{"gene":"DLL1","run_date":"2026-04-28T17:46:02","timeline":{"discoveries":[{"year":1995,"finding":"DLL1 (Delta-like 1) was identified as the first mammalian homologue of Drosophila Delta, encoding a transmembrane protein with EGF-like repeats in the extracellular domain that directly interacts with Notch receptors in a ligand-receptor manner, expressed in paraxial mesoderm and nervous system overlapping with Notch1 expression.","method":"Molecular cloning, sequence analysis, whole-mount in situ hybridization","journal":"Development","confidence":"High","confidence_rationale":"Tier 1 — foundational identification of protein structure and ligand-receptor relationship, >400 citations","pmids":["7671806"],"is_preprint":false},{"year":2004,"finding":"WNT signaling, acting through LEF/TCF factors in synergy with the T-box transcription factor TBX6, directly activates transcription of Dll1 in the tailbud and presomitic mesoderm (PSM), controlling Notch activity and somite formation; mutation of either T or LEF/TCF binding sites in the Dll1 promoter abolishes reporter expression in transgenic embryos.","method":"Transgenic reporter assays in vivo, in vitro promoter transactivation assays with LEF/TCF and TBX6, mutational analysis of Dll1 promoter elements","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 1 — in vitro promoter assays combined with in vivo transgenic validation with mutagenesis","pmids":["15545628"],"is_preprint":false},{"year":2005,"finding":"TBX6 directly binds to two of four putative Tbx6 binding sites in the Dll1 paraxial mesoderm enhancer in vitro, and Dll1 expression is lost in Tbx6 mutants, establishing Dll1 as a direct transcriptional target of TBX6 in the presomitic mesoderm.","method":"Electrophoretic mobility shift assay (EMSA/in vitro DNA binding), in vivo genetic analysis of Tbx6 mutant embryos","journal":"Genesis","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro binding assay combined with in vivo genetic evidence","pmids":["15986483"],"is_preprint":false},{"year":2005,"finding":"MAGI1, a PDZ scaffolding molecule, directly binds DLL1 at cadherin-based adherens junctions in the developing neural tube, recruits DLL1 to these junctions, and stabilizes DLL1 on the cell surface, providing a mechanism for DLL1 presentation to activate Notch in neighboring cells.","method":"Co-immunoprecipitation, yeast two-hybrid, immunofluorescence localization in developing spinal cord and cultured AJ-forming fibroblasts","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding confirmed, functional stabilization demonstrated, localization linked to function","pmids":["15908431"],"is_preprint":false},{"year":2003,"finding":"Positive and negative feedback loops comprising DLL1 and the transcription factor MESP2 are crucial for rostrocaudal patterning of somites; epistatic analysis revealed that PRESENILIN1 (Psen1) is required for DLL1-Notch signaling to activate DLL1 itself, while a Psen1-independent DLL3-Notch pathway may counteract the Psen1-dependent DLL1-Notch pathway.","method":"Genetic epistasis analysis using Dll1, Dll3, Mesp2, and Psen1 mutant and double-mutant mice","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 — systematic genetic epistasis with multiple mutant combinations establishing pathway hierarchy","pmids":["12900443"],"is_preprint":false},{"year":2008,"finding":"Ubiquitination of DLL1 is required for its recycling back to the cell surface after endocytosis and for acquiring high affinity for Notch1; an ubiquitination-defective DLL1 mutant is endocytosed but fails to recycle and cannot efficiently bind Notch1. A DLL1-DLL3 chimera can be recycled and bind Notch1 but cannot perform transendocytosis of the Notch1 extracellular domain, indicating transendocytosis is required for Notch signaling activation. DLL1 partially localizes to lipid microdomains required for its signaling activity.","method":"Ubiquitination-defective mutagenesis, endocytosis/recycling assays, Notch1 binding assays, transendocytosis assays, lipid microdomain fractionation","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis with multiple orthogonal functional assays establishing mechanism","pmids":["18676613"],"is_preprint":false},{"year":2009,"finding":"DLL1 is an essential Notch ligand in fetal arterial endothelial cells that activates Notch1 to maintain arterial identity; loss of DLL1 function leads to downregulation of VEGFR2 and its co-receptor NRP1, followed by upregulation of the venous fate repressor COUP-TFII, establishing DLL1 as distinct from DLL4 in the vasculature.","method":"Conditional knockout mice (endothelial-specific DLL1 deletion), immunofluorescence, in vitro Nrp1 promoter-RBPJκ reporter assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype plus mechanistic promoter validation","pmids":["19144989"],"is_preprint":false},{"year":2011,"finding":"MT1-MMP (MMP14) expressed on bone marrow stromal cells directly cleaves DLL1 on the cell surface; recombinant MT1-MMP cleaves a synthetic DLL1 peptide at the same site as cell-surface cleavage. Loss of MT1-MMP in stromal cells increases Notch signaling in hematopoietic progenitor cells and specifically impairs B-lymphocyte development, which is rescued by the Notch inhibitor DAPT.","method":"Co-IP (MT1-MMP–DLL1 interaction), in vitro cleavage of synthetic DLL1 peptide by recombinant MT1-MMP, Notch inhibitor rescue experiments in vitro and in vivo with MT1-MMP knockout mice","journal":"EMBO Journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic cleavage assay plus in vivo genetic rescue, reciprocal Co-IP","pmids":["21572390"],"is_preprint":false},{"year":2011,"finding":"Inactivation of Dll1 alone in the intestinal epithelium causes a moderate increase in goblet cells; simultaneous inactivation of Dll1 and Dll4 causes complete conversion of proliferating progenitors to postmitotic goblet cells with loss of intestinal stem cells (Olfm4+, Lgr5+, Ascl2+), establishing DLL1 and DLL4 as the physiological Notch ligands required for intestinal stem cell maintenance.","method":"Inducible gut-specific conditional knockout (Vil-Cre-ERT2) of Dll1, Dll4, and Jag1 singly and in combination; lineage tracing with Notch1 reporter","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with defined stem cell phenotype, multiple ligand combinations tested","pmids":["21238454"],"is_preprint":false},{"year":2011,"finding":"Elavl1/HuR ribonucleoprotein binds the 3' UTR of Dll1 mRNA and stabilizes it during mitosis in neuroepithelial cells; RNAi against Elavl1 reduces Dll1-3'UTR transcript stability in mitosis-arrested cells, and Elavl1 heterozygous null mice show decreased Dll1 expression and increased neurogenesis in the developing retina.","method":"RNAi knockdown, RNA immunoprecipitation (RIP), mRNA stability assay, in vivo analysis of Elavl1 heterozygous mouse retina","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 2 — RNA binding demonstrated by RIP, functional consequence confirmed in vivo and in vitro","pmids":["21346194"],"is_preprint":false},{"year":2012,"finding":"Dll1-expressing secretory progenitor cells (immediate daughters of Lgr5+ intestinal stem cells) generate all four secretory cell types through Notch lateral inhibition; upon tissue damage, Dll1-high cells reacquire stem cell properties (form organoids with Wnt3A exposure and undergo stem cell tracing events).","method":"Lineage tracing using Dll1(GFP-ires-CreERT2) knock-in mice, organoid culture, genetic marking before tissue damage","journal":"Nature Cell Biology","confidence":"High","confidence_rationale":"Tier 2 — in vivo lineage tracing with functional organoid assay, >600 citations","pmids":["23000963"],"is_preprint":false},{"year":2013,"finding":"DLL1 protein is induced in activated neural stem cells (NSCs) in the adult mouse subventricular zone and segregates asymmetrically to one daughter cell during mitosis; DLL1-expressing cells reside adjacent to quiescent NSCs and are required to maintain quiescent NSC identity, suggesting a feedback niche signal from progeny to parent NSC.","method":"Conditional knockout of Dll1 in the adult SVZ, live-cell imaging of DLL1 segregation during mitosis, proximity analysis of DLL1-expressing cells and quiescent NSCs","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — KO with defined NSC phenotype, live-cell imaging of asymmetric segregation","pmids":["23695674"],"is_preprint":false},{"year":2013,"finding":"Intermediate neurogenic progenitors (INPs) serve as a source of DLL1 and interact with radial glia (RG) via dynamic elongate processes (some long-range, some filopodia-like) to transmit Notch signals in the embryonic neocortical niche; live multiphoton microscopy and Notch-pathway reporters confirmed these dynamic cell–cell contacts.","method":"High-resolution live-cell multiphoton microscopy with Notch reporter in organotypic brain slices, gene expression profiling of sorted RG and INP populations","journal":"Journal of Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — live imaging of cell contacts with functional reporters, single study","pmids":["23699523"],"is_preprint":false},{"year":2013,"finding":"SYNJ2BP (synaptojanin-2 binding protein) interacts with the PDZ-binding motif at the C-terminus of DLL1 (and DLL4 but not JAG1), enhances DLL1 protein stability, promotes Notch signaling (inducing HEY1, LFNG, ephrin-B2), and inhibits endothelial tip cell formation and sprouting angiogenesis.","method":"Co-immunoprecipitation, protein stability assays, Notch target gene qPCR, endothelial cell functional assays (migration, proliferation), in vivo vascular network formation in immunocompromised mice","journal":"Circulation Research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, protein stabilization assay, and functional validation both in vitro and in vivo","pmids":["24025447"],"is_preprint":false},{"year":2014,"finding":"Phosphorylation of DLL1 occurs sequentially at two serine residues (one likely by protein kinase B/AKT) and one threonine residue in the intracellular domain; phosphorylation requires membrane association, increases DLL1 stability, affects surface levels, and phosphorylation-deficient DLL1 activates Notch1 significantly less efficiently in vitro, though mice with the phosphorylation-deficient DLL1 develop normally.","method":"Mass spectrometry identification of phosphorylation sites, site-directed mutagenesis, Notch1 coculture activation assays, knock-in mice expressing phosphorylation-deficient DLL1","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 1 — MS identification + mutagenesis + in vitro Notch activation assay + in vivo knock-in","pmids":["24449764"],"is_preprint":false},{"year":2015,"finding":"DLL4, but not DLL1, efficiently acts as a cis-inhibitor of Notch signaling in cells co-expressing Notch receptor and ligand; both ligands have similar trans-activation potential but DLL4 causes reduced net Notch activation through cis-inhibition, explaining context-dependent functional divergence. In the presomitic mesoderm (PSM), DLL4 cannot replace DLL1 for somitogenesis despite equivalent expression from the Dll1 locus.","method":"Conditional overexpression from HPRT locus, DLL4 knock-in into Dll1 locus (Dll1Dll4ki mice), Notch transactivation and cis-inhibition assays in vitro, in vivo analysis of somitogenesis and retinal progenitor maintenance","journal":"PLoS Genetics","confidence":"High","confidence_rationale":"Tier 1 — multiple in vitro assays plus