{"gene":"ASB2","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2004,"finding":"ASB2 interacts with the Elongin BC complex and assembles with Cullin5 and Rbx1 to form an ECS-type E3 ubiquitin ligase complex that stimulates polyubiquitination by the E2 ubiquitin-conjugating enzyme Ubc5.","method":"Biochemical reconstitution of the E3 ligase complex; co-immunoprecipitation; in vitro ubiquitination assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted E3 ligase complex in vitro with functional ubiquitination assay, replicated across multiple papers in the corpus","pmids":["15590664"],"is_preprint":false},{"year":2008,"finding":"ASB2 targets filamin A and filamin B for proteasomal degradation; knockdown of endogenous ASB2 in leukemia cells delays retinoic acid-induced differentiation and filamin degradation, while ASB2 expression induces filamin degradation and inhibits cell spreading.","method":"ASB2 knockdown (siRNA) and overexpression in leukemia cells; Western blot for filamin levels; cell spreading assay; proteasome inhibitor rescue","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal loss-of-function and gain-of-function with defined cellular phenotype, replicated by multiple subsequent studies (PMIDs 33717133, 33993984)","pmids":["18799729"],"is_preprint":false},{"year":2001,"finding":"ASB2 expression in myeloid leukemia cells induces growth inhibition and chromatin condensation, recapitulating early commitment events of retinoic acid-induced differentiation; ASB2 mRNA is a retinoic acid-induced target gene in APL cells with expression enhanced by PML-RARα.","method":"Ectopic expression of ASB2 in myeloid leukemia cells; cell cycle and chromatin condensation analysis; mRNA expression assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with defined cellular phenotype, single lab, confirmed in parallel by PMID 11566180","pmids":["11682484"],"is_preprint":false},{"year":2001,"finding":"RARα binds to a functional RARE/RXRE element in the ASB2 gene promoter, directly driving ASB2 transcription in response to all-trans retinoic acid.","method":"Chromatin immunoprecipitation (RARα binding to ASB2 promoter); luciferase reporter assay of RARE/RXRE element","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding and functional reporter assay, single lab, two orthogonal methods","pmids":["11566180"],"is_preprint":false},{"year":2010,"finding":"Notch signaling transcriptionally activates ASB2, which promotes ubiquitination and degradation of E2A (via Skp2) and JAK2 (by direct binding); ASB2 bridges non-canonical cullin-based complexes by interacting with Elongin B/C–Cul5 and also with the F-box protein Skp2–Skp1–Cul1, and dominant-negative Cul1 or Cul5, or their siRNA knockdown, protects E2A and JAK2 from ASB2-mediated degradation.","method":"Co-immunoprecipitation; dominant-negative mutant analysis; siRNA knockdown of Cul1/Cul5; Western blot for substrate levels","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus dominant-negative and siRNA epistasis, single lab, multiple orthogonal methods","pmids":["21119685"],"is_preprint":false},{"year":2018,"finding":"ASB2α induces degradation of IκBα, leading to dissociation of IκBα from NF-κB and consequent NF-κB activation in T-ALL cells downstream of Notch1.","method":"Lentiviral overexpression and shRNA knockdown of ASB2 in T-ALL cell lines; Western blot; co-immunoprecipitation; cell proliferation and apoptosis assays","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined pathway placement (IκBα degradation → NF-κB), single lab, two orthogonal methods","pmids":["30116272"],"is_preprint":false},{"year":2021,"finding":"ASB2 acts as the E3 ubiquitin ligase for SMAD9 (but not SMAD1 or SMAD5), targeting it for proteasomal degradation; this regulates BMP signaling during cardiogenesis, and Asb2 knockdown in zebrafish causes thinned ventricular wall and dilated ventricle that are rescued by simultaneous Smad9 knockdown.","method":"In vitro ubiquitination assay; co-immunoprecipitation; Asb2 and Smad9 morpholino knockdown in zebrafish with epistasis rescue experiment","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro ubiquitination assay plus genetic epistasis (double knockdown rescue) in zebrafish, multiple orthogonal methods","pmids":["34845242"],"is_preprint":false},{"year":2021,"finding":"AHR directly regulates the ASB2 gene promoter, and AHR agonist (FICZ) induces ASB2-dependent filamin A degradation in NK cells; ASB2 knockdown inhibits filamin A degradation and reduces NK cell migration, while filamin A reduction restores migration capacity.","method":"ChIP of AHR at ASB2 promoter; ASB2 knockdown in primary human NK cells; Western blot for filamin A; migration/invasion assays; Ahr-/- mouse NK cells","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus loss-of-function with defined cellular phenotype (migration), single lab, multiple orthogonal methods","pmids":["33717133"],"is_preprint":false},{"year":2021,"finding":"ASB2 downregulation in GCB DLBCL cells inhibits the alternative NF-κB pathway via downregulation of RelB and increased IκBα, and ASB2 is a direct transcriptional target of FLI1 (identified by ChIP-seq and RNA-seq