{"gene":"HECW2","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2003,"finding":"HECW2 (NEDL2) physically interacts with p73 via p73's PY motifs and WW domains of NEDL2, ubiquitinates p73, and paradoxically stabilizes it rather than targeting it for degradation, thereby enhancing p73-dependent transcriptional activation.","method":"Reciprocal co-immunoprecipitation, in vitro pull-down assay, in vitro ubiquitination assay, transcriptional reporter assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal Co-IP, in vitro ubiquitination, and functional transcriptional assay in single paper with multiple orthogonal methods","pmids":["12890487"],"is_preprint":false},{"year":2013,"finding":"HECW2 (NEDL2) is degraded by the APC/C-Cdh1 ubiquitin ligase complex during mitotic exit; Cdh1 recognizes NEDL2's destruction box (R740GSL743) and targets it for proteasomal degradation. NEDL2 associates with mitotic spindles, reaches peak protein levels in mitosis, and its depletion prolongs metaphase while overexpression induces chromosomal lagging.","method":"Immunoprecipitation with mass spectrometry, co-IP in vivo and in vitro, Cdh1 knockdown/overexpression, destruction box mutagenesis, immunofluorescence localization, mitotic timing assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including MS identification, in vitro binding, mutagenesis of destruction box, and functional mitotic phenotype","pmids":["24163370"],"is_preprint":false},{"year":2014,"finding":"HECW2 (NEDL2) is an essential positive regulator of enteric nervous system (ENS) development; NEDL2-deficient mice develop intestinal aganglionosis due to defective enteric neural precursor proliferation mediated through the GDNF/Akt signaling pathway.","method":"Knockout mouse model, bowel motility assessment, histology, Akt signaling pathway analysis","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with defined cellular and molecular phenotype, pathway placement via GDNF/Akt","pmids":["25555806"],"is_preprint":false},{"year":2016,"finding":"HECW2 physically interacts with AMOTL1 and promotes its stability via lysine 63-linked ubiquitination in endothelial cells; HECW2 depletion decreases AMOTL1 levels, loosens cell-to-cell junctions, shifts YAP localization from cytoplasm to nucleus, and increases angiogenic sprouting dependent on ANG-2.","method":"Co-immunoprecipitation, ubiquitination assay with K63-linkage specificity, siRNA knockdown, subcellular fractionation/imaging of YAP, angiogenic sprouting assay","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical interaction, linkage-specific ubiquitination, and functional epistasis with YAP/ANG-2 pathway using multiple methods","pmids":["27498087"],"is_preprint":false},{"year":2016,"finding":"HECW2 (NEDL2) acts as a Nedd8 ligase (not only a ubiquitin ligase), with cysteine 1341 as the catalytic site; this Nedd8 ligase activity is required for GDNF-stimulated Akt activation and ENS/kidney development, while ubiquitin ligase activity is dispensable for these functions. NEDL2 also functions as a scaffold recruiting SHC, Grb2, PI3K (p110/p85), PDK1, and Akt.","method":"Active-site mutagenesis (C1341 mutation), double knockout mice, biochemical scaffold/complex reconstitution, in vivo signaling assays","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1 — active-site mutagenesis distinguishing Nedd8 vs. ubiquitin ligase activity, combined with KO mouse phenotype and scaffold complex reconstitution","pmids":["27119228"],"is_preprint":false},{"year":2018,"finding":"HECW2 interacts with PCNA via a canonical PIP motif and with lamin B1, mediating their ubiquitination and proteasomal degradation. HECW2 also interacts with wild-type lamin A and ubiquitinates it; this interaction is reduced with laminopathy-causing lamin A mutants G232E and Q294P, in which HECW2 is upregulated and causes increased degradation of PCNA and lamin B1.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, PIP motif identification, proteasome inhibitor experiments, lamin A mutant cell lines","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"High","confidence_rationale":"Tier 1-2 — multiple substrates identified by Co-IP and in vitro ubiquitination assay with functional degradation confirmed by proteasome inhibition","pmids":["29753763"],"is_preprint":false},{"year":2018,"finding":"HECW2 interacts with HP1α and HP1β (but not HP1γ) and mediates their ubiquitination and proteasomal degradation; downregulation of HECW2 increases steady-state levels of HP1α and HP1β.","method":"Co-immunoprecipitation, ubiquitination assay, HECW2 overexpression and knockdown, proteasome inhibitor treatment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ubiquitination assay in single lab, multiple substrates tested