{"gene":"MIB1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2013,"finding":"MIB1 functions as a dimer to promote endocytosis of NOTCH ligands DELTA and JAGGED (E3 ubiquitin ligase activity); germline loss-of-function mutations disrupt dimerization, reduce NOTCH1 activity, and cause left ventricular noncompaction cardiomyopathy. Targeted inactivation of Mib1 in mouse myocardium phenocopies inactivation of myocardial Jagged1 or endocardial Notch1, placing Mib1 upstream of Notch1 in cardiac trabecular compaction.","method":"Genetic epistasis in mouse conditional knockouts, zebrafish functional studies, in silico modeling, human pedigree sequencing with reduced NOTCH1 target gene expression","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (mouse KO, zebrafish, cell studies, human genetics), replicated across models","pmids":["23314057"],"is_preprint":false},{"year":2006,"finding":"Zebrafish Mib and Mib2 both possess C-terminal RING finger-dependent E3 ubiquitin ligase activity and are reciprocal E3 ubiquitin ligases and substrates of each other. They share DeltaC as a common substrate but differ in DeltaD internalization. Dominant-negative missense (M1013R) or truncation (C785stop) mutations in the C-terminal RING finger abolish ubiquitylation and internalization of DeltaC, establishing the RING finger as the catalytic domain.","method":"In vitro ubiquitylation assays, site-directed mutagenesis of RING finger domain, Delta internalization assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of E3 ligase activity with mutagenesis, single lab but multiple substrates and mutant alleles tested","pmids":["17196985"],"is_preprint":false},{"year":2012,"finding":"Mib1 E3 ubiquitin ligase is required for Notch ligand activity in the developing spinal cord: conditional knockout mice show depletion of spinal progenitors, premature neuronal differentiation, unbalanced V2 interneuron specification, and loss of astrocytes/oligodendrocytes. The RING domain of Mib1 is required for V2 interneuron specification in chick neural tube, established by misexpression of RING-domain deletion mutants.","method":"Conditional knockout mouse, drug-inducible deletion, chick neural tube misexpression of Mib1 deletion mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with defined cellular phenotypes, domain-function analysis with deletion mutants, multiple species","pmids":["23223237"],"is_preprint":false},{"year":2015,"finding":"Mib1 interacts with Polo-like kinase 4 (Plk4) and ubiquitylates Plk4 on multiple sites, generating Lys11-, Lys29-, and Lys48-linked ubiquitin chains. This controls Plk4 abundance and its interaction with centrosomal proteins, thereby counteracting centriole amplification. Mib1 localizes to centriolar satellites and redistributes to centrioles upon conditions that induce centriole amplification.","method":"Co-immunoprecipitation, mass spectrometry-identified interaction, ubiquitylation assay with linkage-type mapping, subcellular localization by immunofluorescence, gain-of-function centriole amplification assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reciprocal Co-IP, in-cell ubiquitylation with chain-type characterization by MS, functional centriole amplification readout, single lab with multiple orthogonal methods","pmids":["25795303"],"is_preprint":false},{"year":2019,"finding":"The deubiquitinase CYLD antagonizes MIB1 by removing ubiquitin from PCM1 (pericentriolar material protein 1), preventing MIB1-mediated proteasomal degradation of PCM1. Loss of CYLD leads to PCM1 degradation and dismantling of centriolar satellites, disrupting ciliogenesis. Thus MIB1 marks PCM1 for proteasomal degradation, and CYLD reverses this modification.","method":"Proteomic screen for CYLD binding partners, CYLD knockdown with PCM1 degradation readout, co-immunoprecipitation, centriolar satellite and ciliogenesis assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction defined, functional epistasis (CYLD counteracts MIB1 on PCM1), multiple orthogonal readouts in single study","pmids":["31067453"],"is_preprint":false},{"year":2019,"finding":"SNX17 recruits the deubiquitinase USP9X to antagonize MIB1-induced ubiquitination and proteasomal degradation of PCM1 during serum-starvation-induced ciliogenesis. SNX17 deficiency enhances PCM1 and USP9X degradation and disrupts ciliogenesis. Under serum-containing conditions, SNX17 is dispensable for PCM1/USP9X homeostasis.","method":"Co-immunoprecipitation, knockdown of SNX17 with PCM1/USP9X degradation readout, ciliogenesis assay under serum starvation vs. normal conditions","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reciprocal Co-IP and functional knockdown, single lab","pmids":["31671755"],"is_preprint":false},{"year":2016,"finding":"miR-10a/10b directly binds the 3′-UTR of mib1 mRNA and represses its expression in endothelial cells. Loss of miR-10a/10b increases Mib1, impairs tip-cell behavior, and disrupts angiogenesis in a Notch-dependent manner; inhibition of Mib1 or Notch signaling rescues the angiogenic defects in miR-10-deficient zebrafish.","method":"Luciferase 3′-UTR reporter assay, in vivo zebrafish reporter assay, morpholino knockdown, epistasis with Mib1/Notch inhibition rescue","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated 3′-UTR binding by luciferase and in vivo reporter, genetic rescue epistasis, single lab","pmids":["26825552"],"is_preprint":false},{"year":2017,"finding":"Mib1 ubiquitinates Ctnnd1 (p120-catenin) on K547, and this ubiquitination attenuates Rac1 activation. Loss of Mib1 increases random cell migration due to hyperactivated Rac1; knockdown of Ctnnd1 partially rescues posterior lateral line primordium migration defects in mib1 zebrafish mutants, placing the Mib1–Ctnnd1–Rac1 axis in persistent directional cell migration.","method":"siRNA knockdown in wound-closure assay, ubiquitination site mutagenesis (K547), Rac1 activity assay, zebrafish mib1 mutant lateral line analysis with Ctnnd1 morpholino rescue","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ubiquitination site identified by mutagenesis, Rac1 activity assay, in vivo genetic rescue epistasis, multiple orthogonal methods in one