after FLI1 silencing).","method":"FLI1 ChIP-seq; RNA-seq after FLI1 siRNA knockdown; ASB2 siRNA knockdown with Western blot for NF-κB components","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus RNA-seq plus functional knockdown, single lab, multiple orthogonal methods","pmids":["34763718"],"is_preprint":false},{"year":2016,"finding":"ASB2 expression in skeletal muscle is repressed by follistatin (a TGF-β network modulator), and forced ASB2 overexpression reduces skeletal muscle mass, establishing ASB2 as a negative regulator of muscle mass downstream of TGF-β signaling.","method":"Quantitative proteomics and transcriptomics of follistatin-treated muscles; AAV-mediated overexpression of ASB2 in mouse skeletal muscle with muscle mass quantification","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo overexpression with defined phenotype (reduced muscle mass), supported by proteomic/transcriptomic data, single lab","pmids":["27182554"],"is_preprint":false},{"year":2025,"finding":"Skeletal muscle-specific deletion of Asb2 increases muscle mass and strength; desmin was identified as a substrate of the ASB2 E3 ligase, with its preservation proposed to mediate the muscle hypertrophy phenotype.","method":"Conditional Asb2 knockout mice (Acta1-Cre); grip strength and body composition measurements; transcriptomic analysis; siRNA studies identifying desmin as an ASB2 substrate","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo muscle-specific KO with defined phenotype plus substrate identification by siRNA, single lab, two orthogonal methods","pmids":["40641155"],"is_preprint":false},{"year":2026,"finding":"The autophagy receptor NDP52 recruits ASB2 to bind NOX4, mediating K48-linked ubiquitination and autophagic/proteasomal degradation of NOX4, thereby suppressing ferroptosis in cardiomyocytes; this was demonstrated in isoproterenol-induced (in vitro) and TAC-induced (in vivo) heart failure models.","method":"Co-immunoprecipitation; molecular docking; pharmacological and genetic (knockdown/knockout) approaches in cardiomyocytes; in vivo TAC model","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo genetic/pharmacological validation, single lab, multiple orthogonal approaches","pmids":["41662915"],"is_preprint":false},{"year":2024,"finding":"ASB2 E3 ligase activity mediates K48-linked ubiquitination and degradation of CRYAB p.Arg120Gly aggregates in cardiomyocytes downstream of JAK1-STAT3 signaling; Asb2 knockdown abolishes the ability of ruxolitinib (JAK1/2 inhibitor) to clear CRYAB aggregates via the ubiquitin-proteasome system.","method":"siRNA knockdown of Asb2 in neonatal rat ventricular myocytes and hiPSC-CMs; aggregate quantification; RNAseq showing upregulation of Asb2 after Jak1 siRNA treatment; UPS inhibitor rescue experiments","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, genetic epistasis by knockdown without direct biochemical reconstitution of ASB2-CRYAB ubiquitination","pmids":["bio_10.1101_2024.10.11.615348"],"is_preprint":true},{"year":2024,"finding":"CHPF regulates SMAD9 activity via its mediation of ASB2; ASB2 ubiquitinates SMAD9, and CHPF's regulatory effect on SMAD9 in colorectal cancer cells is exerted through modulation of ASB2.","method":"Co-immunoprecipitation; knockdown experiments; Western blot for SMAD9 ubiquitination","journal":"Histology and histopathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP without full mechanistic characterization of the ASB2-SMAD9 interaction beyond PMID 34845242","pmids":["38591191"],"is_preprint":false}],"current_model":"ASB2 is the substrate-recognition (specificity) subunit of an ECS-type E3 ubiquitin ligase complex that assembles with Elongin B/C, Cullin5, and Rbx1 to drive K48-linked polyubiquitination and proteasomal degradation of substrates including filamin A, filamin B, SMAD9, JAK2, E2A (via Skp2), IκBα, NOX4, and desmin; its transcription is directly induced by retinoic acid (via RARα), Notch signaling, AHR, and FLI1, allowing it to regulate hematopoietic differentiation, actin remodeling and cell spreading, BMP signaling during cardiogenesis, NF-κB pathway activity, NK cell migration, and skeletal muscle mass."},"narrative":{"mechanistic_narrative":"ASB2 is the substrate-recognition subunit of an ECS-type (Elongin BC–Cullin5–Rbx1) E3 ubiquitin ligase that drives polyubiquitination of bound substrates and their proteasomal degradation, coupling extracellular and developmental signals to targeted proteolysis [PMID:15590664]. Through this complex ASB2 recognizes a substrate repertoire that includes the actin cross-linkers filamin A and filamin B, whose degradation inhibits cell spreading and underlies retinoic acid-induced myeloid differentiation [PMID:18799729], the BMP effector SMAD9, the cytoskeletal protein desmin, and NOX4 [PMID:34845242, PMID:40641155, PMID:41662915]. ASB2 can also bridge non-canonical cullin assemblies, interacting with both Elongin BC–Cul5 and Skp2–Skp1–Cul1 to mediate degradation of E2A and JAK2 [PMID:21119685]. Its transcription is directly induced by multiple signaling inputs—retinoic acid via RARα binding to a promoter RARE/RXRE element [PMID:11566180], Notch [PMID:30116272], the