with isoform specificity","pmids":["30208514"],"is_preprint":false},{"year":2021,"finding":"HECW2 (NEDL2) localizes to distinct nuclear foci in germinal vesicles of immature oocytes, maternal and paternal pronuclei of zygotes, and blastomere nuclei; antibody-mediated inhibition of NEDL2 in oocytes inhibits sperm DNA decondensation, reduces male pronucleus formation, and accelerates nuclear precursor body formation without affecting fertilization rate or cleavage.","method":"Western blot of isoforms across cell types, immunofluorescence localization, anti-NEDL2 antibody microinjection into oocytes before IVF","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization with functional consequence via antibody microinjection, single study","pmids":["33030211"],"is_preprint":false},{"year":2023,"finding":"HECW2 mediates ubiquitin-proteasome degradation of lamin B1, thereby activating the AKT/mTOR signaling pathway and promoting colorectal cancer progression and chemoresistance.","method":"HECW2 knockdown/overexpression, ubiquitination assay, AKT/mTOR pathway analysis, CRC cell proliferation and drug resistance assays","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway placement via ubiquitination assay and signaling readout, single lab","pmids":["37781079"],"is_preprint":false},{"year":2025,"finding":"HECW2 regulates ubiquitination of ALKBH5, which enhances LDHA mRNA expression through ALKBH5-mediated m6A demethylation, thereby promoting glycolysis in hemangioma endothelial cells; HECW2 knockdown suppresses glycolysis and tumor growth in an IH xenograft model.","method":"HECW2 overexpression/knockdown, ubiquitination assay, glycolysis assays (glucose uptake, lactate, ATP), rescue by LDHA overexpression, in vivo xenograft mouse model","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic cascade from ubiquitination through m6A demethylation to glycolysis, validated in vivo, single lab","pmids":["40520873"],"is_preprint":false}],"current_model":"HECW2 is a HECT- and Nedd8-type E3 ubiquitin ligase that stabilizes p73 through non-degradative ubiquitination, promotes K63-linked ubiquitination of AMOTL1 to maintain endothelial junctions and suppress YAP nuclear translocation, and targets PCNA, lamin B1, HP1α/β, and ALKBH5 for proteasomal degradation; its own protein levels are regulated by APC/C-Cdh1-mediated degradation during mitotic exit, and its Nedd8 ligase activity (requiring C1341) is specifically required for GDNF/Akt signaling in enteric and kidney development."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing HECW2 as a HECT-domain E3 ligase that paradoxically stabilizes rather than degrades its substrate p73 answered how a ubiquitin ligase could function as a transcriptional co-activator.","evidence":"Reciprocal co-IP, in vitro ubiquitination, and transcriptional reporter assays in mammalian cells","pmids":["12890487"],"confidence":"High","gaps":["Ubiquitin chain linkage type on p73 not determined","In vivo relevance to p73-dependent apoptosis or differentiation not tested","No structural basis for WW–PY interaction"]},{"year":2013,"claim":"Identifying HECW2 as an APC/C-Cdh1 substrate that peaks in mitosis and localizes to spindles revealed cell-cycle-dependent regulation and a mitotic function for this ligase.","evidence":"IP-MS identification, destruction box mutagenesis, Cdh1 knockdown/overexpression, immunofluorescence, and mitotic timing assays","pmids":["24163370"],"confidence":"High","gaps":["Mitotic substrates of HECW2 at the spindle not identified","Mechanism by which overexpression causes chromosome lagging unknown","Functional consequence of destruction box mutation in vivo untested"]},{"year":2014,"claim":"Demonstrating that HECW2-deficient mice develop intestinal aganglionosis via defective GDNF/Akt signaling established a non-redundant developmental role in the enteric nervous system.","evidence":"Knockout mouse model with bowel motility, histology, and Akt signaling pathway analysis","pmids":["25555806"],"confidence":"High","gaps":["Whether the ENS phenotype depends on ubiquitin or Nedd8 ligase activity was unresolved at this point","Cell-autonomous versus non-cell-autonomous contributions not dissected"]},{"year":2016,"claim":"Distinguishing HECW2's Nedd8 ligase activity (C1341-dependent) from its ubiquitin ligase activity, and showing only the former is required for GDNF/Akt signaling and ENS/kidney development, redefined HECW2 as a dual-function ligase with separable catalytic outputs.","evidence":"Active-site mutagenesis, double KO mice, scaffold complex reconstitution with SHC/Grb2/PI3K/PDK1/Akt","pmids":["27119228"],"confidence":"High","gaps":["Nedd8 substrate(s) in the GDNF pathway not identified","Whether Nedd8 ligase activity is relevant