as a HECT-domain E3 ubiquitin ligase in sensory neurons to inhibit pathogen avoidance behavior by suppressing the neuropeptide receptor NPR-1. Natural coding polymorphisms in HECW-1 alter this behavioral output.","method":"Neuron-specific rescue experiments, neuron ablation, genetic epistasis analysis, behavioral assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis and cell-type-specific rescue/ablation in multiple independent experiments, replicated across natural alleles","pmids":["22089131"],"is_preprint":false},{"year":2019,"finding":"HECW1 ubiquitinates TTF1/NKX2.1 at lysine 151, leading to its proteasomal degradation. The TTF1-K151R mutant is resistant to HECW1-mediated ubiquitination and degradation. Downregulation of HECW1 attenuates PMA-induced TTF1 ubiquitination and degradation.","method":"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K151R), shRNA knockdown, western blot","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-specific mutagenesis identifying the ubiquitin acceptor lysine plus ubiquitination assay plus knockdown rescue, single lab but multiple orthogonal methods","pmids":["30849519"],"is_preprint":false},{"year":2019,"finding":"HECW1 induces TTF1 ubiquitination and degradation in normal thyroid HTori3 cells (but not in FTC133 carcinoma cells, where FBXL19 is the active E3 ligase instead). Lysine 151 of TTF1 is the ubiquitin acceptor site in both cell types. HECW1 overexpression reverses TTF1-induced cell migration and proliferation.","method":"Overexpression, ubiquitination assay, site-directed mutagenesis, western blot, migration and proliferation assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — extends prior finding to cell-type specificity with ubiquitination assays, single lab, consistent with companion paper","pmids":["31238008"],"is_preprint":false},{"year":2020,"finding":"Estrogen upregulates HECW1 expression in endometrial epithelial cells, and HECW1 promotes ubiquitination and degradation of the polarity protein Scribble, disrupting apical-basal polarity.","method":"3D primary cell culture, ubiquitination assay, western blot, GEO dataset screening, in vivo mouse and human tissue analysis","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — ubiquitination assay plus in vivo correlation data, mechanistic detail somewhat limited in abstract, single lab","pmids":["31616916"],"is_preprint":false},{"year":2021,"finding":"HECW1 promotes ubiquitination and proteasomal degradation of Smad4, reducing its protein (but not mRNA) levels, thereby enhancing proliferation, migration, and invasion of NSCLC cells.","method":"Overexpression and knockdown, ubiquitination assay, MG-132 proteasome inhibitor treatment, western blot, migration/invasion assays","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay with proteasome inhibitor rescue, gain- and loss-of-function, single lab","pmids":["33529121"],"is_preprint":false},{"year":2023,"finding":"NEDL1/HECW1 is expressed primarily in neuronal cell somas. Overexpression of NEDL1 in vitro is associated with increased cell death and cytoplasmic mislocalization of TDP-43.","method":"Immunostaining for subcellular localization, overexpression in neuronal cells, cell viability assay","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic follow-up, localization described but functional link to TDP-43 mislocalization not mechanistically dissected","pmids":["36674783"],"is_preprint":false},{"year":2024,"finding":"HECW1 interacts with DVL1 (Dishevelled-1) and promotes its ubiquitination and degradation, thereby suppressing Wnt/β-catenin signaling (reduced nuclear β-catenin, reduced TCF/LEF transcriptional activity, and reduced c-Myc expression) in cervical cancer cells. Inhibition of DVL1 reversed the pro-proliferative effect of HECW1 knockdown.","method":"Co-immunoprecipitation, ubiquitination assay, TOP-flash reporter assay, siRNA/overexpression, in vivo xenograft","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ubiquitination assay plus epistasis rescue experiment, single lab","pmids":["38266865"],"is_preprint":false},{"year":2024,"finding":"HECW1 interacts with HIPK2 and promotes its ubiquitination and proteasomal degradation, thereby activating AKT signaling and downstream EMT-related gene expression to promote gastric cancer metastasis.","method":"Co-immunoprecipitation, ubiquitination assay, western blot, immunofluorescence, in vivo metastasis model","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ubiquitination assay plus in vivo confirmation, single