study","pmids":["29078376"],"is_preprint":false},{"year":2016,"finding":"Mib1 promotes Notch ligand Dll1 endocytosis by modulating dynamin 2 recruitment: Mib1 promotes the interaction between dynamin 2 and Snx18 in a ubiquitin ligase activity-dependent manner. Mib1 ubiquitin ligase activity is induced by Notch ligand–receptor interactions. Snx18 modestly regulates Dll1 endocytosis.","method":"Co-immunoprecipitation, ubiquitin ligase activity assay, Dll1 endocytosis assay, dominant-negative dynamin 2 and Snx18 knockdown","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP interaction mapping plus functional endocytosis assay, single lab","pmids":["26923255"],"is_preprint":false},{"year":2021,"finding":"MIB1 directly targets the tumor suppressor ST7 for proteasomal degradation via ubiquitination. ST7 suppresses tumor growth by downregulating IQGAP1. MIB1 overexpression in pancreatic cancer cells enhances proliferation and invasion by degrading ST7, leading to upregulation of IQGAP1, defining a MIB1/ST7/IQGAP1 oncogenic axis.","method":"Overexpression and knockdown in pancreatic cancer cells, in vitro and xenograft proliferation/invasion assays, co-immunoprecipitation, proteasome inhibitor rescue","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, functional rescue, in vivo xenograft, single lab","pmids":["33793053"],"is_preprint":false},{"year":2023,"finding":"MIB1 mediates ubiquitination and proteasomal degradation of TOP3B by directly interacting with TOP3B independently of TDRD3. The TDRD3–USP9X complex works downstream of MIB1 to stabilize TOP3B; combined depletion of USP9X, TDRD3, and MIB1 does not increase TOP3B levels beyond MIB1 knockdown alone.","method":"Co-immunoprecipitation, USP9X/MIB1 knockdown with TOP3B ubiquitylation and stability readout, epistasis by combined depletion","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction by Co-IP, epistasis by triple knockdown, biochemical ubiquitylation evidence, single lab","pmids":["37980342"],"is_preprint":false},{"year":2018,"finding":"MIB1 mutations identified in congenital heart disease patients (p.T312Kfs*55 and p.W271G) significantly reduce JAGGED1 ubiquitination and Notch signaling induction in cell-based assays, demonstrating that MIB1 E3 ligase activity toward JAG1 is required for Notch pathway activation in cardiogenesis.","method":"Biochemical ubiquitination assays of JAG1 by mutant vs. wild-type MIB1 in transfected cells, Notch signaling reporter assay","journal":"Clinical science (London, England : 1979)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in-cell ubiquitination and Notch reporter assay, single lab, corroborates prior work","pmids":["30322850"],"is_preprint":false},{"year":2023,"finding":"MIB1 variants identified in familial nonsyndromic bicuspid aortic valve (nsBAV) pedigrees cause BAV on a NOTCH1-sensitized genetic background in two genetically modified mouse models, confirming that MIB1 loss-of-function is causally linked to BAV through reduced Notch pathway activation.","method":"Genetically modified mouse models carrying human MIB1 variants, NOTCH1-sensitized background epistasis, human familial exome sequencing with replication cohorts","journal":"JAMA cardiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent mouse models on sensitized background, multicenter human genetic replication, functional in vivo validation","pmids":["37405741"],"is_preprint":false},{"year":2023,"finding":"MIB1 ubiquitinates and promotes proteasomal degradation of DAPK1; the flavonoid Sanggenon C suppresses GBM cell proliferation by decreasing MIB1 expression, thereby stabilizing DAPK1. Overexpression of MIB1 or knockdown of DAPK1 reverses the anti-proliferative effects, establishing MIB1 as the E3 ligase responsible for DAPK1 degradation.","method":"Western blot proteomic analysis, MIB1 overexpression/knockdown, DAPK1 stability assays, in vitro and in vivo GBM proliferation/apoptosis assays","journal":"MedComm","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional epistasis by rescue experiments, protein stability assay, single lab","pmids":["37346933"],"is_preprint":false},{"year":2019,"finding":"MIB1 is a direct target of miR-198 in prostate cancer; miR-198 overexpression reduces MIB1 protein/mRNA, and MIB1 knockdown recapitulates the anti-proliferative effects of miR-198 (reduced colony formation, G0/G1 arrest, impaired in vivo tumor formation), demonstrating that MIB1 promotes prostate cancer cell proliferation downstream of miR-198.","method":"Luciferase 3′-UTR reporter assay, miR-198 mimic transfection, siRNA knockdown of MIB1, LNCaP xenograft model","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — 3′-UTR reporter validation, functional rescue by MIB1 knockdown, in vivo xenograft, single lab","pmids":["31322262"],"is_preprint":false}],"current_model":"MIB1 is a RING-finger E3 ubiquitin ligase that functions as a dimer to ubiquitinate Notch ligands (DLL1/3/4, JAG1) and promote their endocytosis, thereby activating Notch signaling in adjacent cells; beyond Notch, MIB1 controls centriole homeostasis by ubiquitinating Plk4, regulates centriolar satellite proteostasis by marking PCM1 for proteasomal degradation (antagonized by CYLD and the SNX17–USP9X complex), directs persistent directional cell migration through ubiquitination of Ctnnd1 to suppress Rac1 activity, and promotes cancer cell proliferation by targeting ST7 and DAPK1 for proteasomal degradation."