beyond ENS/kidney contexts unknown","Structural basis for dual specificity not established"]},{"year":2016,"claim":"Showing that HECW2 K63-ubiquitinates AMOTL1 to stabilize it and retain YAP in the cytoplasm connected HECW2 to Hippo pathway regulation and endothelial junction integrity.","evidence":"Co-IP, K63-linkage-specific ubiquitination assay, siRNA knockdown, YAP subcellular fractionation, angiogenic sprouting assay","pmids":["27498087"],"confidence":"High","gaps":["Whether HECW2-AMOTL1 axis operates in non-endothelial tissues untested","Upstream signals controlling HECW2 activity in endothelial cells unknown"]},{"year":2018,"claim":"Identifying PCNA and lamin B1 as degradative substrates of HECW2, and linking altered HECW2–lamin A interaction to laminopathy-causing mutations, expanded the substrate repertoire to nuclear envelope and DNA replication machinery.","evidence":"Co-IP, in vitro ubiquitination, PIP motif identification, proteasome inhibitor experiments, lamin A mutant cell lines","pmids":["29753763"],"confidence":"High","gaps":["Functional consequence of PCNA degradation for DNA replication or repair not assessed","Whether lamin B1 degradation contributes to laminopathy pathology remains unclear"]},{"year":2018,"claim":"Demonstrating selective ubiquitination and degradation of HP1α and HP1β (but not HP1γ) by HECW2 implicated it in heterochromatin regulation with isoform specificity.","evidence":"Co-IP, ubiquitination assay, HECW2 overexpression/knockdown with proteasome inhibitor treatment","pmids":["30208514"],"confidence":"Medium","gaps":["Functional impact on heterochromatin spreading or gene silencing not tested","Basis for HP1 isoform selectivity unknown","Single-lab finding awaits independent confirmation"]},{"year":2021,"claim":"Localization of HECW2 to nuclear foci in oocytes and zygotes, and its requirement for sperm DNA decondensation and pronucleus formation, established a role in the earliest events of mammalian development.","evidence":"Immunofluorescence in oocytes/zygotes, antibody microinjection into oocytes before IVF","pmids":["33030211"],"confidence":"Medium","gaps":["Substrate(s) mediating sperm decondensation not identified","Antibody inhibition approach does not distinguish catalytic from scaffolding functions","Single study with no genetic confirmation"]},{"year":2023,"claim":"Connecting HECW2-mediated lamin B1 degradation to AKT/mTOR activation in colorectal cancer provided a disease-relevant downstream pathway for a previously identified substrate.","evidence":"HECW2 knockdown/overexpression, ubiquitination assay, AKT/mTOR pathway analysis, CRC proliferation and chemoresistance assays","pmids":["37781079"],"confidence":"Medium","gaps":["Mechanism linking lamin B1 loss to AKT/mTOR activation not delineated","In vivo tumor model confirmation limited","Independent replication needed"]},{"year":2025,"claim":"Identification of ALKBH5 as a HECW2 substrate linked ubiquitin-mediated regulation to m6A RNA modification and glycolysis in hemangioma, revealing an epitranscriptomic arm of HECW2 function.","evidence":"Ubiquitination assay, glycolysis assays, LDHA rescue, in vivo xenograft model in hemangioma endothelial cells","pmids":["40520873"],"confidence":"Medium","gaps":["Ubiquitin chain linkage type on ALKBH5 not determined","Whether this pathway operates in normal endothelial physiology unknown","Single-lab finding"]},{"year":null,"claim":"Major open questions include the identity of HECW2's Nedd8 substrate(s) in GDNF signaling, the structural basis for its dual ubiquitin/Nedd8 specificity, how its numerous degradative and non-degradative substrates are prioritized in different cell types, and whether its mitotic spindle association reflects a direct mitotic substrate.","evidence":"","pmids":[],"confidence":"Low","gaps":["Nedd8 substrate in GDNF/Akt pathway unidentified","No structural model of HECW2 HECT domain or WW domains","Context-dependent substrate selection mechanism unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3,5,6,8,9]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,3,4,5,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,6,7]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,4,8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,3,5,6,9]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,4]}],"complexes":[],"partners":["TP73","AMOTL1","PCNA","LMNB1","LMNA","CBX5","CBX1","ALKBH5"],"other_free_text":[]},"mechanistic_narrative":"HECW2 is a HECT-domain E3 ligase with dual ubiquitin and Nedd8 ligase activities that controls the stability of diverse nuclear and cytoplasmic substrates while also functioning as a signaling scaffold. It catalyzes K63-linked ubiquitination of AMOTL1 to stabilize endothelial junctions and