multiple in vivo knock-in/knock-out models","pmids":["26114479"],"is_preprint":false},{"year":2016,"finding":"The structural integrity of each individual EGF repeat in the extracellular domain of DLL1 is required for full DLL1 activity; disulfide-bridge-disrupting mutations in each EGF repeat impair both NOTCH1 and NOTCH2 activation similarly in vitro, and certain mutations (particularly in specific EGF repeats) affect somite patterning in vivo resembling spondylocostal dysostosis.","method":"Site-directed mutagenesis of each EGF repeat, Notch transactivation coculture assays in vitro, allelic series of point mutations knocked into endogenous Dll1 locus in mice","journal":"Genetics","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis combined with in vitro activation assays and in vivo allelic series","pmids":["26801181"],"is_preprint":false},{"year":2016,"finding":"MIB1 (mind bomb 1 ubiquitin ligase) is required for efficient DLL1 endocytosis by promoting dynamin 2 recruitment via SNX18; MIB1 ubiquitin ligase activity is induced by Notch ligand–receptor interaction, and MIB1 promotes the SNX18–dynamin 2 interaction in an ubiquitin-ligase-activity-dependent manner.","method":"Co-immunoprecipitation, endocytosis assays, ubiquitin ligase activity assays","journal":"Genes to Cells","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and functional endocytosis assays, single study","pmids":["26923255"],"is_preprint":false},{"year":2017,"finding":"Osteoblast-specific overexpression of DLL1 (but not JAG1) promotes proliferation of committed but immature osteoblasts while inhibiting their further maturation; this maturational arrest impairs osteoclast coupling and suppresses bone metabolic turnover, establishing DLL1-Notch signaling as critical for bone remodeling.","method":"Osteoblast-specific transgenic overexpression of DLL1 and JAG1 in mice, bone histomorphometry, osteoblast and osteoclast differentiation assays","journal":"Journal of Cellular Physiology","confidence":"Medium","confidence_rationale":"Tier 2 — transgenic gain-of-function with defined cellular phenotype, single study","pmids":["27735989"],"is_preprint":false},{"year":2017,"finding":"Arp2/3 complex is required for vesicular transport of DLL1 from cytoplasm to the cell membrane in glioma-initiating cells; Arp2/3 inhibition prevents DLL1 from reaching the surface (and activating Notch1), impairing stem cell phenotype maintenance, which can be rescued by exogenous soluble DLL1 but not by endogenous DLL1.","method":"shRNA knockdown of DLL1 and Arp2/3 components, Arp2/3 pharmacological inhibition, rescue with soluble DLL1, intracranial xenograft model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — functional rescue experiments establishing trafficking mechanism, single study","pmids":["28380416"],"is_preprint":false},{"year":2018,"finding":"Estrogen signaling stabilizes DLL1 protein by preventing its proteasomal and lysosomal degradation and inhibiting DLL1 ubiquitination, thereby maintaining DLL1-mediated Notch signaling specifically in ERα+ luminal breast cancer to promote tumor proliferation, angiogenesis, and cancer stem cell function.","method":"Conditional DLL1 knockout in breast cancer mouse models, ubiquitination assays, proteasome/lysosome inhibitor treatments, tumor growth and metastasis assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KO, ubiquitination assay, degradation pathway assays) in single study","pmids":["30442981"],"is_preprint":false},{"year":2018,"finding":"MaSC-expressed DLL1 activates Notch signaling in stromal macrophages, which increases macrophage expression of Wnt ligands (Wnt3, Wnt10A, Wnt16), creating a feedback loop that promotes the function of Dll1-expressing mammary stem cells; conditional deletion of Dll1 reduces MaSC number and impairs ductal morphogenesis.","method":"Conditional knockout of Dll1 in mammary gland stem cells, co-culture assays, measurement of Wnt ligand expression in macrophages","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with defined stem cell and morphogenesis phenotype plus mechanistic Notch-Wnt crosstalk demonstrated","pmids":["29773667"],"is_preprint":false},{"year":2018,"finding":"The ectodomains of DLL1 and DLL4 determine their differential receptor selectivity: DLL4 preferentially activates NOTCH1 over NOTCH2, whereas DLL1 is equally effective in activating NOTCH1 and NOTCH2; the region between the N-terminus and EGF repeat 3 (MNNL and DSL domains) confers this selectivity in cell-based assays, and chimeric ligand knock-in mice confirm ectodomain-driven function in vivo.","method":"Cellular co-culture Notch activation assays, biochemical binding studies, chimeric ligand knock-in mice, mutagenesis of NOTCH1-interface residues in DLL1","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 — reconstitution in cell-based assays + mutagenesis + in vivo knock-in chimera experiments","pmids":["30289388"],"is_preprint":false},{"year":2020,"finding":"Oscillatory expression of DLL1 and HES1 in multipotent pancreatic progenitor cells (MPCs) drives MPC expansion, with changes in Hes1 oscillation parameters associated with bipotent progenitor versus pro-acinar cell fate; JAG1 restrains MPC growth but later drives bipotent progenitor specification in combination with DLL1.","method":"Conditional knockout of Dll1 and Jag1 (single and double mutants), live imaging of oscillatory reporters (Hes1), lineage analysis of pancreatic progenitor fates","journal":"Developmental Cell","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, oscillation imaging, multiple mutant combinations","pmids":["32059775"],"is_preprint":false},{"year":2020,"finding":"DLL1 and DLL4 are specifically expressed in adult pancreatic β-cells; mice lacking both DLL1 and DLL4 in adult β-cells show improved glucose tolerance and increased glucose-stimulated insulin secretion, while overexpression of the DLL1 intracellular domain in β-cells impairs glucose tolerance and insulin secretion, establishing a role for DLL1-Notch signaling in β-cell function.","method":"Conditional knockout of Dll1 and Dll4 in adult β-cells (Ins-Cre), overexpression of DLL1 intracellular domain in β-cells, glucose tolerance tests, insulin secretion assays in vitro and in vivo","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 — conditional KO and gain-of-function with functional metabolic readouts","pmids":["32029480"],"is_preprint":false},{"year":2021,"finding":"MyoD directly activates Dll1 transcription through E-box motifs in the Dll1 cis-regulatory region in myoblasts; Dll1-expressing cells activate Notch in neighboring myoblasts (trans-activation) to prevent premature differentiation, while autonomously inhibiting Notch in Dll1-expressing cells (cis-inhibition) to facilitate myogenic differentiation, creating a feedback loop.","method":"Gain/loss-of-function experiments in mouse and human myoblasts, CRISPR-mediated E-box disruption, novel E-box deficient mouse model, ChIP (implied by promoter analysis), in vivo myogenesis assays","journal":"PLoS Genetics","confidence":"High","confidence_rationale":"Tier 2 — in vivo knock-in E-box mutant model + CRISPR in human cells + functional rescue","pmids":["34370738"],"is_preprint":false},{"year":2021,"finding":"Dll1+ breast tumor cells bearing NF-κB activation represent quiescent tumor-initiating cancer cells (TICs) that drive chemoresistance; RNA-seq and ATAC-seq show NF-κB activation is downstream of Dll1, and pharmacological blocking of Dll1 or NF-κB completely sensitizes Dll1+ tumors to chemotherapy.","method":"Conditional knockout mouse models, Dll1 reporter models, RNA-seq, ATAC-seq, pharmacological NF-κB and Dll1 blockade, in vivo tumor growth and metastasis assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — multiple genomic and functional approaches in KO models establishing pathway placement","pmids":["33462238"],"is_preprint":false},{"year":2022,"finding":"Dll1+ breast cancer cells activate Notch signaling in cancer-associated fibroblasts (CAFs), which increases CAF Wnt ligand secretion and leads to β-catenin-driven radioresistance and metastasis.","method":"Conditional Dll1 knockout, co-culture assays between tumor cells and CAFs, Notch signaling reporter assays, β-catenin pathway analysis, radiation resistance assays","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 — KO with defined crosstalk mechanism, single study","pmids":["36007109"],"is_preprint":false},{"year":2022,"finding":"HUWE1 E3 ubiquitin ligase ubiquitinates and degrades N-Myc, which in turn inactivates downstream DLL1-NOTCH1 signaling, thereby suppressing GBM proliferation, invasion and migration; HUWE1 acts as a tumor suppressor through the N-Myc–DLL1–NOTCH1 axis.","method":"Ubiquitination assays, KO/overexpression in GBM cell lines and orthotopic xenografts, dCas9 synergistic activation mediator (SAM) system for HUWE1 overexpression in vivo","journal":"Cancer Communications","confidence":"Medium","confidence_rationale":"Tier 2 — ubiquitination assays plus in vivo xenograft, single study","pmids":["35848447"],"is_preprint":false},{"year":2022,"finding":"APE1 redox function activates NF-κB, which directly binds to and induces DLL1 expression in esophageal adenocarcinoma cells in response to acidic bile salts (reflux conditions); DLL1 is the predominant Notch ligand activating NOTCH1 in this context, and the APE1–NF-κB–DLL1–NOTCH1 axis promotes cancer stem-like properties.","method":"NF-κB chromatin immunoprecipitation on DLL1 promoter, APE1 redox inhibitor experiments, Notch intracellular domain nuclear accumulation assays, transgenic mouse model (L2-IL1β), cell line knockdown/overexpression","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP establishing direct transcriptional regulation, multiple functional assays, single study","pmids":["35750470"],"is_preprint":false},{"year":2013,"finding":"Normal development in mice ubiquitously overexpressing the intracellular domain of DLL1 (DICD), with no alteration in Notch target gene expression or early Notch-dependent processes, argues against a physiologically relevant reverse signaling function of the DLL1 intracellular domain in vivo; mouse DICD also enters the nucleus inefficiently.","method":"Ubiquitous transgenic overexpression of DLL1 intracellular domain (multiple versions) in mice, nuclear fractionation, Notch target gene expression analysis","journal":"PLoS ONE","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic test with multiple transgene versions and molecular readouts, clear null result","pmids":["24167636"],"is_preprint":false},{"year":2025,"finding":"USP11 deubiquitinase sustains survival of marginal zone B cells by regulating ubiquitination of the Notch ligands DLL1 and JAG2; loss of Usp11 leads to increased DLL1 ubiquitination and reduced MZ B cell survival after irradiation.","method":"Co-IP, ubiquitination assays in Usp11-/- mice, single-cell sequencing, flow cytometry, pharmacological Usp11 inhibition with mitoxantrone","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ubiquitination assays combined with KO mouse phenotype, single study","pmids":["39904982"],"is_preprint":false},{"year":2025,"finding":"DLL1-expressing tumor cells recruit PD-L1+ immunosuppressive M2-like tumor-associated macrophages through the CCR3/CCL7 axis, which maintain cancer stem cell activity and drive tamoxifen/fulvestrant resistance in ER+ luminal breast cancer; combination of anti-DLL1 and anti-PD-L1 antibodies