lab","pmids":["39615883"],"is_preprint":false},{"year":2024,"finding":"Nedl1 knockout in mice impaired spatial learning and memory in the Barnes maze, and was accompanied by astrocyte proliferation in the hippocampus and altered amino acid metabolism (increased proline and tryptophan), without affecting neuron or oligodendrocyte numbers.","method":"Nedl1 knockout mouse model, behavioral testing (Barnes maze, elevated plus maze, three-chamber test), histology, metabolomics","journal":"Physiology & behavior","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout with defined behavioral and cellular phenotypes, single lab, no molecular mechanism identified","pmids":["39424023"],"is_preprint":false},{"year":2025,"finding":"HECW1 interacts with NDRG1 and mediates ubiquitination and degradation of NRG2 at lysine 223 (K223). NDRG1 promotes its own interaction with HECW1 to facilitate NRG2 degradation. This NDRG1-NRG2-HECW1 axis regulates autophagy and EGFR TKI resistance in NSCLC.","method":"Co-immunoprecipitation, ubiquitination assay, site-directed identification of K223 as ubiquitin acceptor, RNA-seq, in vivo PDX model","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay with identified ubiquitin site, in vivo confirmation, single lab","pmids":["41193668"],"is_preprint":false}],"current_model":"HECW1 (NEDL1) is a HECT-type E3 ubiquitin ligase, highly expressed in neurons, that ubiquitinates multiple substrates including mutant SOD1, DVL1/Dishevelled-1, TTF1/NKX2.1 (at K151), Smad4, Scribble, HIPK2, and NRG2 (at K223), targeting them for proteasomal degradation; it also non-catalytically enhances p53 transcriptional activity by direct binding, and in C. elegans acts in sensory neurons to suppress neuropeptide receptor NPR-1-mediated pathogen avoidance, while in vivo knockout studies show HECW1/NEDL1 is required for normal hippocampal-dependent learning and memory."},"narrative":{"mechanistic_narrative":"HECW1 (NEDL1) is a neuronally enriched HECT-domain E3 ubiquitin ligase that controls cell signaling and cell fate by directing diverse substrates to proteasomal degradation [PMID:30849519, PMID:33529121, PMID:38266865]. Across multiple cellular contexts it ubiquitinates substrates at defined acceptor lysines and lowers their protein levels: TTF1/NKX2.1 at K151 [PMID:30849519, PMID:31238008], NRG2 at K223 [PMID:41193668], and DVL1, Smad4, Scribble, and HIPK2 [PMID:38266865, PMID:33529121, PMID:31616916, PMID:39615883]. Through these substrates HECW1 modulates major signaling outputs—it suppresses Wnt/β-catenin signaling by degrading DVL1 [PMID:38266865], disrupts apical-basal polarity by degrading Scribble [PMID:31616916], and shapes proliferation, migration, invasion, and EMT in epithelial cancers via Smad4 and HIPK2 turnover [PMID:33529121, PMID:39615883]; substrate selection can be cell-type-specific and partner-directed, as seen with the NDRG1-dependent degradation of NRG2 [PMID:41193668]. Distinct from its catalytic role, HECW1 binds the C-terminus of p53 and enhances p53 transcriptional activity and apoptosis independently of its ligase activity [PMID:18223681]. In the nervous system, HECW1 binds and ubiquitinates mutant but not wild-type SOD1 in proportion to disease severity [PMID:14684739], and gain-of-function overexpression in mice drives motor neuron degeneration [PMID:20976258], while knockout impairs hippocampal-dependent spatial learning and memory [PMID:39424023]; in C. elegans the ortholog acts in sensory neurons to suppress NPR-1-mediated pathogen avoidance [PMID:22089131].","teleology":[{"year":2003,"claim":"Established HECW1/NEDL1 as a ubiquitin ligase with disease-relevant substrate selectivity by showing it ubiquitinates mutant but not wild-type SOD1 and links to Wnt signaling via DVL1.","evidence":"Co-IP, ubiquitination assay, and yeast two-hybrid screening with immunohistochemistry","pmids":["14684739"],"confidence":"Medium","gaps":["No in vitro reconstitution or mutagenesis of the ubiquitin acceptor site","Functional consequence of DVL1 dysfunction not mechanistically resolved at this stage"]},{"year":2008,"claim":"Revealed a catalysis-independent function: HECW1 binds p53 and enhances its transcriptional and apoptotic activity, separating scaffold from ligase roles.","evidence":"Co-IP, in vitro binding, luciferase reporter, siRNA knockdown, apoptosis assays","pmids":["18223681"],"confidence":"Medium","gaps":["Structural basis of the C-terminal p53 interaction not defined","How non-catalytic enhancement integrates with ligase activity unclear"]},{"year":2010,"claim":"Connected