AHR [PMID:33717133], and FLI1 [PMID:34763718]—positioning ASB2 as a signal-responsive effector that regulates hematopoietic differentiation [PMID:18799729, PMID:11682484], NF-κB pathway activity through IκBα and RelB control [PMID:30116272, PMID:34763718], NK cell migration [PMID:33717133], BMP signaling during cardiogenesis [PMID:34845242], and skeletal muscle mass, where it acts as a negative regulator downstream of TGF-β/follistatin [PMID:27182554, PMID:40641155].","teleology":[{"year":2001,"claim":"Established that ASB2 is a retinoic acid-responsive gene whose expression alone can recapitulate early commitment events of myeloid differentiation, linking it functionally to the RAR pathway before its biochemical activity was known.","evidence":"Ectopic ASB2 expression in myeloid leukemia cells with cell cycle/chromatin analysis; RARα ChIP and RARE/RXRE luciferase reporter on the ASB2 promoter","pmids":["11682484","11566180"],"confidence":"Medium","gaps":["Molecular activity of ASB2 protein not yet defined","Direct substrates unknown at this stage"]},{"year":2004,"claim":"Defined the core biochemical identity of ASB2 as the specificity subunit of an ECS-type E3 ligase, answering how it acts mechanistically.","evidence":"In vitro reconstitution of ASB2–Elongin BC–Cul5–Rbx1 complex with Ubc5-dependent ubiquitination assay and co-IP","pmids":["15590664"],"confidence":"High","gaps":["No physiological substrate identified in this study","Ubiquitin linkage type not characterized here"]},{"year":2008,"claim":"Identified filamin A/B as the first physiological substrates, connecting ASB2 ligase activity to actin remodeling and the differentiation phenotype previously observed.","evidence":"Reciprocal siRNA knockdown and overexpression in leukemia cells with filamin Western blots, cell spreading assays, and proteasome inhibitor rescue","pmids":["18799729"],"confidence":"High","gaps":["Substrate recognition determinants not mapped","Whether filamin degradation fully accounts for differentiation effects unresolved"]},{"year":2010,"claim":"Extended the substrate range to E2A and JAK2 and showed ASB2 can bridge distinct cullin scaffolds (Cul1 via Skp2 and Cul5), revealing unexpected complex versatility downstream of Notch.","evidence":"Co-IP, dominant-negative Cul1/Cul5, and siRNA epistasis with substrate Western blots","pmids":["21119685"],"confidence":"Medium","gaps":["Dual cullin model relies on a single lab","Direct ubiquitination of E2A/JAK2 not reconstituted in vitro"]},{"year":2018,"claim":"Placed ASB2 in the NF-κB axis by showing it degrades IκBα to activate NF-κB downstream of Notch1 in T-ALL.","evidence":"Lentiviral overexpression and shRNA knockdown in T-ALL lines with co-IP, Western blot, and proliferation/apoptosis assays","pmids":["30116272"],"confidence":"Medium","gaps":["IκBα ubiquitination by ASB2 not directly reconstituted","Single cell-type context"]},{"year":2021,"claim":"Demonstrated substrate-selective ubiquitination of SMAD9 (not SMAD1/5) with in vivo developmental consequence, establishing an ASB2 role in BMP signaling and cardiogenesis.","evidence":"In vitro ubiquitination, co-IP, and zebrafish Asb2/Smad9 morpholino double-knockdown epistasis rescue","pmids":["34845242"],"confidence":"High","gaps":["Basis of SMAD9 vs SMAD1/5 selectivity unknown","Mammalian cardiac requirement not tested here"]},{"year":2021,"claim":"Showed AHR and FLI1 as additional direct transcriptional drivers of ASB2, expanding its signal-responsive regulation and tying it to NK cell migration and DLBCL NF-κB biology.","evidence":"AHR and FLI1 ChIP/ChIP-seq at the ASB2 promoter, RNA-seq, and ASB2 knockdown with migration assays and NF-κB component Western blots","pmids":["33717133","34763718"],"confidence":"Medium","gaps":["RelB regulation mechanism (direct vs indirect) not resolved","Single-lab findings per context"]},{"year":2025,"claim":"Provided in vivo genetic proof that ASB2 limits skeletal muscle mass and identified desmin as the relevant substrate, refining its role as a TGF-β/follistatin-controlled negative regulator of muscle.","evidence":"Muscle-specific Asb2 conditional knockout mice with strength/composition phenotyping plus siRNA-based desmin substrate identification; earlier AAV overexpression establishing the muscle-mass phenotype","pmids":["40641155","27182554"],"confidence":"Medium","gaps":["Direct desmin ubiquitination not reconstituted in vitro","Contribution of desmin vs other substrates to hypertrophy not quantified"]},{"year":2026,"claim":"Revealed receptor-mediated substrate recruitment, with NDP52 delivering NOX4 to ASB2 for K48-linked degradation that suppresses cardiomyocyte ferroptosis.","evidence":"Co-IP, molecular docking, and genetic/pharmacological manipulation in cardiomyocytes plus in vivo TAC heart failure model","pmids":["41662915"],"confidence":"Medium","gaps":["Mechanism of NDP52-ASB2 cooperation not structurally defined","Relative contribution of autophagic vs proteasomal degradation unclear"]},{"year":null,"claim":"How ASB2 achieves substrate selectivity across its diverse targets (filamins, SMAD9, JAK2, NOX4, desmin) and whether a unifying recognition motif or adaptor logic governs