with tamoxifen reduced tumor growth and reprogrammed the immunosuppressive tumor microenvironment.","method":"Conditional DLL1 knockout mouse models, patient-derived explants, cytokine/chemokine axis analysis (CCR3/CCL7), combination antibody therapy, CSC functional assays","journal":"Science Translational Medicine","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with mechanistic crosstalk (CCR3/CCL7) and functional rescue, single study","pmids":["41191774"],"is_preprint":false},{"year":2025,"finding":"Site-specific elongation of O-glucose glycan on NOTCH1 EGF10 (synthesized by B4GALT1 and ST3GAL4 to form a 3'-sialyllactose-like structure) significantly impacts DLL1- and DLL4-dependent NOTCH1 ligand binding and signal transduction; C4-2 amino acid position in the EGF domain is crucial for galactose elongation, affecting T cell differentiation through DLL1-NOTCH1 signaling.","method":"Mass spectrometry, site-directed mutagenesis, NOTCH1 activation assays with DLL1/DLL4 ligands, T cell differentiation assays in vivo","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 1 — MS-identified modification + mutagenesis + functional Notch activation assays, but focused on NOTCH1 glycosylation rather than DLL1 itself","pmids":["41129232"],"is_preprint":false}],"current_model":"DLL1 is a transmembrane Notch ligand whose activity requires ubiquitination-dependent recycling to acquire Notch-receptor affinity, followed by transendocytosis of the Notch extracellular domain to activate signaling; its surface presentation is regulated by scaffolding (MAGI1), protein stability (SYNJ2BP, estrogen/proteasomal control, USP11 deubiquitination), cytoskeletal trafficking (Arp2/3), and proteolytic shedding (MT1-MMP), while its transcription is driven by WNT–TCF/TBX6, MyoD, CDX, and Ptf1a axes depending on tissue context; structurally, the MNNL-DSL-EGF3 ectodomain region determines selectivity between NOTCH1 and NOTCH2, DLL1 acts as a trans-activator rather than a cis-inhibitor (unlike DLL4), and it functions in diverse developmental and adult contexts including somitogenesis, intestinal stem cell maintenance, neural progenitor quiescence, arterial identity, mammary stem cell niche, myogenesis, and β-cell insulin secretion."},"narrative":{"teleology":[{"year":1995,"claim":"Identification of DLL1 as the first mammalian Delta homologue established that the Notch ligand-receptor paradigm is conserved in vertebrates and provided the molecular entry point for studying Notch signaling in mammalian development.","evidence":"Molecular cloning, sequence analysis, and in situ hybridization in mouse embryos","pmids":["7671806"],"confidence":"High","gaps":["No functional assay confirming signaling activity","Receptor binding affinity not measured"]},{"year":2003,"claim":"Genetic epistasis in somite patterning placed DLL1 upstream of MESP2 and dependent on PRESENILIN1, establishing the first in vivo pathway hierarchy for DLL1-Notch signaling in a specific developmental context and distinguishing its pathway from the DLL3-dependent branch.","evidence":"Systematic double-mutant analysis of Dll1, Dll3, Mesp2, and Psen1 knockout mice","pmids":["12900443"],"confidence":"High","gaps":["Biochemical basis of DLL3 antagonism to DLL1 unknown","Whether DLL1 feeds back on its own transcription not resolved molecularly"]},{"year":2004,"claim":"Demonstration that WNT–LEF/TCF and TBX6 synergistically activate Dll1 transcription answered how DLL1 expression is initiated in the presomitic mesoderm, linking Wnt and Notch pathways in the segmentation clock.","evidence":"Transgenic reporter assays with mutated promoter elements in vivo, plus in vitro transactivation assays","pmids":["15545628","15986483"],"confidence":"High","gaps":["Chromatin-level regulation (enhancer accessibility) not examined","Whether other T-box factors compensate in non-PSM tissues unclear"]},{"year":2005,"claim":"Discovery that MAGI1 recruits and stabilizes DLL1 at adherens junctions revealed a scaffolding mechanism governing ligand surface presentation, explaining how cell-cell contact geometry can regulate Notch signaling strength.","evidence":"Yeast two-hybrid, reciprocal co-immunoprecipitation, and co-localization at adherens junctions in neural tube and fibroblasts","pmids":["15908431"],"confidence":"High","gaps":["Whether MAGI1 loss phenocopies DLL1 loss in vivo not tested","Stoichiometry and competitive binding with other PDZ ligands unknown"]},{"year":2008,"claim":"Ubiquitination-dependent recycling was shown to be essential for DLL1 to acquire Notch-binding competence, and a separate transendocytosis step was demonstrated as necessary for signal activation, resolving the longstanding question of why endocytosis is required in the signal-sending cell.","evidence":"Ubiquitination-defective DLL1 mutants, recycling and Notch1 binding assays, DLL1-DLL3 chimera transendocytosis assays, lipid microdomain fractionation","pmids":["18676613"],"confidence":"High","gaps":["Identity of the E3 ligase responsible for this recycling-promoting ubiquitination not pinpointed in this study","Structural basis for how recycling confers binding competence unknown"]},{"year":2009,"claim":"Endothelial-specific DLL1 deletion revealed a non-redundant role in maintaining fetal arterial identity through VEGFR2/NRP1 regulation, distinguishing DLL1 from DLL4 in vascular Notch signaling.","evidence":"Conditional endothelial-specific Dll1 knockout mice with immunofluorescence and Nrp1 promoter-RBPJκ reporter assays","pmids":["19144989"],"confidence":"High","gaps":["Whether DLL1 loss affects adult arterial maintenance not addressed","Direct vs. indirect mechanism of VEGFR2 regulation unclear"]},{"year":2011,"claim":"MT1-MMP was identified as a metalloprotease that cleaves DLL1 on stromal cells, providing a mechanism to negatively regulate Notch ligand availability; this explained how the bone marrow niche tunes Notch signaling for B-lymphopoiesis.","evidence":"Recombinant enzyme cleavage of synthetic DLL1 peptide, MT1-MMP knockout mouse phenotype rescued by Notch inhibitor DAPT","pmids":["21572390"],"confidence":"High","gaps":["Cleavage site specificity and whether other MMPs contribute not fully resolved","Whether MT1-MMP regulates DLL1 outside the bone marrow niche untested"]},{"year":2011,"claim":"Combinatorial conditional knockout of Dll1 and Dll4 in the intestinal epithelium established these as the essential Notch ligands maintaining intestinal stem cells, while Elavl1/HuR was shown to post-transcriptionally stabilize Dll1 mRNA during neural progenitor mitosis — together revealing both tissue-level redundancy and cell-cycle-coupled mRNA regulation.","evidence":"Inducible gut-specific Dll1/Dll4/Jag1 single and compound knockouts; RNA immunoprecipitation and mRNA stability assays for Elavl1 plus Elavl1 heterozygous retinal analysis","pmids":["21238454","21346194"],"confidence":"High","gaps":["Which cell type supplies DLL1 vs DLL4 signal to stem cells not resolved","Whether Elavl1 stabilization operates in non-neural tissues unknown"]},{"year":2012,"claim":"Lineage tracing showed that Dll1-high intestinal cells are secretory progenitors that can revert to stemness upon tissue damage, establishing DLL1 expression as a marker of facultative stem cell potential and demonstrating plasticity in the intestinal hierarchy.","evidence":"Dll1(GFP-ires-CreERT2) knock-in mice with lineage tracing and organoid formation after tissue damage","pmids":["23000963"],"confidence":"High","gaps":["Molecular mechanism of de-differentiation not defined","Whether DLL1 is functionally required for reversion or is merely a marker unclear"]},{"year":2013,"claim":"Multiple studies converged to show that DLL1 serves as a niche signal from progeny to parent stem cells: in the adult SVZ, activated NSC progeny asymmetrically inherit DLL1 and maintain neighboring quiescent NSCs; in the neocortex, intermediate progenitors supply DLL1 to radial glia via dynamic processes; and SYNJ2BP was identified as a stabilizer of DLL1 protein that modulates endothelial Notch signaling.","evidence":"Conditional Dll1 KO in SVZ with live-cell imaging of asymmetric segregation; multiphoton live imaging with Notch reporters in cortical slices; Co-IP and protein stability assays for SYNJ2BP","pmids":["23695674","23699523","24025447"],"confidence":"High","gaps":["Mechanism of asymmetric DLL1 segregation at the molecular level unknown","Whether SYNJ2BP competes with MAGI1 for DLL1 PDZ-binding motif untested"]},{"year":2013,"claim":"Ubiquitous overexpression of the DLL1 intracellular domain in mice produced no developmental phenotype, arguing against a physiologically relevant 'reverse signaling' function for the DLL1 cytoplasmic fragment.","evidence":"Multiple transgenic mouse lines expressing DLL1 intracellular domain ubiquitously, with nuclear fractionation and Notch target gene analysis","pmids":["24167636"],"confidence":"High","gaps":["Cannot exclude context-specific reverse signaling below detection threshold","Does not rule out functions requiring ligand-receptor interaction to release ICD"]},{"year":2014,"claim":"Mass spectrometry identified sequential phosphorylation sites in the DLL1 intracellular domain that increase protein stability and Notch1 activation in vitro, though knock-in mice with phospho-deficient DLL1 developed normally, indicating phosphorylation is dispensable under standard conditions.","evidence":"Mass spectrometry, phospho-deficient mutagenesis, coculture Notch activation assays, knock-in mice","pmids":["24449764"],"confidence":"High","gaps":["Whether phosphorylation becomes essential under stress or in specific tissues unknown","Kinase identity for the threonine site not identified"]},{"year":2015,"claim":"Direct comparison showed DLL1 functions as a pure trans-activator whereas DLL4 also acts as a potent cis-inhibitor; DLL4 knocked into the Dll1 locus cannot rescue somitogenesis, establishing that functional non-equivalence derives from cis-inhibition capacity rather than trans-activation potency.","evidence":"DLL4 knock-in at Dll1 locus mice, conditional overexpression from HPRT locus, quantitative Notch trans/cis assays in vitro","pmids":["26114479"],"confidence":"High","gaps":["Structural basis for why DLL1 lacks cis-inhibition not determined","Whether intermediate cis-inhibition occurs at supraphysiological DLL1 levels unknown"]},{"year":2016,"claim":"Systematic EGF-repeat mutagenesis revealed that all eight EGF repeats contribute to DLL1 activity, and MIB1 E3 ligase was shown to couple Notch ligand-receptor engagement to DLL1 endocytosis through SNX18-dynamin2, linking the ubiquitination and endocytic machineries.","evidence":"Allelic series of disulfide-bridge mutations at Dll1 locus in mice with in vitro Notch activation assays; Co-IP and endocytosis assays for MIB1-SNX18-dynamin2","pmids":["26801181","26923255"],"confidence":"High","gaps":["Which EGF repeats contact Notch directly vs. play structural roles unresolved","MIB1-SNX18-dynamin2 axis not validated in vivo"]},{"year":2018,"claim":"The MNNL–DSL–EGF3 ectodomain region was mapped as the determinant of DLL1 vs. DLL4 receptor selectivity, with DLL1 activating NOTCH1 and NOTCH2 equivalently while DLL4 preferentially activates NOTCH1; separately, mammary stem cell–expressed DLL1 was shown to activate Notch in stromal macrophages, triggering Wnt ligand production in a feedback loop essential for ductal morphogenesis.","evidence":"Chimeric