HECW1 dosage to neurodegeneration in vivo, showing overexpression drives motor neuron loss and muscle atrophy.","evidence":"Transgenic mouse overexpression with behavioral and histological readouts","pmids":["20976258"],"confidence":"Medium","gaps":["Substrate(s) mediating the degeneration not identified","Relationship to mutant SOD1 handling not tested in this model"]},{"year":2011,"claim":"Demonstrated a conserved, cell-autonomous neuronal role using the C. elegans ortholog: HECW-1 acts in sensory neurons to suppress NPR-1-dependent pathogen avoidance.","evidence":"Neuron-specific rescue, neuron ablation, genetic epistasis, behavioral assays","pmids":["22089131"],"confidence":"High","gaps":["Direct substrate in the NPR-1 pathway not identified","Mammalian behavioral correlate not established at this point"]},{"year":2019,"claim":"Defined a precise substrate-and-site relationship by identifying TTF1/NKX2.1 K151 as the HECW1 ubiquitin acceptor, with cell-type-specific deployment relative to a competing ligase.","evidence":"Ubiquitination assay, K151R site-directed mutagenesis, shRNA knockdown, plus extension to thyroid cell lines","pmids":["30849519","31238008"],"confidence":"High","gaps":["Determinants of cell-type-specific ligase competition (HECW1 vs FBXL19) unresolved","Upstream signals coupling PMA/thyroid context to HECW1 activity unclear"]},{"year":2020,"claim":"Linked HECW1 to epithelial polarity control by showing estrogen-induced HECW1 degrades the polarity scaffold Scribble.","evidence":"3D primary culture, ubiquitination assay, in vivo tissue correlation","pmids":["31616916"],"confidence":"Medium","gaps":["Ubiquitin acceptor site on Scribble not mapped","Mechanistic detail limited"]},{"year":2021,"claim":"Implicated HECW1 in cancer signaling by degrading Smad4 to enhance NSCLC proliferation, migration, and invasion.","evidence":"Gain/loss-of-function, ubiquitination assay, MG-132 rescue, invasion assays","pmids":["33529121"],"confidence":"Medium","gaps":["Smad4 acceptor lysine not identified","Connection to TGF-β pathway context not dissected"]},{"year":2023,"claim":"Tied HECW1 to ALS-relevant proteostasis by associating its overexpression with cell death and cytoplasmic TDP-43 mislocalization in neurons.","evidence":"Immunostaining, overexpression, viability assay in neuronal cells","pmids":["36674783"],"confidence":"Low","gaps":["Functional link to TDP-43 mislocalization not mechanistically dissected","TDP-43 not shown to be a direct substrate"]},{"year":2024,"claim":"Expanded the substrate network and signaling impact: HECW1 degrades DVL1 to suppress Wnt/β-catenin, and degrades HIPK2 to activate AKT/EMT and promote metastasis.","evidence":"Co-IP, ubiquitination assays, reporter assays, epistasis rescue, in vivo xenograft/metastasis models","pmids":["38266865","39615883"],"confidence":"Medium","gaps":["Acceptor lysines on DVL1 and HIPK2 not mapped","Context determining which substrate dominates not defined"]},{"year":2024,"claim":"Provided the first mammalian loss-of-function behavioral phenotype, showing Nedl1 knockout impairs spatial learning with hippocampal astrocyte proliferation and altered amino acid metabolism.","evidence":"Nedl1 knockout mouse, Barnes maze and other behavioral tests, histology, metabolomics","pmids":["39424023"],"confidence":"Medium","gaps":["No molecular substrate linked to the learning phenotype","Cause of the metabolic shift unexplained"]},{"year":2025,"claim":"Showed substrate degradation can be partner-directed, with NDRG1 promoting HECW1-mediated ubiquitination of NRG2 at K223 to control autophagy and EGFR TKI resistance.","evidence":"Co-IP, ubiquitination assay with K223 site identification, RNA-seq, in vivo PDX model","pmids":["41193668"],"confidence":"Medium","gaps":["How NDRG1 enhances the HECW1-substrate interaction structurally unknown","Generality of partner-directed substrate selection untested"]},{"year":null,"claim":"How HECW1 substrate specificity, partner recruitment, and the balance between its catalytic and non-catalytic (p53-enhancing) functions are coordinated across neuronal and epithelial contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying determinant of substrate choice across tissues","Direct molecular substrate underlying neuronal phenotypes (learning, degeneration, TDP-43) not established","No structural model of HECW1-substrate or HECW1-cofactor