target choice remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ASB2–substrate engagement","No defined degron consensus across substrates","Tissue-specific substrate prioritization mechanism unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,6,10,11]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,6,11]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,6]}],"complexes":["ECS (Elongin BC–Cullin5–Rbx1) E3 ubiquitin ligase","Skp2–Skp1–Cul1 (SCF) complex"],"partners":["ELOB","ELOC","CUL5","RBX1","CUL1","SKP2","NDP52"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96Q27","full_name":"Ankyrin repeat and SOCS box protein 2","aliases":[],"length_aa":635,"mass_kda":70.2,"function":"Substrate-recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:15590664, PubMed:16325183). Mediates Notch-induced ubiquitination and degradation of substrates including TCF3/E2A and JAK2 (PubMed:21119685). Required during embryonic heart development for complete heart looping (By similarity). Required for cardiomyocyte differentiation (PubMed:32179481). Specifically promotes the ubiquitination of SMAD9 and targets it for proteasomal degradation, leading to avoid excessive accumulation of SMAD9 (PubMed:34845242). Plays a role in the regulation of NK-cell migration by modulating protein levels of filamin A/FLNA via regulation of its ubiquitination and proteasome degradation (By similarity) Involved in myogenic differentiation and targets filamin FLNB for proteasomal degradation but not filamin FLNA (PubMed:19300455). Also targets DES for proteasomal degradation (By similarity). Acts as a negative regulator of skeletal muscle mass (By similarity) Targets filamins FLNA and FLNB for proteasomal degradation (PubMed:21737450, PubMed:22916308, PubMed:24044920, PubMed:24052262). This leads to enhanced adhesion of hematopoietic cells to fibronectin (PubMed:21737450). Required for FLNA degradation in immature cardiomyocytes which is necessary for actin cytoskeleton remodeling, leading to proper organization of myofibrils and function of mature cardiomyocytes (By similarity). Required for degradation of FLNA and FLNB in immature dendritic cells (DC) which enhances immature DC migration by promoting DC podosome formation and DC-mediated degradation of the extracellular matrix (By similarity). Does not promote proteasomal degradation of tyrosine-protein kinases JAK1 or JAK2 in hematopoietic cells (PubMed:22916308)","subcellular_location":"Cytoplasm, myofibril, sarcomere, Z line","url":"https://www.uniprot.org/uniprotkb/Q96Q27/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ASB2","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/ASB2","total_profiled":1310},"omim":[{"mim_id":"620912","title":"MICAL-LIKE PROTEIN 2; MICALL2","url":"https://www.omim.org/entry/620912"},{"mim_id":"605759","title":"ANKYRIN REPEAT- AND SOCS BOX-CONTAINING PROTEIN 2; ASB2","url":"https://www.omim.org/entry/605759"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli fibrillar center","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":494.8},{"tissue":"tongue","ntpm":147.3}],"url":"https://www.proteinatlas.org/search/ASB2"},"hgnc":{"alias_symbol":["ASB-2"],"prev_symbol":[]},"alphafold":{"accession":"Q96Q27","domains":[{"cath_id":"1.25.40.20","chopping":"218-321","consensus_level":"medium","plddt":97.8929,"start":218,"end":321}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96Q27","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96Q27-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96Q27-F1-predicted_aligned_error_v6.png","plddt_mean":83.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ASB2","jax_strain_url":"https://www.jax.org/strain/search?query=ASB2"},"sequence":{"accession":"Q96Q27","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96Q27.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96Q27/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96Q27"}},"corpus_meta":[{"pmid":"11682484","id":"PMC_11682484","title":"ASB-2 inhibits growth and promotes commitment in myeloid leukemia cells.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11682484","citation_count":77,"is_preprint":false},{"pmid":"18799729","id":"PMC_18799729","title":"ASB2 targets filamins A and B to proteasomal degradation.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18799729","citation_count":76,"is_preprint":false},{"pmid":"15590664","id":"PMC_15590664","title":"ASB2 is an Elongin BC-interacting protein that can assemble with Cullin 5 and Rbx1 to reconstitute an E3 ubiquitin ligase complex.