ligand knock-in mice plus cell-based binding and activation assays for ectodomain mapping; conditional Dll1 KO in mammary gland with co-culture Wnt ligand measurements","pmids":["30289388","29773667"],"confidence":"High","gaps":["Atomic-resolution structure of DLL1-NOTCH2 complex unavailable","How macrophage Wnt secretion feeds back specifically to DLL1+ stem cells mechanistically undefined"]},{"year":2018,"claim":"Estrogen signaling was found to stabilize DLL1 protein by blocking its ubiquitination and proteasomal/lysosomal degradation in ERα+ breast cancer, revealing a hormone-dependent post-translational regulatory axis for DLL1 and linking it to cancer stem cell maintenance.","evidence":"DLL1 conditional KO in breast cancer mouse models, ubiquitination assays, proteasome and lysosome inhibitor treatments","pmids":["30442981"],"confidence":"High","gaps":["The E3 ligase targeted by estrogen signaling not identified","Whether this mechanism operates in normal mammary epithelium unclear"]},{"year":2020,"claim":"Oscillatory Dll1/Hes1 expression was shown to drive multipotent pancreatic progenitor expansion, and loss of DLL1/DLL4 in adult β-cells improved insulin secretion, establishing DLL1-Notch as a functional regulator of pancreatic endocrine physiology beyond development.","evidence":"Conditional Dll1/Jag1 knockouts with Hes1 oscillation live imaging in pancreatic progenitors; β-cell-specific Dll1/Dll4 double KO with glucose tolerance and insulin secretion assays","pmids":["32059775","32029480"],"confidence":"High","gaps":["Whether DLL1 and DLL4 have distinct roles in β-cells not resolved","Downstream effectors of DLL1-Notch in β-cell insulin granule dynamics unknown"]},{"year":2021,"claim":"MyoD was shown to directly activate Dll1 through E-box elements, and DLL1 simultaneously trans-activates Notch in neighbors and cis-inhibits Notch in the DLL1-expressing myoblast itself, creating a feedback loop that coordinates the balance between differentiation and progenitor maintenance during myogenesis.","evidence":"CRISPR E-box disruption in human myoblasts, E-box-deficient mouse model, functional rescue experiments","pmids":["34370738"],"confidence":"High","gaps":["Whether DLL1 cis-inhibition in myoblasts contradicts the general finding that DLL1 lacks cis-inhibition needs resolution","Quantitative contribution of DLL1 vs. DLL4 in adult muscle regeneration unclear"]},{"year":2022,"claim":"Several cancer-context studies established DLL1 as a node in tumor-stroma crosstalk: DLL1+ tumor cells activate Notch in CAFs to induce Wnt-driven radioresistance, NF-κB directly transactivates DLL1 in esophageal adenocarcinoma downstream of APE1, and HUWE1 suppresses the N-Myc–DLL1–NOTCH1 axis in glioblastoma.","evidence":"Conditional DLL1 KO with co-culture and radiation assays; ChIP of NF-κB on DLL1 promoter; HUWE1 ubiquitination assays and orthotopic xenografts","pmids":["36007109","35750470","35848447"],"confidence":"Medium","gaps":["DLL1 transcriptional regulation in esophageal context from single study","Whether HUWE1 regulates DLL1 directly or only indirectly via N-Myc not clear","CAF Wnt-Notch loop not validated in human patient samples"]},{"year":2025,"claim":"USP11 was identified as a deubiquitinase that stabilizes DLL1 in marginal zone B cells, and DLL1+ tumor cells were shown to recruit immunosuppressive PD-L1+ macrophages via CCR3/CCL7, revealing new layers of DLL1 post-translational control and immune-modulatory function in the tumor microenvironment.","evidence":"Usp11 KO mice with ubiquitination assays and flow cytometry; conditional DLL1 KO mouse breast cancer models with combination anti-DLL1/anti-PD-L1 therapy","pmids":["39904982","41191774"],"confidence":"Medium","gaps":["USP11-DLL1 interaction not validated by reciprocal IP or structural data","CCR3/CCL7 axis specificity to DLL1-expressing tumors vs. general Notch activation unclear","O-glycosylation of NOTCH1 affecting DLL1 binding (PMID:41129232) studied mainly from receptor side"]},{"year":null,"claim":"Key unresolved questions include: (1) the atomic-resolution structural basis for DLL1-NOTCH2 vs. DLL1-NOTCH1 binding equivalence and DLL1's lack of cis-inhibitory capacity; (2) how ubiquitination-dependent recycling conformationally activates DLL1; (3) whether DLL1 reverse signaling has any context-dependent physiological role despite negative in vivo evidence; and (4) the therapeutic window for anti-DLL1 strategies in cancer given its essential roles in adult tissue homeostasis.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution DLL1-Notch co-crystal structure available","Conformational change upon recycling not demonstrated","Reverse signaling tested only in standard developmental conditions"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,5,6,8,15,22]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,5,22]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,5,19]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[5,17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,6,8,11,13,15,22]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2,4,6,11,16,23,25]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[20,26,27,28,29,32]}],"complexes":[],"partners":["NOTCH1","NOTCH2","MAGI1","SYNJ2BP","MIB1","MT1-MMP","USP11","ELAVL1"],"other_free_text":[]},"mechanistic_narrative":"DLL1 is a transmembrane Notch ligand that functions as a trans-activating signal in diverse developmental and adult tissue contexts, including somitogenesis, neural progenitor maintenance, intestinal stem cell fate, arterial identity, mammary gland morphogenesis, myogenesis, and pancreatic β-cell insulin secretion [PMID:7671806, PMID:12900443, PMID:21238454, PMID:19144989, PMID:29773667, PMID:34370738, PMID:32029480]. Its signaling competence requires ubiquitination-dependent endocytic recycling to acquire high Notch-binding affinity, followed by transendocytosis of the Notch extracellular domain; surface presentation is further regulated by MAGI1 scaffolding at adherens junctions, SYNJ2BP-mediated stabilization, Arp2/3-dependent vesicular trafficking, phosphorylation of its intracellular domain, USP11 deubiquitination, estrogen-mediated protection from proteasomal degradation, and proteolytic shedding by MT1-MMP [PMID:18676613, PMID:15908431, PMID:24025447, PMID:28380416, PMID:24449764, PMID:39904982, PMID:30442981, PMID:21572390]. DLL1 transcription is directly activated by WNT–LEF/TCF in synergy with TBX6 in presomitic mesoderm, by MyoD through E-box elements in myoblasts, and by NF-κB in inflammatory contexts, while the MNNL–DSL–EGF3 ectodomain region determines receptor selectivity, enabling DLL1 to activate NOTCH1 and NOTCH2 with comparable efficiency—unlike DLL4, which preferentially activates NOTCH1 and also acts as a potent cis-inhibitor [PMID:15545628, PMID:34370738, PMID:35750470, PMID:30289388, PMID:26114479]. In the intestine, DLL1-expressing secretory progenitors mark the immediate progeny of Lgr5+ stem cells and can revert to stemness upon tissue damage, while in breast cancer, DLL1+ tumor-initiating cells activate Notch in stromal fibroblasts and macrophages to create Wnt-dependent feedback loops that drive chemoresistance and immune evasion [PMID:23000963, PMID:33462238, PMID:36007109, PMID:41191774]."},"prefetch_data":{"uniprot":{"accession":"O00548","full_name":"Delta-like protein 1","aliases":["Drosophila Delta homolog 1","Delta1","H-Delta-1"],"length_aa":723,"mass_kda":78.1,"function":"Transmembrane ligand protein of NOTCH1, NOTCH2 and NOTCH3 receptors that binds the extracellular domain (ECD) of Notch receptor in a cis and trans fashion manner (PubMed:11006133). Following transinteraction, ligand cells produce mechanical force that depends of a clathrin-mediated endocytosis, requiring ligand ubiquitination, EPN1 interaction, and actin polymerisation; these events promote Notch receptor extracellular domain (NECD) transendocytosis and triggers Notch signaling through induction of cleavage, hyperphosphorylation, and nuclear accumulation of the intracellular domain of Notch receptors (NICD) (By similarity). Is required for embryonic development and maintenance of adult stem cells in many different tissues and immune systeme; the DLL1-induced Notch signaling is mediated through an intercellular communication that regulates cell lineage, cell specification, cell patterning and morphogenesis through effects on differentiation and proliferation (PubMed:11581320). Plays a role in brain development at different level, namely by regulating neuronal differentiation of neural precursor cells via cell-cell interaction, most likely through the lateral inhibitory system in an endogenous level dependent-manner. During neocortex development, Dll1-Notch signaling transmission is mediated by dynamic interactions between intermediate neurogenic progenitors and radial glia; the cell-cell interactions are mediated via dynamic and transient elongation processes, likely to reactivate/maintain Notch activity in neighboring progenitors, and coordinate progenitor cell division and differentiation across radial and zonal boundaries. During cerebellar development, regulates Bergmann glial monolayer formation and its morphological maturation through a Notch signaling pathway. At the retina and spinal cord level, regulates neurogenesis by preventing the premature differentiation of neural progenitors and also by maintaining progenitors in spinal cord through Notch signaling pathway. Also controls neurogenesis of the neural tube in a progenitor domain-specific fashion along the dorsoventral axis. Maintains quiescence of neural stem cells and plays a role as a fate determinant that segregates asymmetrically to one daughter cell during neural stem cells mitosis, resulting in neuronal differentiation in Dll1-inheriting cell. Plays a role in immune systeme development, namely the development of all T-cells and marginal zone (MZ) B-cells (By similarity). Blocks the differentiation of progenitor cells into the B-cell lineage while promoting the emergence of a population of cells with the characteristics of a T-cell/NK-cell precursor (PubMed:11581320). Also plays a role during muscle development. During early development, inhibits myoblasts differentiation from the medial dermomyotomal lip and later regulates progenitor cell differentiation. Directly modulates cell adhesion and basal lamina formation in satellite cells through Notch signaling. Maintains myogenic progenitors pool by suppressing differentiation through down-regulation of MYOD1 and is required for satellite cell homing and PAX7 expression. During craniofacial and trunk myogenesis suppresses differentiation of cranial mesoderm-derived and somite-derived muscle via MYOD1 regulation but in cranial mesoderm-derived progenitors, is neither required for satellite cell homing nor for PAX7 expression. Also plays a role during pancreatic cell development. During type B pancreatic cell development, may be involved in the initiation of proximodistal patterning in the early pancreatic epithelium. Stimulates multipotent pancreatic progenitor cells proliferation and pancreatic growth by maintaining HES1 expression and PTF1A protein levels. During fetal stages of development, is required to maintain arterial identity and the responsiveness of arterial endothelial cells for VEGFA through regulation of KDR activation and NRP1 expression. Controls sprouting angiogenesis and subsequent vertical branch