complexes"]}],"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":[0,4,5,8,10,11,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,8,10,11,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,3,8,11,13]}],"complexes":[],"partners":["SOD1","DVL1","TP53","NKX2-1","SMAD4","SCRIB","HIPK2","NDRG1"],"other_free_text":[]}},"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":146,"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":53,"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":31,"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":15,"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":8,"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":"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":4,"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":2,"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":"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":"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":10083,"output_tokens":3363,"usd":0.040347,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10822,"output_tokens":3599,"usd":0.072042,"stage2_stop_reason":"end_turn"},"total_usd":0.112389,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"NEDL1 (HECW1) physically binds translocon-associated protein-delta (TRAP-delta) and binds and ubiquitinates mutant (but not wild-type) SOD1, with ubiquitination proportional to disease severity caused by that mutant. NEDL1 also binds Dishevelled-1 (DVL1), a Wnt signaling transducer, via two-hybrid screening. Mutant SOD1 interacted with DVL1 in the presence of NEDL1, causing DVL1 dysfunction.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, yeast two-hybrid screening, immunohistochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and ubiquitination assay in single lab, two orthogonal methods, but no in vitro reconstitution or mutagenesis\",\n      \"pmids\": [\"14684739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NEDL1 (HECW1) binds to the C-terminal region of p53 and enhances p53 transcriptional activity and p53-mediated apoptosis in a catalytic activity-independent manner. NEDL1 knockdown conferred resistance to adriamycin-induced apoptosis in p53 wild-type cells.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, luciferase reporter assay, siRNA knockdown, colony formation assay, flow cytometry\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus in vitro binding plus reporter assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"18223681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RNF43 binds NEDL1 (HECW1) as identified by yeast two-hybrid screening. RNF43 also interacts with p53 and suppresses p53 transcriptional activity, attenuating UV-induced apoptosis, in collaboration with NEDL1.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, luciferase reporter assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid plus co-IP but mechanistic role of HECW1 in the RNF43-p53 axis not directly demonstrated by experiment on HECW1 itself\",\n      \"pmids\": [\"21108931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Overexpression of human NEDL1 (HECW1) in transgenic mice caused motor neuron degeneration, muscle atrophy, and microglial activation in the spinal cord, establishing a gain-of-function neurodegeneration phenotype in vivo.\",\n      \"method\": \"Transgenic mouse model, rotarod/hanging wire/footprint behavioral tests, histology, microglia immunostaining\",\n      \"journal\": \"Journal of biomedicine & biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined in vivo loss-of-function-like phenotype via transgenic overexpression with multiple behavioral and histological readouts, single lab\",\n      \"pmids\": [\"20976258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"C. elegans HECW-1 (ortholog of HECW1) functions as a HECT-domain E3 ubiquitin ligase in sensory neurons to inhibit pathogen avoidance behavior by suppressing the neuropeptide receptor NPR-1. Natural coding polymorphisms in HECW-1 alter this behavioral output.\",\n      \"method\": \"Neuron-specific rescue experiments, neuron ablation, genetic epistasis analysis, behavioral assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis and cell-type-specific rescue/ablation in multiple independent experiments, replicated across natural alleles\",\n      \"pmids\": [\"22089131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HECW1 ubiquitinates TTF1/NKX2.1 at lysine 151, leading to its proteasomal degradation. The TTF1-K151R mutant is resistant to HECW1-mediated ubiquitination and degradation. Downregulation of HECW1 attenuates PMA-induced TTF1 ubiquitination and degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K151R), shRNA knockdown, western blot\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-specific mutagenesis identifying the ubiquitin acceptor lysine plus ubiquitination assay plus knockdown rescue, single lab but 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 HTori3 cells (but not in FTC133 carcinoma cells, where FBXL19 is the active E3 ligase instead). Lysine 151 of TTF1 is the ubiquitin acceptor site in both cell types. HECW1 overexpression reverses TTF1-induced cell migration and proliferation.