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15590664","citation_count":69,"is_preprint":false},{"pmid":"11566180","id":"PMC_11566180","title":"ATRA-regulated Asb-2 gene induced in differentiation of HL-60 leukemia cells.","date":"2001","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/11566180","citation_count":51,"is_preprint":false},{"pmid":"11111040","id":"PMC_11111040","title":"Cloning and characterization of the genes encoding the ankyrin repeat and SOCS box-containing proteins Asb-1, Asb-2, Asb-3 and Asb-4.","date":"2000","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11111040","citation_count":48,"is_preprint":false},{"pmid":"27182554","id":"PMC_27182554","title":"Integrated expression analysis of muscle hypertrophy identifies Asb2 as a negative regulator of muscle mass.","date":"2016","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/27182554","citation_count":45,"is_preprint":false},{"pmid":"21119685","id":"PMC_21119685","title":"Notch-induced Asb2 expression promotes protein ubiquitination by forming non-canonical E3 ligase complexes.","date":"2010","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/21119685","citation_count":43,"is_preprint":false},{"pmid":"33717133","id":"PMC_33717133","title":"AHR Regulates NK Cell Migration via ASB2-Mediated Ubiquitination of Filamin A.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33717133","citation_count":27,"is_preprint":false},{"pmid":"30116272","id":"PMC_30116272","title":"The notch pathway promotes NF-κB activation through Asb2 in T cell acute lymphoblastic leukemia cells.","date":"2018","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/30116272","citation_count":23,"is_preprint":false},{"pmid":"29955039","id":"PMC_29955039","title":"High-throughput analysis of the RNA-induced silencing complex in myotonic dystrophy type 1 patients identifies the dysregulation of miR-29c and its target ASB2.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29955039","citation_count":16,"is_preprint":false},{"pmid":"34763718","id":"PMC_34763718","title":"ASB2 is a direct target of FLI1 that sustains NF-κB pathway activation in germinal center-derived diffuse large B-cell lymphoma.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/34763718","citation_count":12,"is_preprint":false},{"pmid":"34845242","id":"PMC_34845242","title":"ASB2 is a novel E3 ligase of SMAD9 required for cardiogenesis.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34845242","citation_count":10,"is_preprint":false},{"pmid":"33993984","id":"PMC_33993984","title":"Heart defects and embryonic lethality in Asb2 knock out mice correlate with placental defects.","date":"2021","source":"Cells & development","url":"https://pubmed.ncbi.nlm.nih.gov/33993984","citation_count":8,"is_preprint":false},{"pmid":"40641155","id":"PMC_40641155","title":"Skeletal Muscle-Specific Deletion of E3 Ligase Asb2 Enhances Muscle Mass and Strength.","date":"2025","source":"Journal of cachexia, sarcopenia and muscle","url":"https://pubmed.ncbi.nlm.nih.gov/40641155","citation_count":4,"is_preprint":false},{"pmid":"38591191","id":"PMC_38591191","title":"Chondroitin polymerizing factor (CHPF) promotes the progression of colorectal cancer through ASB2-mediated ubiquitylation of SMAD9.","date":"2024","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/38591191","citation_count":4,"is_preprint":false},{"pmid":"27342488","id":"PMC_27342488","title":"[Aberrant Expression Notch1 and Asb2 mRNA in Bone Marrow from Patients with P210(+) Chronic Myeloid Leukemia].","date":"2016","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/27342488","citation_count":1,"is_preprint":false},{"pmid":"41662915","id":"PMC_41662915","title":"The autophagy receptor NDP52 recruits the E3 ligase ASB2 to mediate NOX4 degradation, suppressing cardiomyocyte ferroptosis and ameliorating heart failure.","date":"2026","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41662915","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.11.615348","title":"Ruxolitinib clears CRYAB p.Arg120Gly aggregates through the ubiquitin-proteasome system","date":"2024-10-12","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.11.615348","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11417,"output_tokens":3492,"usd":0.043315,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11142,"output_tokens":3265,"usd":0.068668,"stage2_stop_reason":"end_turn"},"total_usd":0.111983,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"ASB2 interacts with the Elongin BC complex and assembles with Cullin5 and Rbx1 to form an ECS-type E3 ubiquitin ligase complex that stimulates polyubiquitination by the E2 ubiquitin-conjugating enzyme Ubc5.\",\n      \"method\": \"Biochemical reconstitution of the E3 ligase complex; co-immunoprecipitation; in vitro ubiquitination assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted E3 ligase complex in vitro with functional ubiquitination assay, replicated across multiple papers in the corpus\",\n      \"pmids\": [\"15590664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ASB2 targets filamin A and filamin B for proteasomal degradation; knockdown of endogenous ASB2 in leukemia cells delays retinoic acid-induced differentiation and filamin degradation, while ASB2 expression induces filamin degradation and inhibits cell spreading.\",\n      \"method\": \"ASB2 knockdown (siRNA) and overexpression in leukemia cells; Western blot for filamin levels; cell spreading assay; proteasome inhibitor rescue\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal loss-of-function and gain-of-function with defined cellular phenotype, replicated by multiple subsequent studies (PMIDs 33717133, 33993984)\",\n      \"pmids\": [\"18799729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ASB2 expression in myeloid leukemia cells induces growth inhibition and chromatin condensation, recapitulating early commitment events of retinoic acid-induced differentiation; ASB2 mRNA is a retinoic acid-induced target gene in APL cells with expression enhanced by PML-RARα.