},"narrative":{"mechanistic_narrative":"MIB1 is a RING-finger E3 ubiquitin ligase whose best-established role is to drive Notch signaling by ubiquitinating Notch ligands and promoting their endocytosis in signal-sending cells [PMID:23314057, PMID:17196985]. It functions as a dimer, and its C-terminal RING finger is the catalytic domain: missense or truncation mutations there abolish ubiquitylation and ligand internalization [PMID:23314057, PMID:17196985]. MIB1 ubiquitinates DELTA/DLL and JAGGED ligands, and at DLL1 it couples ligand ubiquitination to endocytosis by promoting a ubiquitin-ligase-activity-dependent interaction between dynamin 2 and Snx18, with ligase activity itself induced by ligand–receptor engagement [PMID:26923255]. Through this activity MIB1 acts upstream of Notch1 in multiple developmental contexts, including cardiac trabecular compaction, spinal progenitor maintenance and interneuron/glial specification, and Notch-dependent angiogenic tip-cell behavior, the last regulated by miR-10a/10b repression of mib1 [PMID:23314057, PMID:23223237, PMID:26825552]. Loss-of-function MIB1 mutations that impair dimerization or ligand ubiquitination cause left ventricular noncompaction cardiomyopathy and, on a NOTCH1-sensitized background, bicuspid aortic valve, establishing MIB1 as a Notch-pathway disease gene in cardiogenesis [PMID:23314057, PMID:30322850, PMID:37405741]. Beyond Notch, MIB1 has substrate-specific roles in centrosome and satellite biology—ubiquitinating Plk4 with K11/K29/K48 chains to restrain centriole amplification, and marking PCM1 for proteasomal degradation, an action opposed by the deubiquitinases CYLD and the SNX17–USP9X complex during ciliogenesis [PMID:25795303, PMID:31067453, PMID:31671755]—and it directs persistent directional migration by ubiquitinating Ctnnd1 (p120-catenin) on K547 to dampen Rac1 activity [PMID:29078376]. In cancer cells MIB1 promotes proliferation by targeting the tumor suppressors ST7 and DAPK1, and the topoisomerase TOP3B, for proteasomal degradation [PMID:33793053, PMID:37346933, PMID:37980342].","teleology":[{"year":2006,"claim":"Established that the C-terminal RING finger is MIB1's catalytic domain, answering whether MIB1 is intrinsically an E3 ligase and which domain executes ligand ubiquitination and internalization.","evidence":"In vitro ubiquitylation assays with RING-domain point/truncation mutants and Delta internalization assays in zebrafish Mib/Mib2","pmids":["17196985"],"confidence":"High","gaps":["Cognate E2 enzyme(s) not defined","Chain linkage types on Delta substrates not mapped"]},{"year":2012,"claim":"Showed the RING-dependent ligase activity is required in vivo for Notch ligand function during neural development, linking MIB1 catalysis to progenitor maintenance and cell-fate specification.","evidence":"Conditional/inducible Mib1 knockout mouse and chick neural tube misexpression of RING-deletion mutants","pmids":["23223237"],"confidence":"High","gaps":["Which ligand substrate is most relevant in spinal cord not resolved","Direct substrate ubiquitination not measured in this system"]},{"year":2013,"claim":"Demonstrated MIB1 acts as a dimer upstream of Notch1 in heart development and that human loss-of-function mutations disrupting dimerization cause cardiomyopathy, connecting MIB1 biochemistry to Mendelian disease.","evidence":"Mouse conditional knockouts with genetic epistasis, zebrafish studies, in silico dimer modeling, and human pedigree sequencing","pmids":["23314057"],"confidence":"High","gaps":["Structural basis of dimerization not solved","Direct ligand ubiquitination by mutant proteins not quantified here"]},{"year":2015,"claim":"Identified a Notch-independent substrate, showing MIB1 ubiquitinates Plk4 with K11/K29/K48 chains to limit centriole amplification and localizes to centriolar satellites.","evidence":"Co-IP, MS-mapped ubiquitin linkages, immunofluorescence localization, and centriole amplification assays","pmids":["25795303"],"confidence":"High","gaps":["Fate of Plk4 (degradation vs. signaling) per linkage type not fully separated","Regulation of MIB1 redistribution to centrioles unknown"]},{"year":2016,"claim":"Defined how MIB1 couples ligand ubiquitination to endocytosis and how its activity is regulated, showing ligand–receptor engagement induces MIB1 activity that promotes dynamin 2–Snx18 interaction for Dll1 internalization.","evidence":"Co-IP interaction mapping, ligase activity assays, and Dll1 endocytosis assays with dominant-negative dynamin 2 and Snx18 knockdown","pmids":["26923255"],"confidence":"Medium","gaps":["Snx18 contribution is modest and mechanism partial","Direct ubiquitination of dynamin 2 vs. ligand not separated"]},{"year":2016,"claim":"Placed mib1 under post-transcriptional control, showing miR-10a/10b represses mib1 to tune Notch-dependent angiogenic tip-cell behavior.","evidence":"Luciferase 3'-UTR reporter, zebrafish in vivo reporter, morpholino knockdown, and Mib1/Notch rescue epistasis","pmids":["26825552"],"confidence":"Medium","gaps":["Whether this regulation operates in mammalian angiogenesis not shown","Quantitative contribution to endogenous MIB1 levels unclear"]},{"year":2017,"claim":"Extended MIB1's function beyond Notch to cell migration, identifying Ctnnd1 K547 ubiquitination as a brake on Rac1 that enforces persistent directional migration.","evidence":"Ubiquitination site mutagenesis, Rac1 activity assay, wound-closure migration, and zebrafish lateral-line rescue with Ctnnd1 morpholino","pmids":["29078376"],"confidence":"High","gaps":["Whether K547 ubiquitination is degradative or non-degradative not stated","Molecular link between ubiquitinated Ctnnd1 and Rac1 suppression undefined"]},{"year":2018,"claim":"Provided patient-derived biochemical confirmation that disease mutations impair JAG1 ubiquitination, reinforcing that MIB1 ligase activity toward JAG1 drives cardiogenic Notch activation.","evidence":"In-cell JAG1 ubiquitination assays comparing mutant vs. wild-type MIB1 plus Notch reporter","pmids":["30322850"],"confidence":"Medium","gaps":["Single-lab cell-based assay without in vivo validation in this study","Effect on other ligands not tested"]},{"year":2019,"claim":"Revealed that MIB1's ubiquitination of PCM1 is reversed by deubiquitinases, defining CYLD and the SNX17–USP9X complex as antagonists that protect centriolar satellites during ciliogenesis.","evidence":"Proteomic screens, Co-IP, CYLD/SNX17 knockdown with PCM1 (and USP9X) degradation readouts, and ciliogenesis assays","pmids":["31067453","31671755"],"confidence":"Medium","gaps":["PCM1 ubiquitination site(s) and chain type not mapped","How serum starvation switches SNX17 dependence not explained"]},{"year":2019,"claim":"Linked MIB1 to cancer proliferation, showing miR-198 represses MIB1 and that MIB1 knockdown phenocopies miR-198 anti-proliferative effects in prostate cancer.","evidence":"3'-UTR luciferase reporter, miR-198 mimic, MIB1 siRNA, and LNCaP xenografts","pmids":["31322262"],"confidence":"Medium","gaps":["Relevant