Affinage

HECW1

E3 ubiquitin-protein ligase HECW1 · UniProt Q76N89

Length
1606 aa
Mass
179.6 kDa
Annotated
2026-06-10
16 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2003 Medium

    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

    PMID:14684739

    Open questions at the time
    • No in vitro reconstitution or mutagenesis of the ubiquitin acceptor site
    • Functional consequence of DVL1 dysfunction not mechanistically resolved at this stage
  2. 2008 Medium

    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

    PMID:18223681

    Open questions at the time
    • Structural basis of the C-terminal p53 interaction not defined
    • How non-catalytic enhancement integrates with ligase activity unclear
  3. 2010 Medium

    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

    PMID:20976258

    Open questions at the time
    • Substrate(s) mediating the degeneration not identified
    • Relationship to mutant SOD1 handling not tested in this model
  4. 2011 High

    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

    PMID:22089131

    Open questions at the time
    • Direct substrate in the NPR-1 pathway not identified
    • Mammalian behavioral correlate not established at this point
  5. 2019 High

    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

    PMID:30849519 PMID:31238008

    Open questions at the time
    • Determinants of cell-type-specific ligase competition (HECW1 vs FBXL19) unresolved
    • Upstream signals coupling PMA/thyroid context to HECW1 activity unclear
  6. 2020 Medium

    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

    PMID:31616916

    Open questions at the time
    • Ubiquitin acceptor site on Scribble not mapped
    • Mechanistic detail limited
  7. 2021 Medium

    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

    PMID:33529121

    Open questions at the time
    • Smad4 acceptor lysine not identified
    • Connection to TGF-β pathway context not dissected
  8. 2023 Low

    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

    PMID:36674783

    Open questions at the time
    • Functional link to TDP-43 mislocalization not mechanistically dissected
    • TDP-43 not shown to be a direct substrate
  9. 2024 Medium

    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

    PMID:38266865 PMID:39615883

    Open questions at the time
    • Acceptor lysines on DVL1 and HIPK2 not mapped
    • Context determining which substrate dominates not defined
  10. 2024 Medium

    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

    PMID:39424023

    Open questions at the time
    • No molecular substrate linked to the learning phenotype
    • Cause of the metabolic shift unexplained
  11. 2025 Medium

    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

    PMID:41193668

    Open questions at the time
    • How NDRG1 enhances the HECW1-substrate interaction structurally unknown
    • Generality of partner-directed substrate selection untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016874 ligase activity 7 GO:0098772 molecular function regulator activity 1
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-392499 Metabolism of proteins 5 R-HSA-162582 Signal Transduction 2
Partners
DVL1HIPK2NDRG1NKX2-1SCRIBSMAD4SOD1TP53

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 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. Co-immunoprecipitation, ubiquitination assay, yeast two-hybrid screening, immunohistochemistry The Journal of biological chemistry Medium 14684739
2008 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. Co-immunoprecipitation, in vitro binding assay, luciferase reporter assay, siRNA knockdown, colony formation assay, flow cytometry Oncogene Medium 18223681
2010 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. Yeast two-hybrid screening, co-immunoprecipitation, luciferase reporter assay Biochemical and biophysical research communications Low 21108931
2010 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. Transgenic mouse model, rotarod/hanging wire/footprint behavioral tests, histology, microglia immunostaining Journal of biomedicine & biotechnology Medium 20976258
2011 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. Neuron-specific rescue experiments, neuron ablation, genetic epistasis analysis, behavioral assays Nature High 22089131
2019 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. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K151R), shRNA knockdown, western blot Cellular signalling High 30849519
2019 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. Overexpression, ubiquitination assay, site-directed mutagenesis, western blot, migration and proliferation assays FASEB journal Medium 31238008
2020 Estrogen upregulates HECW1 expression in endometrial epithelial cells, and HECW1 promotes ubiquitination and degradation of the polarity protein Scribble, disrupting apical-basal polarity. 3D primary cell culture, ubiquitination assay, western blot, GEO dataset screening, in vivo mouse and human tissue analysis Biology of reproduction Medium 31616916
2021 HECW1 promotes ubiquitination and proteasomal degradation of Smad4, reducing its protein (but not mRNA) levels, thereby enhancing proliferation, migration, and invasion of NSCLC cells. Overexpression and knockdown, ubiquitination assay, MG-132 proteasome inhibitor treatment, western blot, migration/invasion assays Biochemistry and cell biology Medium 33529121
2023 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. Immunostaining for subcellular localization, overexpression in neuronal cells, cell viability assay International journal of molecular sciences Low 36674783
2024 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. Co-immunoprecipitation, ubiquitination assay, TOP-flash reporter assay, siRNA/overexpression, in vivo xenograft Experimental cell research Medium 38266865
2024 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. Co-immunoprecipitation, ubiquitination assay, western blot, immunofluorescence, in vivo metastasis model Laboratory investigation Medium 39615883
2024 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. Nedl1 knockout mouse model, behavioral testing (Barnes maze, elevated plus maze, three-chamber test), histology, metabolomics Physiology & behavior Medium 39424023
2025 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. Co-immunoprecipitation, ubiquitination assay, site-directed identification of K223 as ubiquitin acceptor, RNA-seq, in vivo PDX model Acta pharmacologica Sinica Medium 41193668