sequester YAP in the cytoplasm, and non-degradative ubiquitination of p73 to enhance its transcriptional activity, whereas it targets PCNA, lamin B1, HP1α/β, and ALKBH5 for proteasomal degradation [PMID:12890487, PMID:27498087, PMID:29753763, PMID:30208514, PMID:40520873]. Its Nedd8 ligase activity, dependent on catalytic cysteine C1341, is specifically required for GDNF-stimulated Akt activation and enteric nervous system development, where it scaffolds SHC, Grb2, PI3K, PDK1, and Akt; HECW2-deficient mice accordingly develop intestinal aganglionosis [PMID:27119228, PMID:25555806]. HECW2 itself is a substrate of APC/C-Cdh1, which degrades it during mitotic exit via a destruction box motif, and its depletion prolongs metaphase while its overexpression causes chromosome lagging [PMID:24163370]."},"prefetch_data":{"uniprot":{"accession":"Q9P2P5","full_name":"E3 ubiquitin-protein ligase HECW2","aliases":["HECT, C2 and WW domain-containing protein 2","HECT-type E3 ubiquitin transferase HECW2","NEDD4-like E3 ubiquitin-protein ligase 2"],"length_aa":1572,"mass_kda":175.8,"function":"E3 ubiquitin-protein ligase that mediates ubiquitination of TP73. Acts to stabilize TP73 and enhance activation of transcription by TP73 (PubMed:12890487). Involved in the regulation of mitotic metaphase/anaphase transition (PubMed:24163370)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/Q9P2P5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HECW2","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/HECW2","total_profiled":1310},"omim":[{"mim_id":"617268","title":"NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, SEIZURES, AND ABSENT LANGUAGE; NDHSAL","url":"https://www.omim.org/entry/617268"},{"mim_id":"617245","title":"HECT, C2, AND WW DOMAINS-CONTAINING E3 UBIQUITIN-PROTEIN LIGASE 2; HECW2","url":"https://www.omim.org/entry/617245"},{"mim_id":"606234","title":"IKAROS FAMILY ZINC FINGER 2; IKZF2","url":"https://www.omim.org/entry/606234"},{"mim_id":"601990","title":"TUMOR PROTEIN p73; TP73","url":"https://www.omim.org/entry/601990"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HECW2"},"hgnc":{"alias_symbol":["KIAA1301","NEDL2"],"prev_symbol":[]},"alphafold":{"accession":"Q9P2P5","domains":[{"cath_id":"2.60.40.2840","chopping":"61-166","consensus_level":"high","plddt":79.8105,"start":61,"end":166},{"cath_id":"2.60.40.150","chopping":"186-324","consensus_level":"high","plddt":78.9084,"start":186,"end":324},{"cath_id":"2.20.70.10","chopping":"927-1013","consensus_level":"medium","plddt":90.0939,"start":927,"end":1013},{"cath_id":"-","chopping":"1082-1149","consensus_level":"high","plddt":88.9221,"start":1082,"end":1149},{"cath_id":"3.90.1750.10","chopping":"1191-1365_1400-1453","consensus_level":"medium","plddt":86.5341,"start":1191,"end":1453},{"cath_id":"3.30.2410.10","chopping":"1454-1572","consensus_level":"medium","plddt":82.5696,"start":1454,"end":1572}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2P5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2P5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2P5-F1-predicted_aligned_error_v6.png","plddt_mean":60.41},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HECW2","jax_strain_url":"https://www.jax.org/strain/search?query=HECW2"},"sequence":{"accession":"Q9P2P5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P2P5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P2P5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2P5"}},"corpus_meta":[{"pmid":"12890487","id":"PMC_12890487","title":"A novel HECT-type E3 ubiquitin ligase, NEDL2, stabilizes p73 and enhances its transcriptional activity.","date":"2003","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12890487","citation_count":86,"is_preprint":false},{"pmid":"29260931","id":"PMC_29260931","title":"Engagement of circular RNA HECW2 in the nonautophagic role of ATG5 implicated in the endothelial-mesenchymal transition.","date":"2018","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/29260931","citation_count":82,"is_preprint":false},{"pmid":"27334371","id":"PMC_27334371","title":"Mutations in HECW2 are associated with intellectual disability and epilepsy.","date":"2016","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27334371","citation_count":58,"is_preprint":false},{"pmid":"27498087","id":"PMC_27498087","title":"The endothelial E3 ligase HECW2 promotes endothelial cell junctions by increasing AMOTL1 protein stability via K63-linked ubiquitination.","date":"2016","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/27498087","citation_count":43,"is_preprint":false},{"pmid":"24163370","id":"PMC_24163370","title":"The HECT type ubiquitin ligase NEDL2 is degraded by anaphase-promoting complex/cyclosome (APC/C)-Cdh1, and its tight regulation maintains the metaphase to anaphase transition.