MIB1 substrate driving prostate proliferation not identified","Single-lab study"]},{"year":2021,"claim":"Identified an oncogenic MIB1 substrate axis, showing MIB1 degrades the tumor suppressor ST7 to upregulate IQGAP1 and promote pancreatic cancer proliferation and invasion.","evidence":"Overexpression/knockdown in pancreatic cancer cells, Co-IP, proteasome-inhibitor rescue, and xenografts","pmids":["33793053"],"confidence":"Medium","gaps":["ST7 ubiquitination site not mapped","Generality across tumor types not tested"]},{"year":2023,"claim":"Expanded MIB1's substrate repertoire to TOP3B and DAPK1, defining MIB1 as the E3 ligase degrading these proteins, with TDRD3–USP9X stabilizing TOP3B downstream and DAPK1 degradation underlying GBM proliferation.","evidence":"Co-IP, triple-knockdown epistasis for TOP3B; protein-stability and rescue assays plus GBM proliferation/apoptosis models for DAPK1","pmids":["37980342","37346933"],"confidence":"Medium","gaps":["Ubiquitination sites on TOP3B and DAPK1 not mapped","Single-lab studies, chain linkage types undefined"]},{"year":2023,"claim":"Causally tied MIB1 loss-of-function to bicuspid aortic valve through Notch, demonstrating in vivo disease mechanism on a NOTCH1-sensitized background.","evidence":"Two genetically modified mouse models with human MIB1 variants on NOTCH1-sensitized background and multicenter human familial exome replication","pmids":["37405741"],"confidence":"High","gaps":["Cell type and developmental window of the critical Notch defect not pinpointed","Variant-specific biochemical effects not all characterized"]},{"year":null,"claim":"How MIB1 substrate selection is partitioned between Notch ligands and its many non-Notch targets (Plk4, PCM1, Ctnnd1, ST7, DAPK1, TOP3B), and which ubiquitin chain linkages dictate degradation versus trafficking, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of MIB1 substrate recognition","Cognate E2 enzymes not defined across substrates","Chain-linkage-to-fate rules characterized only for Plk4"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1,2,3,7]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,3,7,9,10,13]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,8,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,4,9,10,13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,2,6,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,11,12,13]}],"complexes":[],"partners":["DLL1","JAG1","PLK4","PCM1","CTNND1","ST7","TOP3B","DAPK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86YT6","full_name":"E3 ubiquitin-protein ligase MIB1","aliases":["DAPK-interacting protein 1","DIP-1","Mind bomb homolog 1","RING-type E3 ubiquitin transferase MIB1","Zinc finger ZZ type with ankyrin repeat domain protein 2"],"length_aa":1006,"mass_kda":110.1,"function":"E3 ubiquitin-protein ligase that mediates ubiquitination of Delta receptors, which act as ligands of Notch proteins. Positively regulates the Delta-mediated Notch signaling by ubiquitinating the intracellular domain of Delta, leading to endocytosis of Delta receptors. Probably mediates ubiquitination and subsequent proteasomal degradation of DAPK1, thereby antagonizing anti-apoptotic effects of DAPK1 to promote TNF-induced apoptosis (By similarity). Involved in ubiquitination of centriolar satellite CEP131, CEP290 and PCM1 proteins and hence inhibits primary cilium formation in proliferating cells. Mediates 'Lys-63'-linked polyubiquitination of TBK1, which probably participates in kinase activation (Microbial infection) During adenovirus infection, mediates ubiquitination of Core-capsid bridging protein. 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Correlation with p53, steroid receptor status, proliferative indices (PCNA, MIB1) and survival.","date":"2004","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/15274338","citation_count":15,"is_preprint":false},{"pmid":"9293894","id":"PMC_9293894","title":"MIB-1 expression in breast carcinomas with medullary features. An immunohistological study including correlations with p53 and bcl-2.","date":"1997","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/9293894","citation_count":15,"is_preprint":false},{"pmid":"11893030","id":"PMC_11893030","title":"MIB-1 expression in cervical Papanicolaou tests correlates with dysplasia in subsequent cervical biopsies.","date":"2002","source":"Applied immunohistochemistry & molecular morphology : AIMM","url":"https://pubmed.ncbi.nlm.nih.gov/11893030","citation_count":14,"is_preprint":false},{"pmid":"22234091","id":"PMC_22234091","title":"Frequency of Ki-67 (MIB-1) and P53 expressions among patients with prostate cancer.","date":"2011","source":"Indian journal of pathology & microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/22234091","citation_count":14,"is_preprint":false},{"pmid":"10545794","id":"PMC_10545794","title":"MIB-1 immunoreactivity correlates with blood vessel density and survival in disseminated malignant melanoma.","date":"1999","source":"Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/10545794","citation_count":14,"is_preprint":false},{"pmid":"37346933","id":"PMC_37346933","title":"Sanggenon C inhibits cell proliferation and induces apoptosis by regulating the MIB1/DAPK1 axis in glioblastoma.","date":"2023","source":"MedComm","url":"https://pubmed.ncbi.nlm.nih.gov/37346933","citation_count":13,"is_preprint":false},{"pmid":"37488742","id":"PMC_37488742","title":"SNORA73B promotes endometrial cancer progression through targeting MIB1 and regulating host gene RCC1 alternative splicing.","date":"2023","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37488742","citation_count":13,"is_preprint":false},{"pmid":"26995334","id":"PMC_26995334","title":"Survivin, caspase-3 and MIB-1 expression in astrocytic tumors of various grades.","date":"2016","source":"Advances in medical 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ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/9924341","citation_count":13,"is_preprint":false},{"pmid":"12530035","id":"PMC_12530035","title":"Differential diagnosis of keratoacanthoma and squamous cell carcinoma of the epidermis by MIB-1 