\",\n      \"method\": \"Overexpression, ubiquitination assay, site-directed mutagenesis, western blot, migration and proliferation assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — extends prior finding to cell-type specificity with ubiquitination assays, single lab, consistent with companion paper\",\n      \"pmids\": [\"31238008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Estrogen upregulates HECW1 expression in endometrial epithelial cells, and HECW1 promotes ubiquitination and degradation of the polarity protein Scribble, disrupting apical-basal polarity.\",\n      \"method\": \"3D primary cell culture, ubiquitination assay, western blot, GEO dataset screening, in vivo mouse and human tissue analysis\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — ubiquitination assay plus in vivo correlation data, mechanistic detail somewhat limited in abstract, single lab\",\n      \"pmids\": [\"31616916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HECW1 promotes ubiquitination and proteasomal degradation of Smad4, reducing its protein (but not mRNA) levels, thereby enhancing proliferation, migration, and invasion of NSCLC cells.\",\n      \"method\": \"Overexpression and knockdown, ubiquitination assay, MG-132 proteasome inhibitor treatment, western blot, migration/invasion assays\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay with proteasome inhibitor rescue, gain- and loss-of-function, single lab\",\n      \"pmids\": [\"33529121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NEDL1/HECW1 is expressed primarily in neuronal cell somas. Overexpression of NEDL1 in vitro is associated with increased cell death and cytoplasmic mislocalization of TDP-43.\",\n      \"method\": \"Immunostaining for subcellular localization, overexpression in neuronal cells, cell viability assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic follow-up, localization described but functional link to TDP-43 mislocalization not mechanistically dissected\",\n      \"pmids\": [\"36674783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HECW1 interacts with DVL1 (Dishevelled-1) and promotes its ubiquitination and degradation, thereby suppressing Wnt/β-catenin signaling (reduced nuclear β-catenin, reduced TCF/LEF transcriptional activity, and reduced c-Myc expression) in cervical cancer cells. Inhibition of DVL1 reversed the pro-proliferative effect of HECW1 knockdown.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, TOP-flash reporter assay, siRNA/overexpression, in vivo xenograft\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ubiquitination assay plus epistasis rescue experiment, single lab\",\n      \"pmids\": [\"38266865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HECW1 interacts with HIPK2 and promotes its ubiquitination and proteasomal degradation, thereby activating AKT signaling and downstream EMT-related gene expression to promote gastric cancer metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, western blot, immunofluorescence, in vivo metastasis model\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ubiquitination assay plus in vivo confirmation, single lab\",\n      \"pmids\": [\"39615883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Nedl1 knockout in mice impaired spatial learning and memory in the Barnes maze, and was accompanied by astrocyte proliferation in the hippocampus and altered amino acid metabolism (increased proline and tryptophan), without affecting neuron or oligodendrocyte numbers.\",\n      \"method\": \"Nedl1 knockout mouse model, behavioral testing (Barnes maze, elevated plus maze, three-chamber test), histology, metabolomics\",\n      \"journal\": \"Physiology & behavior\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with defined behavioral and cellular phenotypes, single lab, no molecular mechanism identified\",\n      \"pmids\": [\"39424023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HECW1 interacts with NDRG1 and mediates ubiquitination and degradation of NRG2 at lysine 223 (K223). NDRG1 promotes its own interaction with HECW1 to facilitate NRG2 degradation. This NDRG1-NRG2-HECW1 axis regulates autophagy and EGFR TKI resistance in NSCLC.