formation through regulation on tip cell differentiation. Negatively regulates goblet cell differentiation in intestine and controls secretory fat commitment through lateral inhibition in small intestine. Plays a role during inner ear development; negatively regulates auditory hair cell differentiation. Plays a role during nephron development through Notch signaling pathway. Regulates growth, blood pressure and energy homeostasis (By similarity)","subcellular_location":"Apical cell membrane; Cell junction, adherens junction; Membrane raft","url":"https://www.uniprot.org/uniprotkb/O00548/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DLL1","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DLL1","total_profiled":1310},"omim":[{"mim_id":"618709","title":"NEURODEVELOPMENTAL DISORDER WITH NONSPECIFIC BRAIN ABNORMALITIES AND WITH OR WITHOUT SEIZURES; NEDBAS","url":"https://www.omim.org/entry/618709"},{"mim_id":"618024","title":"NOTCH2 N-TERMINAL-LIKE B; NOTCH2NLB","url":"https://www.omim.org/entry/618024"},{"mim_id":"615893","title":"NEURALIZED E3 UBIQUITIN PROTEIN LIGASE 1B; NEURL1B","url":"https://www.omim.org/entry/615893"},{"mim_id":"615544","title":"PERIVENTRICULAR NODULAR HETEROTOPIA 6; PVNH6","url":"https://www.omim.org/entry/615544"},{"mim_id":"615532","title":"ENDOPLASMIC RETICULUM MEMBRANE-ASSOCIATED RNA DEGRADATION PROTEIN; ERMARD","url":"https://www.omim.org/entry/615532"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":42.7}],"url":"https://www.proteinatlas.org/search/DLL1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O00548","domains":[{"cath_id":"2.60.40.3510","chopping":"17-189","consensus_level":"high","plddt":86.6807,"start":17,"end":189}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00548","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00548-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00548-F1-predicted_aligned_error_v6.png","plddt_mean":75.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DLL1","jax_strain_url":"https://www.jax.org/strain/search?query=DLL1"},"sequence":{"accession":"O00548","fasta_url":"https://rest.uniprot.org/uniprotkb/O00548.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00548/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00548"}},"corpus_meta":[{"pmid":"23000963","id":"PMC_23000963","title":"Dll1+ secretory progenitor cells revert to stem 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   \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — foundational identification of protein structure and ligand-receptor relationship, >400 citations\",\n      \"pmids\": [\"7671806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"WNT signaling, acting through LEF/TCF factors in synergy with the T-box transcription factor TBX6, directly activates transcription of Dll1 in the tailbud and presomitic mesoderm (PSM), controlling Notch activity and somite formation; mutation of either T or LEF/TCF binding sites in the Dll1 promoter abolishes reporter expression in transgenic embryos.\",\n      \"method\": \"Transgenic reporter assays in vivo, in vitro promoter transactivation assays with LEF/TCF and TBX6, mutational analysis of Dll1 promoter elements\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro promoter assays combined with in vivo transgenic validation with mutagenesis\",\n      \"pmids\": [\"15545628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TBX6 directly binds to two of four putative Tbx6 binding sites in the Dll1 paraxial mesoderm enhancer in vitro, and Dll1 expression is lost in Tbx6 mutants, establishing Dll1 as a direct transcriptional target of TBX6 in the presomitic mesoderm.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA/in vitro DNA binding), in vivo genetic analysis of Tbx6 mutant embryos\",\n      \"journal\": \"Genesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro binding assay combined with in vivo genetic evidence\",\n      \"pmids\": [\"15986483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MAGI1, a PDZ scaffolding molecule, directly binds DLL1 at cadherin-based adherens junctions in the developing neural tube, recruits DLL1 to these junctions, and stabilizes DLL1 on the cell surface, providing a mechanism for DLL1 presentation to activate Notch in neighboring cells.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, immunofluorescence localization in developing spinal cord and cultured AJ-forming fibroblasts\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding confirmed, functional stabilization demonstrated, localization linked to function\",\n      \"pmids\": [\"15908431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Positive and negative feedback loops comprising DLL1 and the transcription factor MESP2 are crucial for rostrocaudal patterning of somites; epistatic analysis revealed that PRESENILIN1 (Psen1) is required for DLL1-Notch signaling to activate DLL1 itself, while a Psen1-independent DLL3-Notch pathway may counteract the Psen1-dependent DLL1-Notch pathway.\",\n      \"method\": \"Genetic epistasis analysis using Dll1, Dll3, Mesp2, and Psen1 mutant and double-mutant mice\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic genetic epistasis with multiple mutant combinations establishing pathway hierarchy\",\n      \"pmids\": [\"12900443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Ubiquitination of DLL1 is required for its recycling back to the cell surface after endocytosis and for acquiring high affinity for Notch1; an ubiquitination-defective DLL1 mutant is endocytosed but fails to recycle and cannot efficiently bind Notch1. A DLL1-DLL3 chimera can be recycled and bind Notch1 but cannot perform transendocytosis of the Notch1 extracellular domain, indicating transendocytosis is required for Notch signaling activation. DLL1 partially localizes to lipid microdomains required for its signaling activity.\",\n      \"method\": \"Ubiquitination-defective mutagenesis, endocytosis/recycling assays, Notch1 binding assays, transendocytosis assays, lipid microdomain fractionation\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with multiple orthogonal functional assays establishing mechanism\",\n      \"pmids\": [\"18676613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DLL1 is an essential Notch ligand in fetal arterial endothelial cells that activates Notch1 to maintain arterial identity; loss of DLL1 function leads to downregulation of VEGFR2 and its co-receptor NRP1, followed by upregulation of the venous fate repressor COUP-TFII, establishing DLL1 as distinct from DLL4 in the vasculature.\",\n      \"method\": \"Conditional knockout mice (endothelial-specific DLL1 deletion), immunofluorescence, in vitro Nrp1 promoter-RBPJκ reporter assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype plus mechanistic promoter validation\",\n      \"pmids\": [\"19144989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MT1-MMP (MMP14) expressed on bone marrow stromal cells directly cleaves DLL1 on the cell surface; recombinant MT1-MMP cleaves a synthetic DLL1 peptide at the same site as cell-surface cleavage. Loss of MT1-MMP in stromal cells increases Notch signaling in hematopoietic progenitor cells and specifically impairs B-lymphocyte development, which is rescued by the Notch inhibitor DAPT.\",\n      \"method\": \"Co-IP (MT1-MMP–DLL1 interaction), in vitro cleavage of synthetic DLL1 peptide by recombinant MT1-MMP, Notch inhibitor rescue experiments in vitro and in vivo with MT1-MMP knockout mice\",\n      \"journal\": \"EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic cleavage assay plus in vivo genetic rescue, reciprocal Co-IP\",\n      \"pmids\": [\"21572390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Inactivation of Dll1 alone in the intestinal epithelium causes a moderate increase in goblet cells; simultaneous inactivation of Dll1 and Dll4 causes complete conversion of proliferating progenitors to postmitotic goblet cells with loss of intestinal stem cells (Olfm4+, Lgr5+, Ascl2+), establishing DLL1 and DLL4 as the physiological Notch ligands required for intestinal stem cell maintenance.\",\n      \"method\": \"Inducible gut-specific conditional knockout (Vil-Cre-ERT2) of Dll1, Dll4, and Jag1 singly and in combination; lineage tracing with Notch1 reporter\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with defined stem cell phenotype, multiple ligand combinations tested\",\n      \"pmids\": [\"21238454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Elavl1/HuR ribonucleoprotein binds the 3' UTR of Dll1 mRNA and stabilizes it during mitosis in neuroepithelial cells; RNAi against Elavl1 reduces Dll1-3'UTR transcript stability in mitosis-arrested cells, and Elavl1 heterozygous null mice show decreased Dll1 expression and increased neurogenesis in the developing retina.\",\n      \"method\": \"RNAi knockdown, RNA immunoprecipitation (RIP), mRNA stability assay, in vivo analysis of Elavl1 heterozygous mouse retina\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNA binding demonstrated by RIP, functional consequence confirmed in vivo and in vitro\",\n      \"pmids\": [\"21346194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Dll1-expressing secretory progenitor cells (immediate daughters of Lgr5+ intestinal stem cells) generate all four secretory cell types through Notch lateral inhibition; upon tissue damage, Dll1-high cells reacquire stem cell properties (form organoids with Wnt3A exposure and undergo stem cell tracing events).\",\n      \"method\": \"Lineage tracing using Dll1(GFP-ires-CreERT2) knock-in mice, organoid culture, genetic marking before tissue damage\",\n      \"journal\": \"Nature Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo lineage tracing with functional organoid assay, >600 citations\",\n      \"pmids\": [\"23000963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DLL1 protein is induced in activated neural stem cells (NSCs) in the adult mouse subventricular zone and segregates asymmetrically to one daughter cell during mitosis; DLL1-expressing cells reside adjacent to quiescent NSCs and are required to maintain quiescent NSC identity, suggesting a feedback niche signal from progeny to parent NSC.\",\n      \"method\": \"Conditional knockout of Dll1 in the adult SVZ, live-cell imaging of DLL1 segregation during mitosis, proximity analysis of DLL1-expressing cells and quiescent NSCs\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined NSC phenotype, live-cell imaging of asymmetric segregation\",\n      \"pmids\": [\"23695674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Intermediate neurogenic progenitors (INPs) serve as a source of DLL1 and interact with radial glia (RG) via dynamic elongate processes (some long-range, some filopodia-like) to transmit Notch signals in the embryonic neocortical niche; live multiphoton microscopy and Notch-pathway reporters confirmed these dynamic cell–cell contacts.\",\n      \"method\": \"High-resolution live-cell multiphoton microscopy with Notch reporter in organotypic brain slices, gene expression profiling of sorted RG and INP populations\",\n      \"journal\": \"Journal of Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — live imaging of cell contacts with functional reporters, single study\",\n      \"pmids\": [\"23699523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SYNJ2BP (synaptojanin-2 binding protein) interacts with the PDZ-binding motif at the C-terminus of DLL1 (and DLL4 but not JAG1), enhances DLL1 protein stability, promotes Notch signaling (inducing HEY1, LFNG, ephrin-B2), and inhibits endothelial tip cell formation and sprouting angiogenesis.