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24163370","citation_count":40,"is_preprint":false},{"pmid":"29753763","id":"PMC_29753763","title":"E3 ubiquitin ligase HECW2 targets PCNA and lamin B1.","date":"2018","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/29753763","citation_count":33,"is_preprint":false},{"pmid":"32916175","id":"PMC_32916175","title":"Circ_HECW2 functions as a miR-30e-5p sponge to regulate LPS-induced endothelial-mesenchymal transition by mediating NEGR1 expression.","date":"2020","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/32916175","citation_count":23,"is_preprint":false},{"pmid":"21143916","id":"PMC_21143916","title":"Knobbed acrosome defect is associated with a region containing the genes STK17b and HECW2 on porcine chromosome 15.","date":"2010","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/21143916","citation_count":23,"is_preprint":false},{"pmid":"25555806","id":"PMC_25555806","title":"NEDL2 is an essential regulator of enteric neural development and GDNF/Ret signaling.","date":"2014","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/25555806","citation_count":18,"is_preprint":false},{"pmid":"27119228","id":"PMC_27119228","title":"NEDL2 regulates enteric nervous system and kidney development in its Nedd8 ligase activity-dependent manner.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27119228","citation_count":14,"is_preprint":false},{"pmid":"33030211","id":"PMC_33030211","title":"NEDD4-like ubiquitin ligase 2 protein (NEDL2) in porcine spermatozoa, oocytes, and preimplantation embryos and its role in oocyte fertilization†.","date":"2021","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/33030211","citation_count":13,"is_preprint":false},{"pmid":"30208514","id":"PMC_30208514","title":"E3 ubiquitin ligase HECW2 mediates the proteasomal degradation of HP1 isoforms.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/30208514","citation_count":12,"is_preprint":false},{"pmid":"36213989","id":"PMC_36213989","title":"Circ_HECW2 regulates ox-LDL-induced dysfunction of cardiovascular endothelial cells by miR-942-5p/TLR4 axis.","date":"2025","source":"Clinical hemorheology and microcirculation","url":"https://pubmed.ncbi.nlm.nih.gov/36213989","citation_count":12,"is_preprint":false},{"pmid":"34047014","id":"PMC_34047014","title":"HECW2-related disorder in four Japanese patients.","date":"2021","source":"American journal of medical genetics. 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Gly1452Ser) in a Chinese Patient with Developmental Delay, Neurodevelopmental Delay, and Hypotonia.","date":"2025","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/40469502","citation_count":0,"is_preprint":false},{"pmid":"40705299","id":"PMC_40705299","title":"HECW2 Gene Mutation: A Rare Cause of West Syndrome: A Case Report.","date":"2025","source":"Neurology India","url":"https://pubmed.ncbi.nlm.nih.gov/40705299","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16021,"output_tokens":2627,"usd":0.043734},"stage2":{"model":"claude-opus-4-6","input_tokens":5965,"output_tokens":2827,"usd":0.15075},"total_usd":0.194484,"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\": \"HECW2 (NEDL2) physically interacts with p73 via p73's PY motifs and WW domains of NEDL2, ubiquitinates p73, and paradoxically stabilizes it rather than targeting it for degradation, thereby enhancing p73-dependent transcriptional activation.\",\n      \"method\": \"Reciprocal co-immunoprecipitation, in vitro pull-down assay, in vitro ubiquitination assay, transcriptional reporter assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal Co-IP, in vitro ubiquitination, and functional transcriptional assay in single paper with multiple orthogonal methods\",\n      \"pmids\": [\"12890487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HECW2 (NEDL2) is degraded by the APC/C-Cdh1 ubiquitin ligase complex during mitotic exit; Cdh1 recognizes NEDL2's destruction box (R740GSL743) and targets it for proteasomal degradation. NEDL2 associates with mitotic spindles, reaches peak protein levels in mitosis, and its depletion prolongs metaphase while overexpression induces chromosomal lagging.\",\n      \"method\": \"Immunoprecipitation with mass spectrometry, co-IP in vivo and in vitro, Cdh1 knockdown/overexpression, destruction box mutagenesis, immunofluorescence localization, mitotic timing assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including MS identification, in vitro binding, mutagenesis of destruction box, and functional mitotic phenotype\",\n      \"pmids\": [\"24163370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HECW2 (NEDL2) is an essential positive regulator of enteric nervous system (ENS) development; NEDL2-deficient mice develop intestinal aganglionosis due to defective enteric neural precursor proliferation mediated through the GDNF/Akt signaling pathway.