\",\n      \"method\": \"Ectopic expression of ASB2 in myeloid leukemia cells; cell cycle and chromatin condensation analysis; mRNA expression assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with defined cellular phenotype, single lab, confirmed in parallel by PMID 11566180\",\n      \"pmids\": [\"11682484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"RARα binds to a functional RARE/RXRE element in the ASB2 gene promoter, directly driving ASB2 transcription in response to all-trans retinoic acid.\",\n      \"method\": \"Chromatin immunoprecipitation (RARα binding to ASB2 promoter); luciferase reporter assay of RARE/RXRE element\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding and functional reporter assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"11566180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Notch signaling transcriptionally activates ASB2, which promotes ubiquitination and degradation of E2A (via Skp2) and JAK2 (by direct binding); ASB2 bridges non-canonical cullin-based complexes by interacting with Elongin B/C–Cul5 and also with the F-box protein Skp2–Skp1–Cul1, and dominant-negative Cul1 or Cul5, or their siRNA knockdown, protects E2A and JAK2 from ASB2-mediated degradation.\",\n      \"method\": \"Co-immunoprecipitation; dominant-negative mutant analysis; siRNA knockdown of Cul1/Cul5; Western blot for substrate levels\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus dominant-negative and siRNA epistasis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"21119685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ASB2α induces degradation of IκBα, leading to dissociation of IκBα from NF-κB and consequent NF-κB activation in T-ALL cells downstream of Notch1.\",\n      \"method\": \"Lentiviral overexpression and shRNA knockdown of ASB2 in T-ALL cell lines; Western blot; co-immunoprecipitation; cell proliferation and apoptosis assays\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined pathway placement (IκBα degradation → NF-κB), single lab, two orthogonal methods\",\n      \"pmids\": [\"30116272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ASB2 acts as the E3 ubiquitin ligase for SMAD9 (but not SMAD1 or SMAD5), targeting it for proteasomal degradation; this regulates BMP signaling during cardiogenesis, and Asb2 knockdown in zebrafish causes thinned ventricular wall and dilated ventricle that are rescued by simultaneous Smad9 knockdown.\",\n      \"method\": \"In vitro ubiquitination assay; co-immunoprecipitation; Asb2 and Smad9 morpholino knockdown in zebrafish with epistasis rescue experiment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro ubiquitination assay plus genetic epistasis (double knockdown rescue) in zebrafish, multiple orthogonal methods\",\n      \"pmids\": [\"34845242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AHR directly regulates the ASB2 gene promoter, and AHR agonist (FICZ) induces ASB2-dependent filamin A degradation in NK cells; ASB2 knockdown inhibits filamin A degradation and reduces NK cell migration, while filamin A reduction restores migration capacity.\",\n      \"method\": \"ChIP of AHR at ASB2 promoter; ASB2 knockdown in primary human NK cells; Western blot for filamin A; migration/invasion assays; Ahr-/- mouse NK cells\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus loss-of-function with defined cellular phenotype (migration), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33717133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ASB2 downregulation in GCB DLBCL cells inhibits the alternative NF-κB pathway via downregulation of RelB and increased IκBα, and ASB2 is a direct transcriptional target of FLI1 (identified by ChIP-seq and RNA-seq after FLI1 silencing).\",\n      \"method\": \"FLI1 ChIP-seq; RNA-seq after FLI1 siRNA knockdown; ASB2 siRNA knockdown with Western blot for NF-κB components\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus RNA-seq plus functional knockdown, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34763718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ASB2 expression in skeletal muscle is repressed by follistatin (a TGF-β network modulator), and forced ASB2 overexpression reduces skeletal muscle mass, establishing ASB2 as a negative regulator of muscle mass downstream of TGF-β signaling.\",\n      \"method\": \"Quantitative proteomics and transcriptomics of follistatin-treated muscles; AAV-mediated overexpression of ASB2 in mouse skeletal muscle with muscle mass quantification\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo overexpression with defined phenotype (reduced muscle mass), supported by proteomic/transcriptomic data, single lab\",\n      \"pmids\": [\"27182554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Skeletal muscle-specific deletion of Asb2 increases muscle mass and strength; desmin was identified as a substrate of the ASB2 E3 ligase, with its preservation proposed to mediate the muscle hypertrophy phenotype.