immunohistometry.","date":"2002","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/12530035","citation_count":13,"is_preprint":false},{"pmid":"11158814","id":"PMC_11158814","title":"Comparison of microcirculation patterns and MIB-1 immunoreactivity in iris and posterior uveal melanoma.","date":"2001","source":"Ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/11158814","citation_count":12,"is_preprint":false},{"pmid":"12465771","id":"PMC_12465771","title":"bcl-2 and MIB-1 labeling indexes in cats with lymphoma.","date":"2002","source":"Journal of veterinary internal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12465771","citation_count":12,"is_preprint":false},{"pmid":"23202049","id":"PMC_23202049","title":"Towards MIB-1 and p53 detection in glioma magnetic resonance image: a novel computational image analysis method.","date":"2012","source":"Physics in medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/23202049","citation_count":12,"is_preprint":false},{"pmid":"36320066","id":"PMC_36320066","title":"Population-based estimate for the correlation of the Oncotype Dx Breast Recurrence Score® result and Ki-67 IHC MIB-1 pharmDx in HR+, HER2-, node-positive early breast cancer.","date":"2022","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/36320066","citation_count":12,"is_preprint":false},{"pmid":"34757030","id":"PMC_34757030","title":"Evaluation of the MIB-producing potential based on real-time qPCR in drinking water reservoirs.","date":"2021","source":"Environmental research","url":"https://pubmed.ncbi.nlm.nih.gov/34757030","citation_count":12,"is_preprint":false},{"pmid":"9059038","id":"PMC_9059038","title":"Tumor cell counting using an image analysis program for MIB-1 immunohistochemistry.","date":"1997","source":"Neurologia medico-chirurgica","url":"https://pubmed.ncbi.nlm.nih.gov/9059038","citation_count":12,"is_preprint":false},{"pmid":"26923255","id":"PMC_26923255","title":"Mib1 modulates dynamin 2 recruitment via Snx18 to promote Dll1 endocytosis for efficient Notch signaling.","date":"2016","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/26923255","citation_count":12,"is_preprint":false},{"pmid":"34298854","id":"PMC_34298854","title":"FORGE: A Novel Scoring System to Predict the MIB-1 Labeling Index in Intracranial Meningiomas.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34298854","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54878,"output_tokens":4206,"usd":0.113862,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11976,"output_tokens":4512,"usd":0.08634,"stage2_stop_reason":"end_turn"},"total_usd":0.200202,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"MIB1 functions as a dimer to promote endocytosis of NOTCH ligands DELTA and JAGGED (E3 ubiquitin ligase activity); germline loss-of-function mutations disrupt dimerization, reduce NOTCH1 activity, and cause left ventricular noncompaction cardiomyopathy. Targeted inactivation of Mib1 in mouse myocardium phenocopies inactivation of myocardial Jagged1 or endocardial Notch1, placing Mib1 upstream of Notch1 in cardiac trabecular compaction.\",\n      \"method\": \"Genetic epistasis in mouse conditional knockouts, zebrafish functional studies, in silico modeling, human pedigree sequencing with reduced NOTCH1 target gene expression\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (mouse KO, zebrafish, cell studies, human genetics), replicated across models\",\n      \"pmids\": [\"23314057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Zebrafish Mib and Mib2 both possess C-terminal RING finger-dependent E3 ubiquitin ligase activity and are reciprocal E3 ubiquitin ligases and substrates of each other. They share DeltaC as a common substrate but differ in DeltaD internalization. Dominant-negative missense (M1013R) or truncation (C785stop) mutations in the C-terminal RING finger abolish ubiquitylation and internalization of DeltaC, establishing the RING finger as the catalytic domain.\",\n      \"method\": \"In vitro ubiquitylation assays, site-directed mutagenesis of RING finger domain, Delta internalization assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of E3 ligase activity with mutagenesis, single lab but multiple substrates and mutant alleles tested\",\n      \"pmids\": [\"17196985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mib1 E3 ubiquitin ligase is required for Notch ligand activity in the developing spinal cord: conditional knockout mice show depletion of spinal progenitors, premature neuronal differentiation, unbalanced V2 interneuron specification, and loss of astrocytes/oligodendrocytes. The RING domain of Mib1 is required for V2 interneuron specification in chick neural tube, established by misexpression of RING-domain deletion mutants.\",\n      \"method\": \"Conditional knockout mouse, drug-inducible deletion, chick neural tube misexpression of Mib1 deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with defined cellular phenotypes, domain-function analysis with deletion mutants, multiple species\",\n      \"pmids\": [\"23223237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Mib1 interacts with Polo-like kinase 4 (Plk4) and ubiquitylates Plk4 on multiple sites, generating Lys11-, Lys29-, and Lys48-linked ubiquitin chains. This controls Plk4 abundance and its interaction with centrosomal proteins, thereby counteracting centriole amplification. Mib1 localizes to centriolar satellites and redistributes to centrioles upon conditions that induce centriole amplification.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry-identified interaction, ubiquitylation assay with linkage-type mapping, subcellular localization by immunofluorescence, gain-of-function centriole amplification assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reciprocal Co-IP, in-cell ubiquitylation with chain-type characterization by MS, functional centriole amplification readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25795303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The deubiquitinase CYLD antagonizes MIB1 by removing ubiquitin from PCM1 (pericentriolar material protein 1), preventing MIB1-mediated proteasomal degradation of PCM1. Loss of CYLD leads to PCM1 degradation and dismantling of centriolar satellites, disrupting ciliogenesis. Thus MIB1 marks PCM1 for proteasomal degradation, and CYLD reverses this modification.