\",\n      \"method\": \"Knockout mouse model, bowel motility assessment, histology, Akt signaling pathway analysis\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with defined cellular and molecular phenotype, pathway placement via GDNF/Akt\",\n      \"pmids\": [\"25555806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HECW2 physically interacts with AMOTL1 and promotes its stability via lysine 63-linked ubiquitination in endothelial cells; HECW2 depletion decreases AMOTL1 levels, loosens cell-to-cell junctions, shifts YAP localization from cytoplasm to nucleus, and increases angiogenic sprouting dependent on ANG-2.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with K63-linkage specificity, siRNA knockdown, subcellular fractionation/imaging of YAP, angiogenic sprouting assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical interaction, linkage-specific ubiquitination, and functional epistasis with YAP/ANG-2 pathway using multiple methods\",\n      \"pmids\": [\"27498087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HECW2 (NEDL2) acts as a Nedd8 ligase (not only a ubiquitin ligase), with cysteine 1341 as the catalytic site; this Nedd8 ligase activity is required for GDNF-stimulated Akt activation and ENS/kidney development, while ubiquitin ligase activity is dispensable for these functions. NEDL2 also functions as a scaffold recruiting SHC, Grb2, PI3K (p110/p85), PDK1, and Akt.\",\n      \"method\": \"Active-site mutagenesis (C1341 mutation), double knockout mice, biochemical scaffold/complex reconstitution, in vivo signaling assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — active-site mutagenesis distinguishing Nedd8 vs. ubiquitin ligase activity, combined with KO mouse phenotype and scaffold complex reconstitution\",\n      \"pmids\": [\"27119228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HECW2 interacts with PCNA via a canonical PIP motif and with lamin B1, mediating their ubiquitination and proteasomal degradation. HECW2 also interacts with wild-type lamin A and ubiquitinates it; this interaction is reduced with laminopathy-causing lamin A mutants G232E and Q294P, in which HECW2 is upregulated and causes increased degradation of PCNA and lamin B1.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, PIP motif identification, proteasome inhibitor experiments, lamin A mutant cell lines\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple substrates identified by Co-IP and in vitro ubiquitination assay with functional degradation confirmed by proteasome inhibition\",\n      \"pmids\": [\"29753763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HECW2 interacts with HP1α and HP1β (but not HP1γ) and mediates their ubiquitination and proteasomal degradation; downregulation of HECW2 increases steady-state levels of HP1α and HP1β.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, HECW2 overexpression and knockdown, proteasome inhibitor treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ubiquitination assay in single lab, multiple substrates tested with isoform specificity\",\n      \"pmids\": [\"30208514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HECW2 (NEDL2) localizes to distinct nuclear foci in germinal vesicles of immature oocytes, maternal and paternal pronuclei of zygotes, and blastomere nuclei; antibody-mediated inhibition of NEDL2 in oocytes inhibits sperm DNA decondensation, reduces male pronucleus formation, and accelerates nuclear precursor body formation without affecting fertilization rate or cleavage.\",\n      \"method\": \"Western blot of isoforms across cell types, immunofluorescence localization, anti-NEDL2 antibody microinjection into oocytes before IVF\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional consequence via antibody microinjection, single study\",\n      \"pmids\": [\"33030211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HECW2 mediates ubiquitin-proteasome degradation of lamin B1, thereby activating the AKT/mTOR signaling pathway and promoting colorectal cancer progression and chemoresistance.\",\n      \"method\": \"HECW2 knockdown/overexpression, ubiquitination assay, AKT/mTOR pathway analysis, CRC cell proliferation and drug resistance assays\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway placement via ubiquitination assay and signaling readout, single lab\",\n      \"pmids\": [\"37781079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HECW2 regulates ubiquitination of ALKBH5, which enhances LDHA mRNA expression through ALKBH5-mediated m6A demethylation, thereby promoting glycolysis in hemangioma endothelial cells; HECW2 knockdown suppresses glycolysis and tumor growth in an IH xenograft model.