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, site-directed identification of K223 as ubiquitin acceptor, RNA-seq, in vivo PDX model\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay with identified ubiquitin site, in vivo confirmation, single lab\",\n      \"pmids\": [\"41193668\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HECW1 (NEDL1) is a HECT-type E3 ubiquitin ligase, highly expressed in neurons, that ubiquitinates multiple substrates including mutant SOD1, DVL1/Dishevelled-1, TTF1/NKX2.1 (at K151), Smad4, Scribble, HIPK2, and NRG2 (at K223), targeting them for proteasomal degradation; it also non-catalytically enhances p53 transcriptional activity by direct binding, and in C. elegans acts in sensory neurons to suppress neuropeptide receptor NPR-1-mediated pathogen avoidance, while in vivo knockout studies show HECW1/NEDL1 is required for normal hippocampal-dependent learning and memory.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HECW1 (NEDL1) is a neuronally enriched HECT-domain E3 ubiquitin ligase that controls cell signaling and cell fate by directing diverse substrates to proteasomal degradation [#5, #8, #10]. Across multiple cellular contexts it ubiquitinates substrates at defined acceptor lysines and lowers their protein levels: TTF1/NKX2.1 at K151 [#5, #6], NRG2 at K223 [#13], and DVL1, Smad4, Scribble, and HIPK2 [#10, #8, #7, #11]. Through these substrates HECW1 modulates major signaling outputs—it suppresses Wnt/\\u03b2-catenin signaling by degrading DVL1 [#10], disrupts apical-basal polarity by degrading Scribble [#7], and shapes proliferation, migration, invasion, and EMT in epithelial cancers via Smad4 and HIPK2 turnover [#8, #11]; substrate selection can be cell-type-specific and partner-directed, as seen with the NDRG1-dependent degradation of NRG2 [#13]. Distinct from its catalytic role, HECW1 binds the C-terminus of p53 and enhances p53 transcriptional activity and apoptosis independently of its ligase activity [#1]. In the nervous system, HECW1 binds and ubiquitinates mutant but not wild-type SOD1 in proportion to disease severity [#0], and gain-of-function overexpression in mice drives motor neuron degeneration [#3], while knockout impairs hippocampal-dependent spatial learning and memory [#12]; in C. elegans the ortholog acts in sensory neurons to suppress NPR-1-mediated pathogen avoidance [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established HECW1/NEDL1 as a ubiquitin ligase with disease-relevant substrate selectivity by showing it ubiquitinates mutant but not wild-type SOD1 and links to Wnt signaling via DVL1.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, and yeast two-hybrid screening with immunohistochemistry\",\n      \"pmids\": [\"14684739\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution or mutagenesis of the ubiquitin acceptor site\", \"Functional consequence of DVL1 dysfunction not mechanistically resolved at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed a catalysis-independent function: HECW1 binds p53 and enhances its transcriptional and apoptotic activity, separating scaffold from ligase roles.\",\n      \"evidence\": \"Co-IP, in vitro binding, luciferase reporter, siRNA knockdown, apoptosis assays\",\n      \"pmids\": [\"18223681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the C-terminal p53 interaction not defined\", \"How non-catalytic enhancement integrates with ligase activity unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected HECW1 dosage to neurodegeneration in vivo, showing overexpression drives motor neuron loss and muscle atrophy.\",\n      \"evidence\": \"Transgenic mouse overexpression with behavioral and histological readouts\",\n      \"pmids\": [\"20976258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate(s) mediating the degeneration not identified\", \"Relationship to mutant SOD1 handling not tested in this model\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated a conserved, cell-autonomous neuronal role using the C. elegans ortholog: HECW-1 acts in sensory neurons to suppress NPR-1-dependent pathogen avoidance.