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 NEDL1, a novel ubiquitin-protein isopeptide ligase for dishevelled-1, targets mutant superoxide dismutase-1. The Journal of biological chemistry 146 14684739
2011 Natural polymorphisms in C. elegans HECW-1 E3 ligase affect pathogen avoidance behaviour. Nature 77 22089131
2010 RNF43 interacts with NEDL1 and regulates p53-mediated transcription. Biochemical and biophysical research communications 53 21108931
2008 A novel HECT-type E3 ubiquitin protein ligase NEDL1 enhances the p53-mediated apoptotic cell death in its catalytic activity-independent manner. Oncogene 51 18223681
2010 Muscle atrophy and motor neuron degeneration in human NEDL1 transgenic mice. Journal of biomedicine & biotechnology 31 20976258
2021 E3 ubiquitin ligase HECW1 promotes the metastasis of non-small cell lung cancer cells through mediating the ubiquitination of Smad4. Biochemistry and cell biology = Biochimie et biologie cellulaire 17 33529121
2020 Estrogen degrades Scribble in endometrial epithelial cells through E3 ubiquitin ligase HECW1 in the development of diffuse adenomyosis†. Biology of reproduction 15 31616916
2019 Two distinct E3 ligases, SCFFBXL19 and HECW1, degrade thyroid transcription factor 1 in normal thyroid epithelial and follicular thyroid carcinoma cells, respectively. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 15 31238008
2024 HECW1 restrains cervical cancer cell growth by promoting DVL1 ubiquitination and downregulating the activation of Wnt/β-catenin signaling. Experimental cell research 8 38266865
2019 The E3 ubiquitin ligase HECW1 targets thyroid transcription factor 1 (TTF1/NKX2.1) for its degradation in the ubiquitin-proteasome system. Cellular signalling 8 30849519
2022 Circular RNA Hecw1 Regulates the Inflammatory Imbalance in Spinal Cord Injury via miR-3551-3p/LRRTM1 Axis. Applied biochemistry and biotechnology 6 35699802
2023 Study of Ubiquitin Pathway Genes in a French Population with Amyotrophic Lateral Sclerosis: Focus on HECW1 Encoding the E3 Ligase NEDL1. International journal of molecular sciences 4 36674783
2024 HECW1-Mediated Ubiquitination of HIPK2 Drives Metastasis in Gastric Cancer Through the AKT Signaling Pathway. Laboratory investigation; a journal of technical methods and pathology 2 39615883
2025 Nedl1 knockout ameliorates cognitive impairment and improves epilepsy threshold in pilocarpine-induced epileptic mice. Acta epileptologica 0 40217560
2025 Magnolin overcomes EGFR TKI resistance in NSCLC by modulation of NDRG1-NRG2-HECW1 pathway. Acta pharmacologica Sinica 0 41193668
2024 Nedl1 knockout impaired the learning and memory of mice. Physiology & behavior 0 39424023

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