\",\n      \"method\": \"HECW2 overexpression/knockdown, ubiquitination assay, glycolysis assays (glucose uptake, lactate, ATP), rescue by LDHA overexpression, in vivo xenograft mouse model\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic cascade from ubiquitination through m6A demethylation to glycolysis, validated in vivo, single lab\",\n      \"pmids\": [\"40520873\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HECW2 is a HECT- and Nedd8-type E3 ubiquitin ligase that stabilizes p73 through non-degradative ubiquitination, promotes K63-linked ubiquitination of AMOTL1 to maintain endothelial junctions and suppress YAP nuclear translocation, and targets PCNA, lamin B1, HP1α/β, and ALKBH5 for proteasomal degradation; its own protein levels are regulated by APC/C-Cdh1-mediated degradation during mitotic exit, and its Nedd8 ligase activity (requiring C1341) is specifically required for GDNF/Akt signaling in enteric and kidney development.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HECW2 is a HECT-domain E3 ligase with dual ubiquitin and Nedd8 ligase activities that controls the stability of diverse nuclear and cytoplasmic substrates while also functioning as a signaling scaffold. It catalyzes K63-linked ubiquitination of AMOTL1 to stabilize endothelial junctions and sequester YAP in the cytoplasm, and non-degradative ubiquitination of p73 to enhance its transcriptional activity, whereas it targets PCNA, lamin B1, HP1α/β, and ALKBH5 for proteasomal degradation [PMID:12890487, PMID:27498087, PMID:29753763, PMID:30208514, PMID:40520873]. Its Nedd8 ligase activity, dependent on catalytic cysteine C1341, is specifically required for GDNF-stimulated Akt activation and enteric nervous system development, where it scaffolds SHC, Grb2, PI3K, PDK1, and Akt; HECW2-deficient mice accordingly develop intestinal aganglionosis [PMID:27119228, PMID:25555806]. HECW2 itself is a substrate of APC/C-Cdh1, which degrades it during mitotic exit via a destruction box motif, and its depletion prolongs metaphase while its overexpression causes chromosome lagging [PMID:24163370].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing HECW2 as a HECT-domain E3 ligase that paradoxically stabilizes rather than degrades its substrate p73 answered how a ubiquitin ligase could function as a transcriptional co-activator.\",\n      \"evidence\": \"Reciprocal co-IP, in vitro ubiquitination, and transcriptional reporter assays in mammalian cells\",\n      \"pmids\": [\"12890487\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin chain linkage type on p73 not determined\", \"In vivo relevance to p73-dependent apoptosis or differentiation not tested\", \"No structural basis for WW–PY interaction\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying HECW2 as an APC/C-Cdh1 substrate that peaks in mitosis and localizes to spindles revealed cell-cycle-dependent regulation and a mitotic function for this ligase.\",\n      \"evidence\": \"IP-MS identification, destruction box mutagenesis, Cdh1 knockdown/overexpression, immunofluorescence, and mitotic timing assays\",\n      \"pmids\": [\"24163370\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mitotic substrates of HECW2 at the spindle not identified\", \"Mechanism by which overexpression causes chromosome lagging unknown\", \"Functional consequence of destruction box mutation in vivo untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that HECW2-deficient mice develop intestinal aganglionosis via defective GDNF/Akt signaling established a non-redundant developmental role in the enteric nervous system.\",\n      \"evidence\": \"Knockout mouse model with bowel motility, histology, and Akt signaling pathway analysis\",\n      \"pmids\": [\"25555806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the ENS phenotype depends on ubiquitin or Nedd8 ligase activity was unresolved at this point\", \"Cell-autonomous versus non-cell-autonomous contributions not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Distinguishing HECW2's Nedd8 ligase activity (C1341-dependent) from its ubiquitin ligase activity, and showing only the former is required for GDNF/Akt signaling and ENS/kidney development, redefined HECW2 as a dual-function ligase with separable catalytic outputs.\",\n      \"evidence\": \"Active-site mutagenesis, double KO mice, scaffold complex reconstitution with SHC/Grb2/PI3K/PDK1/Akt\",\n      \"pmids\": [\"27119228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nedd8 substrate(s) in the GDNF pathway not identified\", \"Whether Nedd8 ligase activity is relevant beyond ENS/kidney contexts unknown\", \"Structural basis for dual specificity not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showing that HECW2 K63-ubiquitinates AMOTL1 to stabilize it and retain YAP in the cytoplasm connected HECW2 to Hippo pathway regulation and endothelial junction integrity.