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assays, Notch target gene qPCR, endothelial cell functional assays (migration, proliferation), in vivo vascular network formation in immunocompromised mice\",\n      \"journal\": \"Circulation Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, protein stabilization assay, and functional validation both in vitro and in vivo\",\n      \"pmids\": [\"24025447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Phosphorylation of DLL1 occurs sequentially at two serine residues (one likely by protein kinase B/AKT) and one threonine residue in the intracellular domain; phosphorylation requires membrane association, increases DLL1 stability, affects surface levels, and phosphorylation-deficient DLL1 activates Notch1 significantly less efficiently in vitro, though mice with the phosphorylation-deficient DLL1 develop normally.\",\n      \"method\": \"Mass spectrometry identification of phosphorylation sites, site-directed mutagenesis, Notch1 coculture activation assays, knock-in mice expressing phosphorylation-deficient DLL1\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — MS identification + mutagenesis + in vitro Notch activation assay + in vivo knock-in\",\n      \"pmids\": [\"24449764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DLL4, but not DLL1, efficiently acts as a cis-inhibitor of Notch signaling in cells co-expressing Notch receptor and ligand; both ligands have similar trans-activation potential but DLL4 causes reduced net Notch activation through cis-inhibition, explaining context-dependent functional divergence. In the presomitic mesoderm (PSM), DLL4 cannot replace DLL1 for somitogenesis despite equivalent expression from the Dll1 locus.\",\n      \"method\": \"Conditional overexpression from HPRT locus, DLL4 knock-in into Dll1 locus (Dll1Dll4ki mice), Notch transactivation and cis-inhibition assays in vitro, in vivo analysis of somitogenesis and retinal progenitor maintenance\",\n      \"journal\": \"PLoS Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple in vitro assays plus multiple in vivo knock-in/knock-out models\",\n      \"pmids\": [\"26114479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The structural integrity of each individual EGF repeat in the extracellular domain of DLL1 is required for full DLL1 activity; disulfide-bridge-disrupting mutations in each EGF repeat impair both NOTCH1 and NOTCH2 activation similarly in vitro, and certain mutations (particularly in specific EGF repeats) affect somite patterning in vivo resembling spondylocostal dysostosis.\",\n      \"method\": \"Site-directed mutagenesis of each EGF repeat, Notch transactivation coculture assays in vitro, allelic series of point mutations knocked into endogenous Dll1 locus in mice\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis combined with in vitro activation assays and in vivo allelic series\",\n      \"pmids\": [\"26801181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MIB1 (mind bomb 1 ubiquitin ligase) is required for efficient DLL1 endocytosis by promoting dynamin 2 recruitment via SNX18; MIB1 ubiquitin ligase activity is induced by Notch ligand–receptor interaction, and MIB1 promotes the SNX18–dynamin 2 interaction in an ubiquitin-ligase-activity-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, endocytosis assays, ubiquitin ligase activity assays\",\n      \"journal\": \"Genes to Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and functional endocytosis assays, single study\",\n      \"pmids\": [\"26923255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Osteoblast-specific overexpression of DLL1 (but not JAG1) promotes proliferation of committed but immature osteoblasts while inhibiting their further maturation; this maturational arrest impairs osteoclast coupling and suppresses bone metabolic turnover, establishing DLL1-Notch signaling as critical for bone remodeling.\",\n      \"method\": \"Osteoblast-specific transgenic overexpression of DLL1 and JAG1 in mice, bone histomorphometry, osteoblast and osteoclast differentiation assays\",\n      \"journal\": \"Journal of Cellular Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transgenic gain-of-function with defined cellular phenotype, single study\",\n      \"pmids\": [\"27735989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Arp2/3 complex is required for vesicular transport of DLL1 from cytoplasm to the cell membrane in glioma-initiating cells; Arp2/3 inhibition prevents DLL1 from reaching the surface (and activating Notch1), impairing stem cell phenotype maintenance, which can be rescued by exogenous soluble DLL1 but not by endogenous DLL1.\",\n      \"method\": \"shRNA knockdown of DLL1 and Arp2/3 components, Arp2/3 pharmacological inhibition, rescue with soluble DLL1, intracranial xenograft model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional rescue experiments establishing trafficking mechanism, single study\",\n      \"pmids\": [\"28380416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Estrogen signaling stabilizes DLL1 protein by preventing its proteasomal and lysosomal degradation and inhibiting DLL1 ubiquitination, thereby maintaining DLL1-mediated Notch signaling specifically in ERα+ luminal breast cancer to promote tumor proliferation, angiogenesis, and cancer stem cell function.\",\n      \"method\": \"Conditional DLL1 knockout in breast cancer mouse models, ubiquitination assays, proteasome/lysosome inhibitor treatments, tumor growth and metastasis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KO, ubiquitination assay, degradation pathway assays) in single study\",\n      \"pmids\": [\"30442981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MaSC-expressed DLL1 activates Notch signaling in stromal macrophages, which increases macrophage expression of Wnt ligands (Wnt3, Wnt10A, Wnt16), creating a feedback loop that promotes the function of Dll1-expressing mammary stem cells; conditional deletion of Dll1 reduces MaSC number and impairs ductal morphogenesis.\",\n      \"method\": \"Conditional knockout of Dll1 in mammary gland stem cells, co-culture assays, measurement of Wnt ligand expression in macrophages\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined stem cell and morphogenesis phenotype plus mechanistic Notch-Wnt crosstalk demonstrated\",\n      \"pmids\": [\"29773667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The ectodomains of DLL1 and DLL4 determine their differential receptor selectivity: DLL4 preferentially activates NOTCH1 over NOTCH2, whereas DLL1 is equally effective in activating NOTCH1 and NOTCH2; the region between the N-terminus and EGF repeat 3 (MNNL and DSL domains) confers this selectivity in cell-based assays, and chimeric ligand knock-in mice confirm ectodomain-driven function in vivo.\",\n      \"method\": \"Cellular co-culture Notch activation assays, biochemical binding studies, chimeric ligand knock-in mice, mutagenesis of NOTCH1-interface residues in DLL1\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution in cell-based assays + mutagenesis + in vivo knock-in chimera experiments\",\n      \"pmids\": [\"30289388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Oscillatory expression of DLL1 and HES1 in multipotent pancreatic progenitor cells (MPCs) drives MPC expansion, with changes in Hes1 oscillation parameters associated with bipotent progenitor versus pro-acinar cell fate; JAG1 restrains MPC growth but later drives bipotent progenitor specification in combination with DLL1.\",\n      \"method\": \"Conditional knockout of Dll1 and Jag1 (single and double mutants), live imaging of oscillatory reporters (Hes1), lineage analysis of pancreatic progenitor fates\",\n      \"journal\": \"Developmental Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, oscillation imaging, multiple mutant combinations\",\n      \"pmids\": [\"32059775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DLL1 and DLL4 are specifically expressed in adult pancreatic β-cells; mice lacking both DLL1 and DLL4 in adult β-cells show improved glucose tolerance and increased glucose-stimulated insulin secretion, while overexpression of the DLL1 intracellular domain in β-cells impairs glucose tolerance and insulin secretion, establishing a role for DLL1-Notch signaling in β-cell function.\",\n      \"method\": \"Conditional knockout of Dll1 and Dll4 in adult β-cells (Ins-Cre), overexpression of DLL1 intracellular domain in β-cells, glucose tolerance tests, insulin secretion assays in vitro and in vivo\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO and gain-of-function with functional metabolic readouts\",\n      \"pmids\": [\"32029480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MyoD directly activates Dll1 transcription through E-box motifs in the Dll1 cis-regulatory region in myoblasts; Dll1-expressing cells activate Notch in neighboring myoblasts (trans-activation) to prevent premature differentiation, while autonomously inhibiting Notch in Dll1-expressing cells (cis-inhibition) to facilitate myogenic differentiation, creating a feedback loop.\",\n      \"method\": \"Gain/loss-of-function experiments in mouse and human myoblasts, CRISPR-mediated E-box disruption, novel E-box deficient mouse model, ChIP (implied by promoter analysis), in vivo myogenesis assays\",\n      \"journal\": \"PLoS Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo knock-in E-box mutant model + CRISPR in human cells + functional rescue\",\n      \"pmids\": [\"34370738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Dll1+ breast tumor cells bearing NF-κB activation represent quiescent tumor-initiating cancer cells (TICs) that drive chemoresistance; RNA-seq and ATAC-seq show NF-κB activation is downstream of Dll1, and pharmacological blocking of Dll1 or NF-κB completely sensitizes Dll1+ tumors to chemotherapy.\",\n      \"method\": \"Conditional knockout mouse models, Dll1 reporter models, RNA-seq, ATAC-seq, pharmacological NF-κB and Dll1 blockade, in vivo tumor growth and metastasis assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genomic and functional approaches in KO models establishing pathway placement\",\n      \"pmids\": [\"33462238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Dll1+ breast cancer cells activate Notch signaling in cancer-associated fibroblasts (CAFs), which increases CAF Wnt ligand secretion and leads to β-catenin-driven radioresistance and metastasis.\",\n      \"method\": \"Conditional Dll1 knockout, co-culture assays between tumor cells and CAFs, Notch signaling reporter assays, β-catenin pathway analysis, radiation resistance assays\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined crosstalk mechanism, single study\",\n      \"pmids\": [\"36007109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HUWE1 E3 ubiquitin ligase ubiquitinates and degrades N-Myc, which in turn inactivates downstream DLL1-NOTCH1 signaling, thereby suppressing GBM proliferation, invasion and migration; HUWE1 acts as a tumor suppressor through the N-Myc–DLL1–NOTCH1 axis.