\",\n      \"evidence\": \"Neuron-specific rescue, neuron ablation, genetic epistasis, behavioral assays\",\n      \"pmids\": [\"22089131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate in the NPR-1 pathway not identified\", \"Mammalian behavioral correlate not established at this point\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a precise substrate-and-site relationship by identifying TTF1/NKX2.1 K151 as the HECW1 ubiquitin acceptor, with cell-type-specific deployment relative to a competing ligase.\",\n      \"evidence\": \"Ubiquitination assay, K151R site-directed mutagenesis, shRNA knockdown, plus extension to thyroid cell lines\",\n      \"pmids\": [\"30849519\", \"31238008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of cell-type-specific ligase competition (HECW1 vs FBXL19) unresolved\", \"Upstream signals coupling PMA/thyroid context to HECW1 activity unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked HECW1 to epithelial polarity control by showing estrogen-induced HECW1 degrades the polarity scaffold Scribble.\",\n      \"evidence\": \"3D primary culture, ubiquitination assay, in vivo tissue correlation\",\n      \"pmids\": [\"31616916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin acceptor site on Scribble not mapped\", \"Mechanistic detail limited\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Implicated HECW1 in cancer signaling by degrading Smad4 to enhance NSCLC proliferation, migration, and invasion.\",\n      \"evidence\": \"Gain/loss-of-function, ubiquitination assay, MG-132 rescue, invasion assays\",\n      \"pmids\": [\"33529121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Smad4 acceptor lysine not identified\", \"Connection to TGF-\\u03b2 pathway context not dissected\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Tied HECW1 to ALS-relevant proteostasis by associating its overexpression with cell death and cytoplasmic TDP-43 mislocalization in neurons.\",\n      \"evidence\": \"Immunostaining, overexpression, viability assay in neuronal cells\",\n      \"pmids\": [\"36674783\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Functional link to TDP-43 mislocalization not mechanistically dissected\", \"TDP-43 not shown to be a direct substrate\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded the substrate network and signaling impact: HECW1 degrades DVL1 to suppress Wnt/\\u03b2-catenin, and degrades HIPK2 to activate AKT/EMT and promote metastasis.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, reporter assays, epistasis rescue, in vivo xenograft/metastasis models\",\n      \"pmids\": [\"38266865\", \"39615883\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acceptor lysines on DVL1 and HIPK2 not mapped\", \"Context determining which substrate dominates not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the first mammalian loss-of-function behavioral phenotype, showing Nedl1 knockout impairs spatial learning with hippocampal astrocyte proliferation and altered amino acid metabolism.\",\n      \"evidence\": \"Nedl1 knockout mouse, Barnes maze and other behavioral tests, histology, metabolomics\",\n      \"pmids\": [\"39424023\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular substrate linked to the learning phenotype\", \"Cause of the metabolic shift unexplained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed substrate degradation can be partner-directed, with NDRG1 promoting HECW1-mediated ubiquitination of NRG2 at K223 to control autophagy and EGFR TKI resistance.\",\n      \"evidence\": \"Co-IP, ubiquitination assay with K223 site identification, RNA-seq, in vivo PDX model\",\n      \"pmids\": [\"41193668\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How NDRG1 enhances the HECW1-substrate interaction structurally unknown\", \"Generality of partner-directed substrate selection untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HECW1 substrate specificity, partner recruitment, and the balance between its catalytic and non-catalytic (p53-enhancing) functions are coordinated across neuronal and epithelial contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying determinant of substrate choice across tissues\", \"Direct molecular substrate underlying neuronal phenotypes (learning, degeneration, TDP-43) not established\", \"No structural model of HECW1-substrate or HECW1-cofactor complexes\"]\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, 4, 5, 8, 10, 11, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 8, 10, 11, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 3, 8, 11, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SOD1\", \"DVL1\", \"TP53\", \"NKX2-1\", \"SMAD4\", \"SCRIB\", \"HIPK2\", \"NDRG1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}