\",\n      \"method\": \"Proteomic screen for CYLD binding partners, CYLD knockdown with PCM1 degradation readout, co-immunoprecipitation, centriolar satellite and ciliogenesis assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction defined, functional epistasis (CYLD counteracts MIB1 on PCM1), multiple orthogonal readouts in single study\",\n      \"pmids\": [\"31067453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SNX17 recruits the deubiquitinase USP9X to antagonize MIB1-induced ubiquitination and proteasomal degradation of PCM1 during serum-starvation-induced ciliogenesis. SNX17 deficiency enhances PCM1 and USP9X degradation and disrupts ciliogenesis. Under serum-containing conditions, SNX17 is dispensable for PCM1/USP9X homeostasis.\",\n      \"method\": \"Co-immunoprecipitation, knockdown of SNX17 with PCM1/USP9X degradation readout, ciliogenesis assay under serum starvation vs. normal conditions\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reciprocal Co-IP and functional knockdown, single lab\",\n      \"pmids\": [\"31671755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-10a/10b directly binds the 3′-UTR of mib1 mRNA and represses its expression in endothelial cells. Loss of miR-10a/10b increases Mib1, impairs tip-cell behavior, and disrupts angiogenesis in a Notch-dependent manner; inhibition of Mib1 or Notch signaling rescues the angiogenic defects in miR-10-deficient zebrafish.\",\n      \"method\": \"Luciferase 3′-UTR reporter assay, in vivo zebrafish reporter assay, morpholino knockdown, epistasis with Mib1/Notch inhibition rescue\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated 3′-UTR binding by luciferase and in vivo reporter, genetic rescue epistasis, single lab\",\n      \"pmids\": [\"26825552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mib1 ubiquitinates Ctnnd1 (p120-catenin) on K547, and this ubiquitination attenuates Rac1 activation. Loss of Mib1 increases random cell migration due to hyperactivated Rac1; knockdown of Ctnnd1 partially rescues posterior lateral line primordium migration defects in mib1 zebrafish mutants, placing the Mib1–Ctnnd1–Rac1 axis in persistent directional cell migration.\",\n      \"method\": \"siRNA knockdown in wound-closure assay, ubiquitination site mutagenesis (K547), Rac1 activity assay, zebrafish mib1 mutant lateral line analysis with Ctnnd1 morpholino rescue\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ubiquitination site identified by mutagenesis, Rac1 activity assay, in vivo genetic rescue epistasis, multiple orthogonal methods in one study\",\n      \"pmids\": [\"29078376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mib1 promotes Notch ligand Dll1 endocytosis by modulating dynamin 2 recruitment: Mib1 promotes the interaction between dynamin 2 and Snx18 in a ubiquitin ligase activity-dependent manner. Mib1 ubiquitin ligase activity is induced by Notch ligand–receptor interactions. Snx18 modestly regulates Dll1 endocytosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitin ligase activity assay, Dll1 endocytosis assay, dominant-negative dynamin 2 and Snx18 knockdown\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP interaction mapping plus functional endocytosis assay, single lab\",\n      \"pmids\": [\"26923255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MIB1 directly targets the tumor suppressor ST7 for proteasomal degradation via ubiquitination. ST7 suppresses tumor growth by downregulating IQGAP1. MIB1 overexpression in pancreatic cancer cells enhances proliferation and invasion by degrading ST7, leading to upregulation of IQGAP1, defining a MIB1/ST7/IQGAP1 oncogenic axis.\",\n      \"method\": \"Overexpression and knockdown in pancreatic cancer cells, in vitro and xenograft proliferation/invasion assays, co-immunoprecipitation, proteasome inhibitor rescue\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, functional rescue, in vivo xenograft, single lab\",\n      \"pmids\": [\"33793053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MIB1 mediates ubiquitination and proteasomal degradation of TOP3B by directly interacting with TOP3B independently of TDRD3. The TDRD3–USP9X complex works downstream of MIB1 to stabilize TOP3B; combined depletion of USP9X, TDRD3, and MIB1 does not increase TOP3B levels beyond MIB1 knockdown alone.\",\n      \"method\": \"Co-immunoprecipitation, USP9X/MIB1 knockdown with TOP3B ubiquitylation and stability readout, epistasis by combined depletion\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction by Co-IP, epistasis by triple knockdown, biochemical ubiquitylation evidence, single lab\",\n      \"pmids\": [\"37980342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MIB1 mutations identified in congenital heart disease patients (p.T312Kfs*55 and p.W271G) significantly reduce JAGGED1 ubiquitination and Notch signaling induction in cell-based assays, demonstrating that MIB1 E3 ligase activity toward JAG1 is required for Notch pathway activation in cardiogenesis.\",\n      \"method\": \"Biochemical ubiquitination assays of JAG1 by mutant vs. wild-type MIB1 in transfected cells, Notch signaling reporter assay\",\n      \"journal\": \"Clinical science (London, England : 1979)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in-cell ubiquitination and Notch reporter assay, single lab, corroborates prior work\",\n      \"pmids\": [\"30322850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MIB1 variants identified in familial nonsyndromic bicuspid aortic valve (nsBAV) pedigrees cause BAV on a NOTCH1-sensitized genetic background in two genetically modified mouse models, confirming that MIB1 loss-of-function is causally linked to BAV through reduced Notch pathway activation.