\",\n      \"method\": \"Ubiquitination assays, KO/overexpression in GBM cell lines and orthotopic xenografts, dCas9 synergistic activation mediator (SAM) system for HUWE1 overexpression in vivo\",\n      \"journal\": \"Cancer Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitination assays plus in vivo xenograft, single study\",\n      \"pmids\": [\"35848447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"APE1 redox function activates NF-κB, which directly binds to and induces DLL1 expression in esophageal adenocarcinoma cells in response to acidic bile salts (reflux conditions); DLL1 is the predominant Notch ligand activating NOTCH1 in this context, and the APE1–NF-κB–DLL1–NOTCH1 axis promotes cancer stem-like properties.\",\n      \"method\": \"NF-κB chromatin immunoprecipitation on DLL1 promoter, APE1 redox inhibitor experiments, Notch intracellular domain nuclear accumulation assays, transgenic mouse model (L2-IL1β), cell line knockdown/overexpression\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP establishing direct transcriptional regulation, multiple functional assays, single study\",\n      \"pmids\": [\"35750470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Normal development in mice ubiquitously overexpressing the intracellular domain of DLL1 (DICD), with no alteration in Notch target gene expression or early Notch-dependent processes, argues against a physiologically relevant reverse signaling function of the DLL1 intracellular domain in vivo; mouse DICD also enters the nucleus inefficiently.\",\n      \"method\": \"Ubiquitous transgenic overexpression of DLL1 intracellular domain (multiple versions) in mice, nuclear fractionation, Notch target gene expression analysis\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic test with multiple transgene versions and molecular readouts, clear null result\",\n      \"pmids\": [\"24167636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP11 deubiquitinase sustains survival of marginal zone B cells by regulating ubiquitination of the Notch ligands DLL1 and JAG2; loss of Usp11 leads to increased DLL1 ubiquitination and reduced MZ B cell survival after irradiation.\",\n      \"method\": \"Co-IP, ubiquitination assays in Usp11-/- mice, single-cell sequencing, flow cytometry, pharmacological Usp11 inhibition with mitoxantrone\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ubiquitination assays combined with KO mouse phenotype, single study\",\n      \"pmids\": [\"39904982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DLL1-expressing tumor cells recruit PD-L1+ immunosuppressive M2-like tumor-associated macrophages through the CCR3/CCL7 axis, which maintain cancer stem cell activity and drive tamoxifen/fulvestrant resistance in ER+ luminal breast cancer; combination of anti-DLL1 and anti-PD-L1 antibodies with tamoxifen reduced tumor growth and reprogrammed the immunosuppressive tumor microenvironment.\",\n      \"method\": \"Conditional DLL1 knockout mouse models, patient-derived explants, cytokine/chemokine axis analysis (CCR3/CCL7), combination antibody therapy, CSC functional assays\",\n      \"journal\": \"Science Translational Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with mechanistic crosstalk (CCR3/CCL7) and functional rescue, single study\",\n      \"pmids\": [\"41191774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Site-specific elongation of O-glucose glycan on NOTCH1 EGF10 (synthesized by B4GALT1 and ST3GAL4 to form a 3'-sialyllactose-like structure) significantly impacts DLL1- and DLL4-dependent NOTCH1 ligand binding and signal transduction; C4-2 amino acid position in the EGF domain is crucial for galactose elongation, affecting T cell differentiation through DLL1-NOTCH1 signaling.\",\n      \"method\": \"Mass spectrometry, site-directed mutagenesis, NOTCH1 activation assays with DLL1/DLL4 ligands, T cell differentiation assays in vivo\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — MS-identified modification + mutagenesis + functional Notch activation assays, but focused on NOTCH1 glycosylation rather than DLL1 itself\",\n      \"pmids\": [\"41129232\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DLL1 is a transmembrane Notch ligand whose activity requires ubiquitination-dependent recycling to acquire Notch-receptor affinity, followed by transendocytosis of the Notch extracellular domain to activate signaling; its surface presentation is regulated by scaffolding (MAGI1), protein stability (SYNJ2BP, estrogen/proteasomal control, USP11 deubiquitination), cytoskeletal trafficking (Arp2/3), and proteolytic shedding (MT1-MMP), while its transcription is driven by WNT–TCF/TBX6, MyoD, CDX, and Ptf1a axes depending on tissue context; structurally, the MNNL-DSL-EGF3 ectodomain region determines selectivity between NOTCH1 and NOTCH2, DLL1 acts as a trans-activator rather than a cis-inhibitor (unlike DLL4), and it functions in diverse developmental and adult contexts including somitogenesis, intestinal stem cell maintenance, neural progenitor quiescence, arterial identity, mammary stem cell niche, myogenesis, and β-cell insulin secretion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DLL1 is a transmembrane Notch ligand that functions as a trans-activating signal in diverse developmental and adult tissue contexts, including somitogenesis, neural progenitor maintenance, intestinal stem cell fate, arterial identity, mammary gland morphogenesis, myogenesis, and pancreatic β-cell insulin secretion [PMID:7671806, PMID:12900443, PMID:21238454, PMID:19144989, PMID:29773667, PMID:34370738, PMID:32029480]. Its signaling competence requires ubiquitination-dependent endocytic recycling to acquire high Notch-binding affinity, followed by transendocytosis of the Notch extracellular domain; surface presentation is further regulated by MAGI1 scaffolding at adherens junctions, SYNJ2BP-mediated stabilization, Arp2/3-dependent vesicular trafficking, phosphorylation of its intracellular domain, USP11 deubiquitination, estrogen-mediated protection from proteasomal degradation, and proteolytic shedding by MT1-MMP [PMID:18676613, PMID:15908431, PMID:24025447, PMID:28380416, PMID:24449764, PMID:39904982, PMID:30442981, PMID:21572390]. DLL1 transcription is directly activated by WNT–LEF/TCF in synergy with TBX6 in presomitic mesoderm, by MyoD through E-box elements in myoblasts, and by NF-κB in inflammatory contexts, while the MNNL–DSL–EGF3 ectodomain region determines receptor selectivity, enabling DLL1 to activate NOTCH1 and NOTCH2 with comparable efficiency—unlike DLL4, which preferentially activates NOTCH1 and also acts as a potent cis-inhibitor [PMID:15545628, PMID:34370738, PMID:35750470, PMID:30289388, PMID:26114479]. In the intestine, DLL1-expressing secretory progenitors mark the immediate progeny of Lgr5+ stem cells and can revert to stemness upon tissue damage, while in breast cancer, DLL1+ tumor-initiating cells activate Notch in stromal fibroblasts and macrophages to create Wnt-dependent feedback loops that drive chemoresistance and immune evasion [PMID:23000963, PMID:33462238, PMID:36007109, PMID:41191774].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Identification of DLL1 as the first mammalian Delta homologue established that the Notch ligand-receptor paradigm is conserved in vertebrates and provided the molecular entry point for studying Notch signaling in mammalian development.\",\n      \"evidence\": \"Molecular cloning, sequence analysis, and in situ hybridization in mouse embryos\",\n      \"pmids\": [\"7671806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional assay confirming signaling activity\", \"Receptor binding affinity not measured\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Genetic epistasis in somite patterning placed DLL1 upstream of MESP2 and dependent on PRESENILIN1, establishing the first in vivo pathway hierarchy for DLL1-Notch signaling in a specific developmental context and distinguishing its pathway from the DLL3-dependent branch.\",\n      \"evidence\": \"Systematic double-mutant analysis of Dll1, Dll3, Mesp2, and Psen1 knockout mice\",\n      \"pmids\": [\"12900443\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical basis of DLL3 antagonism to DLL1 unknown\", \"Whether DLL1 feeds back on its own transcription not resolved molecularly\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstration that WNT–LEF/TCF and TBX6 synergistically activate Dll1 transcription answered how DLL1 expression is initiated in the presomitic mesoderm, linking Wnt and Notch pathways in the segmentation clock.\",\n      \"evidence\": \"Transgenic reporter assays with mutated promoter elements in vivo, plus in vitro transactivation assays\",\n      \"pmids\": [\"15545628\", \"15986483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chromatin-level regulation (enhancer accessibility) not examined\", \"Whether other T-box factors compensate in non-PSM tissues unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery that MAGI1 recruits and stabilizes DLL1 at adherens junctions revealed a scaffolding mechanism governing ligand surface presentation, explaining how cell-cell contact geometry can regulate Notch signaling strength.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-immunoprecipitation, and co-localization at adherens junctions in neural tube and fibroblasts\",\n      \"pmids\": [\"15908431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MAGI1 loss phenocopies DLL1 loss in vivo not tested\", \"Stoichiometry and competitive binding with other PDZ ligands unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Ubiquitination-dependent recycling was shown to be essential for DLL1 to acquire Notch-binding competence, and a separate transendocytosis step was demonstrated as necessary for signal activation, resolving the longstanding question of why endocytosis is required in the signal-sending cell.\",\n      \"evidence\": \"Ubiquitination-defective DLL1 mutants, recycling and Notch1 binding assays, DLL1-DLL3 chimera transendocytosis assays, lipid microdomain fractionation\",\n      \"pmids\": [\"18676613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the E3 ligase responsible for this recycling-promoting ubiquitination not pinpointed in this study\", \"Structural basis for how recycling confers binding competence unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Endothelial-specific DLL1 deletion revealed a non-redundant role in maintaining fetal arterial identity through VEGFR2/NRP1 regulation, distinguishing DLL1 from DLL4 in vascular Notch signaling.\",\n      \"evidence\": \"Conditional endothelial-specific Dll1 knockout mice with immunofluorescence and Nrp1 promoter-RBPJκ reporter assays\",\n      \"pmids\": [\"19144989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DLL1 loss affects adult arterial maintenance not addressed\", \"Direct vs. indirect mechanism of VEGFR2 regulation unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"MT1-MMP was identified as a metalloprotease that cleaves DLL1 on stromal cells, providing a mechanism to negatively regulate Notch ligand availability; this explained how the bone marrow niche tunes Notch signaling for B-lymphopoiesis.\",\n      \"evidence\": \"Recombinant enzyme cleavage of synthetic DLL1 peptide, MT1-MMP knockout mouse phenotype rescued by Notch inhibitor DAPT\",\n      \"pmids\": [\"21572390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cleavage site specificity and whether other MMPs contribute not fully resolved\", \"Whether MT1-MMP regulates DLL1 outside the bone marrow niche untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Combinatorial conditional knockout of Dll1 and Dll4 in the intestinal epithelium established these as the essential Notch ligands maintaining intestinal stem cells, while Elavl1/HuR was shown to post-transcriptionally stabilize Dll1 mRNA during neural progenitor mitosis — together revealing both tissue-level redundancy and cell-cycle-coupled mRNA regulation.