\",\n      \"evidence\": \"Co-IP, K63-linkage-specific ubiquitination assay, siRNA knockdown, YAP subcellular fractionation, angiogenic sprouting assay\",\n      \"pmids\": [\"27498087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HECW2-AMOTL1 axis operates in non-endothelial tissues untested\", \"Upstream signals controlling HECW2 activity in endothelial cells unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying PCNA and lamin B1 as degradative substrates of HECW2, and linking altered HECW2–lamin A interaction to laminopathy-causing mutations, expanded the substrate repertoire to nuclear envelope and DNA replication machinery.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination, PIP motif identification, proteasome inhibitor experiments, lamin A mutant cell lines\",\n      \"pmids\": [\"29753763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of PCNA degradation for DNA replication or repair not assessed\", \"Whether lamin B1 degradation contributes to laminopathy pathology remains unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating selective ubiquitination and degradation of HP1α and HP1β (but not HP1γ) by HECW2 implicated it in heterochromatin regulation with isoform specificity.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, HECW2 overexpression/knockdown with proteasome inhibitor treatment\",\n      \"pmids\": [\"30208514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional impact on heterochromatin spreading or gene silencing not tested\", \"Basis for HP1 isoform selectivity unknown\", \"Single-lab finding awaits independent confirmation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Localization of HECW2 to nuclear foci in oocytes and zygotes, and its requirement for sperm DNA decondensation and pronucleus formation, established a role in the earliest events of mammalian development.\",\n      \"evidence\": \"Immunofluorescence in oocytes/zygotes, antibody microinjection into oocytes before IVF\",\n      \"pmids\": [\"33030211\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate(s) mediating sperm decondensation not identified\", \"Antibody inhibition approach does not distinguish catalytic from scaffolding functions\", \"Single study with no genetic confirmation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connecting HECW2-mediated lamin B1 degradation to AKT/mTOR activation in colorectal cancer provided a disease-relevant downstream pathway for a previously identified substrate.\",\n      \"evidence\": \"HECW2 knockdown/overexpression, ubiquitination assay, AKT/mTOR pathway analysis, CRC proliferation and chemoresistance assays\",\n      \"pmids\": [\"37781079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking lamin B1 loss to AKT/mTOR activation not delineated\", \"In vivo tumor model confirmation limited\", \"Independent replication needed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of ALKBH5 as a HECW2 substrate linked ubiquitin-mediated regulation to m6A RNA modification and glycolysis in hemangioma, revealing an epitranscriptomic arm of HECW2 function.\",\n      \"evidence\": \"Ubiquitination assay, glycolysis assays, LDHA rescue, in vivo xenograft model in hemangioma endothelial cells\",\n      \"pmids\": [\"40520873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin chain linkage type on ALKBH5 not determined\", \"Whether this pathway operates in normal endothelial physiology unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions include the identity of HECW2's Nedd8 substrate(s) in GDNF signaling, the structural basis for its dual ubiquitin/Nedd8 specificity, how its numerous degradative and non-degradative substrates are prioritized in different cell types, and whether its mitotic spindle association reflects a direct mitotic substrate.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Nedd8 substrate in GDNF/Akt pathway unidentified\", \"No structural model of HECW2 HECT domain or WW domains\", \"Context-dependent substrate selection mechanism unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3, 5, 6, 8, 9]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 3, 4, 5, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 6, 7]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 4, 8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 3, 5, 6, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TP73\", \"AMOTL1\", \"PCNA\", \"LMNB1\", \"LMNA\", \"CBX5\", \"CBX1\", \"ALKBH5\"],\n    \"other_free_text\": []\n  }\n}\n```"}