\",\n      \"method\": \"Genetically modified mouse models carrying human MIB1 variants, NOTCH1-sensitized background epistasis, human familial exome sequencing with replication cohorts\",\n      \"journal\": \"JAMA cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent mouse models on sensitized background, multicenter human genetic replication, functional in vivo validation\",\n      \"pmids\": [\"37405741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MIB1 ubiquitinates and promotes proteasomal degradation of DAPK1; the flavonoid Sanggenon C suppresses GBM cell proliferation by decreasing MIB1 expression, thereby stabilizing DAPK1. Overexpression of MIB1 or knockdown of DAPK1 reverses the anti-proliferative effects, establishing MIB1 as the E3 ligase responsible for DAPK1 degradation.\",\n      \"method\": \"Western blot proteomic analysis, MIB1 overexpression/knockdown, DAPK1 stability assays, in vitro and in vivo GBM proliferation/apoptosis assays\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional epistasis by rescue experiments, protein stability assay, single lab\",\n      \"pmids\": [\"37346933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MIB1 is a direct target of miR-198 in prostate cancer; miR-198 overexpression reduces MIB1 protein/mRNA, and MIB1 knockdown recapitulates the anti-proliferative effects of miR-198 (reduced colony formation, G0/G1 arrest, impaired in vivo tumor formation), demonstrating that MIB1 promotes prostate cancer cell proliferation downstream of miR-198.\",\n      \"method\": \"Luciferase 3′-UTR reporter assay, miR-198 mimic transfection, siRNA knockdown of MIB1, LNCaP xenograft model\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — 3′-UTR reporter validation, functional rescue by MIB1 knockdown, in vivo xenograft, single lab\",\n      \"pmids\": [\"31322262\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MIB1 is a RING-finger E3 ubiquitin ligase that functions as a dimer to ubiquitinate Notch ligands (DLL1/3/4, JAG1) and promote their endocytosis, thereby activating Notch signaling in adjacent cells; beyond Notch, MIB1 controls centriole homeostasis by ubiquitinating Plk4, regulates centriolar satellite proteostasis by marking PCM1 for proteasomal degradation (antagonized by CYLD and the SNX17–USP9X complex), directs persistent directional cell migration through ubiquitination of Ctnnd1 to suppress Rac1 activity, and promotes cancer cell proliferation by targeting ST7 and DAPK1 for proteasomal degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MIB1 is a RING-finger E3 ubiquitin ligase whose best-established role is to drive Notch signaling by ubiquitinating Notch ligands and promoting their endocytosis in signal-sending cells [#0, #1]. It functions as a dimer, and its C-terminal RING finger is the catalytic domain: missense or truncation mutations there abolish ubiquitylation and ligand internalization [#0, #1]. MIB1 ubiquitinates DELTA/DLL and JAGGED ligands, and at DLL1 it couples ligand ubiquitination to endocytosis by promoting a ubiquitin-ligase-activity-dependent interaction between dynamin 2 and Snx18, with ligase activity itself induced by ligand\\u2013receptor engagement [#8]. Through this activity MIB1 acts upstream of Notch1 in multiple developmental contexts, including cardiac trabecular compaction, spinal progenitor maintenance and interneuron/glial specification, and Notch-dependent angiogenic tip-cell behavior, the last regulated by miR-10a/10b repression of mib1 [#0, #2, #6]. Loss-of-function MIB1 mutations that impair dimerization or ligand ubiquitination cause left ventricular noncompaction cardiomyopathy and, on a NOTCH1-sensitized background, bicuspid aortic valve, establishing MIB1 as a Notch-pathway disease gene in cardiogenesis [#0, #11, #12]. Beyond Notch, MIB1 has substrate-specific roles in centrosome and satellite biology\\u2014ubiquitinating Plk4 with K11/K29/K48 chains to restrain centriole amplification, and marking PCM1 for proteasomal degradation, an action opposed by the deubiquitinases CYLD and the SNX17\\u2013USP9X complex during ciliogenesis [#3, #4, #5]\\u2014and it directs persistent directional migration by ubiquitinating Ctnnd1 (p120-catenin) on K547 to dampen Rac1 activity [#7]. In cancer cells MIB1 promotes proliferation by targeting the tumor suppressors ST7 and DAPK1, and the topoisomerase TOP3B, for proteasomal degradation [#9, #13, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that the C-terminal RING finger is MIB1's catalytic domain, answering whether MIB1 is intrinsically an E3 ligase and which domain executes ligand ubiquitination and internalization.\",\n      \"evidence\": \"In vitro ubiquitylation assays with RING-domain point/truncation mutants and Delta internalization assays in zebrafish Mib/Mib2\",\n      \"pmids\": [\"17196985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cognate E2 enzyme(s) not defined\", \"Chain linkage types on Delta substrates not mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed the RING-dependent ligase activity is required in vivo for Notch ligand function during neural development, linking MIB1 catalysis to progenitor maintenance and cell-fate specification.\",\n      \"evidence\": \"Conditional/inducible Mib1 knockout mouse and chick neural tube misexpression of RING-deletion mutants\",\n      \"pmids\": [\"23223237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which ligand substrate is most relevant in spinal cord not resolved\", \"Direct substrate ubiquitination not measured in this system\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated MIB1 acts as a dimer upstream of Notch1 in heart development and that human loss-of-function mutations disrupting dimerization cause cardiomyopathy, connecting MIB1 biochemistry to Mendelian disease.\",\n      \"evidence\": \"Mouse conditional knockouts with genetic epistasis, zebrafish studies, in silico dimer modeling, and human pedigree sequencing\",\n      \"pmids\": [\"23314057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of dimerization not solved\", \"Direct ligand ubiquitination by mutant proteins not quantified here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a Notch-independent substrate, showing MIB1 ubiquitinates Plk4 with K11/K29/K48 chains to limit centriole amplification and localizes to centriolar satellites.