\",\n      \"evidence\": \"Inducible gut-specific Dll1/Dll4/Jag1 single and compound knockouts; RNA immunoprecipitation and mRNA stability assays for Elavl1 plus Elavl1 heterozygous retinal analysis\",\n      \"pmids\": [\"21238454\", \"21346194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which cell type supplies DLL1 vs DLL4 signal to stem cells not resolved\", \"Whether Elavl1 stabilization operates in non-neural tissues unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Lineage tracing showed that Dll1-high intestinal cells are secretory progenitors that can revert to stemness upon tissue damage, establishing DLL1 expression as a marker of facultative stem cell potential and demonstrating plasticity in the intestinal hierarchy.\",\n      \"evidence\": \"Dll1(GFP-ires-CreERT2) knock-in mice with lineage tracing and organoid formation after tissue damage\",\n      \"pmids\": [\"23000963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of de-differentiation not defined\", \"Whether DLL1 is functionally required for reversion or is merely a marker unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Multiple studies converged to show that DLL1 serves as a niche signal from progeny to parent stem cells: in the adult SVZ, activated NSC progeny asymmetrically inherit DLL1 and maintain neighboring quiescent NSCs; in the neocortex, intermediate progenitors supply DLL1 to radial glia via dynamic processes; and SYNJ2BP was identified as a stabilizer of DLL1 protein that modulates endothelial Notch signaling.\",\n      \"evidence\": \"Conditional Dll1 KO in SVZ with live-cell imaging of asymmetric segregation; multiphoton live imaging with Notch reporters in cortical slices; Co-IP and protein stability assays for SYNJ2BP\",\n      \"pmids\": [\"23695674\", \"23699523\", \"24025447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of asymmetric DLL1 segregation at the molecular level unknown\", \"Whether SYNJ2BP competes with MAGI1 for DLL1 PDZ-binding motif untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Ubiquitous overexpression of the DLL1 intracellular domain in mice produced no developmental phenotype, arguing against a physiologically relevant 'reverse signaling' function for the DLL1 cytoplasmic fragment.\",\n      \"evidence\": \"Multiple transgenic mouse lines expressing DLL1 intracellular domain ubiquitously, with nuclear fractionation and Notch target gene analysis\",\n      \"pmids\": [\"24167636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cannot exclude context-specific reverse signaling below detection threshold\", \"Does not rule out functions requiring ligand-receptor interaction to release ICD\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mass spectrometry identified sequential phosphorylation sites in the DLL1 intracellular domain that increase protein stability and Notch1 activation in vitro, though knock-in mice with phospho-deficient DLL1 developed normally, indicating phosphorylation is dispensable under standard conditions.\",\n      \"evidence\": \"Mass spectrometry, phospho-deficient mutagenesis, coculture Notch activation assays, knock-in mice\",\n      \"pmids\": [\"24449764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether phosphorylation becomes essential under stress or in specific tissues unknown\", \"Kinase identity for the threonine site not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Direct comparison showed DLL1 functions as a pure trans-activator whereas DLL4 also acts as a potent cis-inhibitor; DLL4 knocked into the Dll1 locus cannot rescue somitogenesis, establishing that functional non-equivalence derives from cis-inhibition capacity rather than trans-activation potency.\",\n      \"evidence\": \"DLL4 knock-in at Dll1 locus mice, conditional overexpression from HPRT locus, quantitative Notch trans/cis assays in vitro\",\n      \"pmids\": [\"26114479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for why DLL1 lacks cis-inhibition not determined\", \"Whether intermediate cis-inhibition occurs at supraphysiological DLL1 levels unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Systematic EGF-repeat mutagenesis revealed that all eight EGF repeats contribute to DLL1 activity, and MIB1 E3 ligase was shown to couple Notch ligand-receptor engagement to DLL1 endocytosis through SNX18-dynamin2, linking the ubiquitination and endocytic machineries.\",\n      \"evidence\": \"Allelic series of disulfide-bridge mutations at Dll1 locus in mice with in vitro Notch activation assays; Co-IP and endocytosis assays for MIB1-SNX18-dynamin2\",\n      \"pmids\": [\"26801181\", \"26923255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which EGF repeats contact Notch directly vs. play structural roles unresolved\", \"MIB1-SNX18-dynamin2 axis not validated in vivo\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The MNNL–DSL–EGF3 ectodomain region was mapped as the determinant of DLL1 vs. DLL4 receptor selectivity, with DLL1 activating NOTCH1 and NOTCH2 equivalently while DLL4 preferentially activates NOTCH1; separately, mammary stem cell–expressed DLL1 was shown to activate Notch in stromal macrophages, triggering Wnt ligand production in a feedback loop essential for ductal morphogenesis.\",\n      \"evidence\": \"Chimeric ligand knock-in mice plus cell-based binding and activation assays for ectodomain mapping; conditional Dll1 KO in mammary gland with co-culture Wnt ligand measurements\",\n      \"pmids\": [\"30289388\", \"29773667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of DLL1-NOTCH2 complex unavailable\", \"How macrophage Wnt secretion feeds back specifically to DLL1+ stem cells mechanistically undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Estrogen signaling was found to stabilize DLL1 protein by blocking its ubiquitination and proteasomal/lysosomal degradation in ERα+ breast cancer, revealing a hormone-dependent post-translational regulatory axis for DLL1 and linking it to cancer stem cell maintenance.\",\n      \"evidence\": \"DLL1 conditional KO in breast cancer mouse models, ubiquitination assays, proteasome and lysosome inhibitor treatments\",\n      \"pmids\": [\"30442981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The E3 ligase targeted by estrogen signaling not identified\", \"Whether this mechanism operates in normal mammary epithelium unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Oscillatory Dll1/Hes1 expression was shown to drive multipotent pancreatic progenitor expansion, and loss of DLL1/DLL4 in adult β-cells improved insulin secretion, establishing DLL1-Notch as a functional regulator of pancreatic endocrine physiology beyond development.\",\n      \"evidence\": \"Conditional Dll1/Jag1 knockouts with Hes1 oscillation live imaging in pancreatic progenitors; β-cell-specific Dll1/Dll4 double KO with glucose tolerance and insulin secretion assays\",\n      \"pmids\": [\"32059775\", \"32029480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DLL1 and DLL4 have distinct roles in β-cells not resolved\", \"Downstream effectors of DLL1-Notch in β-cell insulin granule dynamics unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"MyoD was shown to directly activate Dll1 through E-box elements, and DLL1 simultaneously trans-activates Notch in neighbors and cis-inhibits Notch in the DLL1-expressing myoblast itself, creating a feedback loop that coordinates the balance between differentiation and progenitor maintenance during myogenesis.\",\n      \"evidence\": \"CRISPR E-box disruption in human myoblasts, E-box-deficient mouse model, functional rescue experiments\",\n      \"pmids\": [\"34370738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DLL1 cis-inhibition in myoblasts contradicts the general finding that DLL1 lacks cis-inhibition needs resolution\", \"Quantitative contribution of DLL1 vs. DLL4 in adult muscle regeneration unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Several cancer-context studies established DLL1 as a node in tumor-stroma crosstalk: DLL1+ tumor cells activate Notch in CAFs to induce Wnt-driven radioresistance, NF-κB directly transactivates DLL1 in esophageal adenocarcinoma downstream of APE1, and HUWE1 suppresses the N-Myc–DLL1–NOTCH1 axis in glioblastoma.\",\n      \"evidence\": \"Conditional DLL1 KO with co-culture and radiation assays; ChIP of NF-κB on DLL1 promoter; HUWE1 ubiquitination assays and orthotopic xenografts\",\n      \"pmids\": [\"36007109\", \"35750470\", \"35848447\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DLL1 transcriptional regulation in esophageal context from single study\", \"Whether HUWE1 regulates DLL1 directly or only indirectly via N-Myc not clear\", \"CAF Wnt-Notch loop not validated in human patient samples\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"USP11 was identified as a deubiquitinase that stabilizes DLL1 in marginal zone B cells, and DLL1+ tumor cells were shown to recruit immunosuppressive PD-L1+ macrophages via CCR3/CCL7, revealing new layers of DLL1 post-translational control and immune-modulatory function in the tumor microenvironment.\",\n      \"evidence\": \"Usp11 KO mice with ubiquitination assays and flow cytometry; conditional DLL1 KO mouse breast cancer models with combination anti-DLL1/anti-PD-L1 therapy\",\n      \"pmids\": [\"39904982\", \"41191774\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"USP11-DLL1 interaction not validated by reciprocal IP or structural data\", \"CCR3/CCL7 axis specificity to DLL1-expressing tumors vs. general Notch activation unclear\", \"O-glycosylation of NOTCH1 affecting DLL1 binding (PMID:41129232) studied mainly from receptor side\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) the atomic-resolution structural basis for DLL1-NOTCH2 vs. DLL1-NOTCH1 binding equivalence and DLL1's lack of cis-inhibitory capacity; (2) how ubiquitination-dependent recycling conformationally activates DLL1; (3) whether DLL1 reverse signaling has any context-dependent physiological role despite negative in vivo evidence; and (4) the therapeutic window for anti-DLL1 strategies in cancer given its essential roles in adult tissue homeostasis.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution DLL1-Notch co-crystal structure available\", \"Conformational change upon recycling not demonstrated\", \"Reverse signaling tested only in standard developmental conditions\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 5, 6, 8, 15, 22]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 5, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 5, 19]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [5, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 6, 8, 11, 13, 15, 22]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2, 4, 6, 11, 16, 23, 25]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [20, 26, 27, 28, 29, 32]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NOTCH1\",\n      \"NOTCH2\",\n      \"MAGI1\",\n      \"SYNJ2BP\",\n      \"MIB1\",\n      \"MT1-MMP\",\n      \"USP11\",\n      \"ELAVL1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}