\",\n      \"method\": \"Conditional Asb2 knockout mice (Acta1-Cre); grip strength and body composition measurements; transcriptomic analysis; siRNA studies identifying desmin as an ASB2 substrate\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo muscle-specific KO with defined phenotype plus substrate identification by siRNA, single lab, two orthogonal methods\",\n      \"pmids\": [\"40641155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The autophagy receptor NDP52 recruits ASB2 to bind NOX4, mediating K48-linked ubiquitination and autophagic/proteasomal degradation of NOX4, thereby suppressing ferroptosis in cardiomyocytes; this was demonstrated in isoproterenol-induced (in vitro) and TAC-induced (in vivo) heart failure models.\",\n      \"method\": \"Co-immunoprecipitation; molecular docking; pharmacological and genetic (knockdown/knockout) approaches in cardiomyocytes; in vivo TAC model\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo genetic/pharmacological validation, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"41662915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ASB2 E3 ligase activity mediates K48-linked ubiquitination and degradation of CRYAB p.Arg120Gly aggregates in cardiomyocytes downstream of JAK1-STAT3 signaling; Asb2 knockdown abolishes the ability of ruxolitinib (JAK1/2 inhibitor) to clear CRYAB aggregates via the ubiquitin-proteasome system.\",\n      \"method\": \"siRNA knockdown of Asb2 in neonatal rat ventricular myocytes and hiPSC-CMs; aggregate quantification; RNAseq showing upregulation of Asb2 after Jak1 siRNA treatment; UPS inhibitor rescue experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, genetic epistasis by knockdown without direct biochemical reconstitution of ASB2-CRYAB ubiquitination\",\n      \"pmids\": [\"bio_10.1101_2024.10.11.615348\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CHPF regulates SMAD9 activity via its mediation of ASB2; ASB2 ubiquitinates SMAD9, and CHPF's regulatory effect on SMAD9 in colorectal cancer cells is exerted through modulation of ASB2.\",\n      \"method\": \"Co-immunoprecipitation; knockdown experiments; Western blot for SMAD9 ubiquitination\",\n      \"journal\": \"Histology and histopathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP without full mechanistic characterization of the ASB2-SMAD9 interaction beyond PMID 34845242\",\n      \"pmids\": [\"38591191\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ASB2 is the substrate-recognition (specificity) subunit of an ECS-type E3 ubiquitin ligase complex that assembles with Elongin B/C, Cullin5, and Rbx1 to drive K48-linked polyubiquitination and proteasomal degradation of substrates including filamin A, filamin B, SMAD9, JAK2, E2A (via Skp2), IκBα, NOX4, and desmin; its transcription is directly induced by retinoic acid (via RARα), Notch signaling, AHR, and FLI1, allowing it to regulate hematopoietic differentiation, actin remodeling and cell spreading, BMP signaling during cardiogenesis, NF-κB pathway activity, NK cell migration, and skeletal muscle mass.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ASB2 is the substrate-recognition subunit of an ECS-type (Elongin BC–Cullin5–Rbx1) E3 ubiquitin ligase that drives polyubiquitination of bound substrates and their proteasomal degradation, coupling extracellular and developmental signals to targeted proteolysis [#0]. Through this complex ASB2 recognizes a substrate repertoire that includes the actin cross-linkers filamin A and filamin B, whose degradation inhibits cell spreading and underlies retinoic acid-induced myeloid differentiation [#1], the BMP effector SMAD9, the cytoskeletal protein desmin, and NOX4 [#6, #10, #11]. ASB2 can also bridge non-canonical cullin assemblies, interacting with both Elongin BC–Cul5 and Skp2–Skp1–Cul1 to mediate degradation of E2A and JAK2 [#4]. Its transcription is directly induced by multiple signaling inputs—retinoic acid via RARα binding to a promoter RARE/RXRE element [#3], Notch [#5], the AHR [#7], and FLI1 [#8]—positioning ASB2 as a signal-responsive effector that regulates hematopoietic differentiation [#1, #2], NF-κB pathway activity through IκBα and RelB control [#5, #8], NK cell migration [#7], BMP signaling during cardiogenesis [#6], and skeletal muscle mass, where it acts as a negative regulator downstream of TGF-β/follistatin [#9, #10].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that ASB2 is a retinoic acid-responsive gene whose expression alone can recapitulate early commitment events of myeloid differentiation, linking it functionally to the RAR pathway before its biochemical activity was known.\",\n      \"evidence\": \"Ectopic ASB2 expression in myeloid leukemia cells with cell cycle/chromatin analysis; RARα ChIP and RARE/RXRE luciferase reporter on the ASB2 promoter\",\n      \"pmids\": [\"11682484\", \"11566180\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular activity of ASB2 protein not yet defined\", \"Direct substrates unknown at this stage\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined the core biochemical identity of ASB2 as the specificity subunit of an ECS-type E3 ligase, answering how it acts mechanistically.