\",\n      \"evidence\": \"Co-IP, MS-mapped ubiquitin linkages, immunofluorescence localization, and centriole amplification assays\",\n      \"pmids\": [\"25795303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Fate of Plk4 (degradation vs. signaling) per linkage type not fully separated\", \"Regulation of MIB1 redistribution to centrioles unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined how MIB1 couples ligand ubiquitination to endocytosis and how its activity is regulated, showing ligand\\u2013receptor engagement induces MIB1 activity that promotes dynamin 2\\u2013Snx18 interaction for Dll1 internalization.\",\n      \"evidence\": \"Co-IP interaction mapping, ligase activity assays, and Dll1 endocytosis assays with dominant-negative dynamin 2 and Snx18 knockdown\",\n      \"pmids\": [\"26923255\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Snx18 contribution is modest and mechanism partial\", \"Direct ubiquitination of dynamin 2 vs. ligand not separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed mib1 under post-transcriptional control, showing miR-10a/10b represses mib1 to tune Notch-dependent angiogenic tip-cell behavior.\",\n      \"evidence\": \"Luciferase 3'-UTR reporter, zebrafish in vivo reporter, morpholino knockdown, and Mib1/Notch rescue epistasis\",\n      \"pmids\": [\"26825552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this regulation operates in mammalian angiogenesis not shown\", \"Quantitative contribution to endogenous MIB1 levels unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended MIB1's function beyond Notch to cell migration, identifying Ctnnd1 K547 ubiquitination as a brake on Rac1 that enforces persistent directional migration.\",\n      \"evidence\": \"Ubiquitination site mutagenesis, Rac1 activity assay, wound-closure migration, and zebrafish lateral-line rescue with Ctnnd1 morpholino\",\n      \"pmids\": [\"29078376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether K547 ubiquitination is degradative or non-degradative not stated\", \"Molecular link between ubiquitinated Ctnnd1 and Rac1 suppression undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided patient-derived biochemical confirmation that disease mutations impair JAG1 ubiquitination, reinforcing that MIB1 ligase activity toward JAG1 drives cardiogenic Notch activation.\",\n      \"evidence\": \"In-cell JAG1 ubiquitination assays comparing mutant vs. wild-type MIB1 plus Notch reporter\",\n      \"pmids\": [\"30322850\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab cell-based assay without in vivo validation in this study\", \"Effect on other ligands not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed that MIB1's ubiquitination of PCM1 is reversed by deubiquitinases, defining CYLD and the SNX17\\u2013USP9X complex as antagonists that protect centriolar satellites during ciliogenesis.\",\n      \"evidence\": \"Proteomic screens, Co-IP, CYLD/SNX17 knockdown with PCM1 (and USP9X) degradation readouts, and ciliogenesis assays\",\n      \"pmids\": [\"31067453\", \"31671755\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PCM1 ubiquitination site(s) and chain type not mapped\", \"How serum starvation switches SNX17 dependence not explained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked MIB1 to cancer proliferation, showing miR-198 represses MIB1 and that MIB1 knockdown phenocopies miR-198 anti-proliferative effects in prostate cancer.\",\n      \"evidence\": \"3'-UTR luciferase reporter, miR-198 mimic, MIB1 siRNA, and LNCaP xenografts\",\n      \"pmids\": [\"31322262\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relevant MIB1 substrate driving prostate proliferation not identified\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified an oncogenic MIB1 substrate axis, showing MIB1 degrades the tumor suppressor ST7 to upregulate IQGAP1 and promote pancreatic cancer proliferation and invasion.\",\n      \"evidence\": \"Overexpression/knockdown in pancreatic cancer cells, Co-IP, proteasome-inhibitor rescue, and xenografts\",\n      \"pmids\": [\"33793053\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ST7 ubiquitination site not mapped\", \"Generality across tumor types not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded MIB1's substrate repertoire to TOP3B and DAPK1, defining MIB1 as the E3 ligase degrading these proteins, with TDRD3\\u2013USP9X stabilizing TOP3B downstream and DAPK1 degradation underlying GBM proliferation.\",\n      \"evidence\": \"Co-IP, triple-knockdown epistasis for TOP3B; protein-stability and rescue assays plus GBM proliferation/apoptosis models for DAPK1\",\n      \"pmids\": [\"37980342\", \"37346933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination sites on TOP3B and DAPK1 not mapped\", \"Single-lab studies, chain linkage types undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Causally tied MIB1 loss-of-function to bicuspid aortic valve through Notch, demonstrating in vivo disease mechanism on a NOTCH1-sensitized background.\",\n      \"evidence\": \"Two genetically modified mouse models with human MIB1 variants on NOTCH1-sensitized background and multicenter human familial exome replication\",\n      \"pmids\": [\"37405741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell type and developmental window of the critical Notch defect not pinpointed\", \"Variant-specific biochemical effects not all characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MIB1 substrate selection is partitioned between Notch ligands and its many non-Notch targets (Plk4, PCM1, Ctnnd1, ST7, DAPK1, TOP3B), and which ubiquitin chain linkages dictate degradation versus trafficking, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of MIB1 substrate recognition\", \"Cognate E2 enzymes not defined across substrates\", \"Chain-linkage-to-fate rules characterized only for Plk4\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1, 2, 3, 7]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 3, 7, 9, 10, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 8, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 4, 9, 10, 13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2, 6, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 11, 12, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DLL1\", \"JAG1\", \"PLK4\", \"PCM1\", \"CTNND1\", \"ST7\", \"TOP3B\", \"DAPK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}