\",\n      \"evidence\": \"In vitro reconstitution of ASB2–Elongin BC–Cul5–Rbx1 complex with Ubc5-dependent ubiquitination assay and co-IP\",\n      \"pmids\": [\"15590664\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No physiological substrate identified in this study\", \"Ubiquitin linkage type not characterized here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified filamin A/B as the first physiological substrates, connecting ASB2 ligase activity to actin remodeling and the differentiation phenotype previously observed.\",\n      \"evidence\": \"Reciprocal siRNA knockdown and overexpression in leukemia cells with filamin Western blots, cell spreading assays, and proteasome inhibitor rescue\",\n      \"pmids\": [\"18799729\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate recognition determinants not mapped\", \"Whether filamin degradation fully accounts for differentiation effects unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended the substrate range to E2A and JAK2 and showed ASB2 can bridge distinct cullin scaffolds (Cul1 via Skp2 and Cul5), revealing unexpected complex versatility downstream of Notch.\",\n      \"evidence\": \"Co-IP, dominant-negative Cul1/Cul5, and siRNA epistasis with substrate Western blots\",\n      \"pmids\": [\"21119685\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dual cullin model relies on a single lab\", \"Direct ubiquitination of E2A/JAK2 not reconstituted in vitro\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed ASB2 in the NF-κB axis by showing it degrades IκBα to activate NF-κB downstream of Notch1 in T-ALL.\",\n      \"evidence\": \"Lentiviral overexpression and shRNA knockdown in T-ALL lines with co-IP, Western blot, and proliferation/apoptosis assays\",\n      \"pmids\": [\"30116272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IκBα ubiquitination by ASB2 not directly reconstituted\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated substrate-selective ubiquitination of SMAD9 (not SMAD1/5) with in vivo developmental consequence, establishing an ASB2 role in BMP signaling and cardiogenesis.\",\n      \"evidence\": \"In vitro ubiquitination, co-IP, and zebrafish Asb2/Smad9 morpholino double-knockdown epistasis rescue\",\n      \"pmids\": [\"34845242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis of SMAD9 vs SMAD1/5 selectivity unknown\", \"Mammalian cardiac requirement not tested here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed AHR and FLI1 as additional direct transcriptional drivers of ASB2, expanding its signal-responsive regulation and tying it to NK cell migration and DLBCL NF-κB biology.\",\n      \"evidence\": \"AHR and FLI1 ChIP/ChIP-seq at the ASB2 promoter, RNA-seq, and ASB2 knockdown with migration assays and NF-κB component Western blots\",\n      \"pmids\": [\"33717133\", \"34763718\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RelB regulation mechanism (direct vs indirect) not resolved\", \"Single-lab findings per context\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided in vivo genetic proof that ASB2 limits skeletal muscle mass and identified desmin as the relevant substrate, refining its role as a TGF-β/follistatin-controlled negative regulator of muscle.\",\n      \"evidence\": \"Muscle-specific Asb2 conditional knockout mice with strength/composition phenotyping plus siRNA-based desmin substrate identification; earlier AAV overexpression establishing the muscle-mass phenotype\",\n      \"pmids\": [\"40641155\", \"27182554\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct desmin ubiquitination not reconstituted in vitro\", \"Contribution of desmin vs other substrates to hypertrophy not quantified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealed receptor-mediated substrate recruitment, with NDP52 delivering NOX4 to ASB2 for K48-linked degradation that suppresses cardiomyocyte ferroptosis.\",\n      \"evidence\": \"Co-IP, molecular docking, and genetic/pharmacological manipulation in cardiomyocytes plus in vivo TAC heart failure model\",\n      \"pmids\": [\"41662915\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of NDP52-ASB2 cooperation not structurally defined\", \"Relative contribution of autophagic vs proteasomal degradation unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ASB2 achieves substrate selectivity across its diverse targets (filamins, SMAD9, JAK2, NOX4, desmin) and whether a unifying recognition motif or adaptor logic governs target choice remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ASB2–substrate engagement\", \"No defined degron consensus across substrates\", \"Tissue-specific substrate prioritization mechanism unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 6, 10, 11]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 6, 11]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"complexes\": [\"ECS (Elongin BC–Cullin5–Rbx1) E3 ubiquitin ligase\", \"Skp2–Skp1–Cul1 (SCF) complex\"],\n    \"partners\": [\"ELOB\", \"ELOC\", \"CUL5\", \"RBX1\", \"CUL1\", \"SKP2\", \"NDP52\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":4,"faith_pct":75.0}}