Affinage

DLL1

Delta-like protein 1 · UniProt O00548

Length
723 aa
Mass
78.1 kDa
Annotated
2026-06-09
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DLL1 is a mammalian transmembrane Notch ligand whose extracellular EGF-like repeats engage Notch receptors to drive cell-to-cell signaling and binary cell-fate decisions across many embryonic and adult tissues (PMID:7671806). Its ectodomain dictates receptor selectivity: the region between the N-terminus and EGF repeat 3 confers the ability to activate NOTCH1 and NOTCH2 with equal efficiency, distinguishing it from DLL4 which preferentially activates NOTCH1, and each individual EGF repeat is required for full transactivation of both receptors (PMID:26801181, PMID:30289388). Productive signaling requires DLL1 to be made receptor-binding competent: ubiquitination drives endocytic recycling needed to acquire high affinity for NOTCH1, and ligand-pulling transendocytosis of the Notch ectodomain depends on the DLL1 intracellular domain (PMID:18676613). Surface availability and stability are tuned through trafficking and turnover—Arp2/3-dependent vesicular transport to the membrane (PMID:28380416), MAGI1-mediated recruitment to adherens junctions (PMID:15908431), SYNJ2BP binding to its PDZ motif (PMID:24025447), sequential intracellular phosphorylation primed by protein kinase B (PMID:24449764), MT1-MMP ectodomain shedding (PMID:21572390), and competing ubiquitination/deubiquitination by Mib1 and Usp11 (PMID:26923255, PMID:39904982)—whereas the intracellular domain does not mediate a reverse-signaling function in vivo (PMID:24167636). DLL1 transcription is directly activated by WNT/LEF-TCF cooperating with TBX6, by Cdx factors, by MyoD in muscle, and by NF-κB, while HuR/Elavl1 stabilizes its mRNA during mitosis (PMID:15545628, PMID:22015720, PMID:34370738, PMID:35750470, PMID:21346194). Functionally, DLL1 maintains intestinal and neural stem cells, arterial endothelial identity, T-cell development, and stem-cell/niche cross-talk, and partial loss-of-function mutations in EGF repeats produce somite-patterning defects resembling spondylocostal dysostosis (PMID:21238454, PMID:23695674, PMID:19144989, PMID:35371023, PMID:26801181).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1995 High

    Established DLL1 as a mammalian transmembrane Notch ligand, answering whether the Drosophila Delta paradigm extends to vertebrate development.

    Evidence Molecular cloning, sequence analysis, and in situ hybridization in mouse embryos

    PMID:7671806

    Open questions at the time
    • Did not resolve which Notch receptor(s) DLL1 preferentially activates
    • No mechanism of ligand activation or trafficking defined
  2. 2004 High

    Identified how DLL1 expression is positioned in the presomitic mesoderm by showing WNT/LEF-TCF cooperates with TBX6 to directly drive the Dll1 promoter.

    Evidence Promoter reporter assays plus transgenic mouse embryo reporters with site-directed mutagenesis of T-box and LEF/TCF sites

    PMID:15545628

    Open questions at the time
    • Tissue-specific enhancers outside PSM not addressed
    • Did not establish direct TBX6 DNA contacts
  3. 2005 Medium

    Confirmed direct TBX6 binding to a Dll1 enhancer and identified MAGI1 as a junctional scaffold that stabilizes DLL1 at the cell surface, linking transcriptional control and surface presentation.

    Evidence EMSA for TBX6 binding; Co-IP, pulldown, immunolocalization, and surface-stability assays for MAGI1

    PMID:15908431 PMID:15986483

    Open questions at the time
    • MAGI1 effect on signaling output not quantified
    • Single-lab findings
  4. 2008 High

    Defined the activation mechanism by showing ubiquitination-driven recycling makes DLL1 receptor-binding competent and that intracellular-domain-dependent transendocytosis is required for Notch activation.

    Evidence Ubiquitination-defective and DLL1-DLL3 chimeric constructs with endocytosis/recycling, binding, transendocytosis, and lipid microdomain assays

    PMID:18676613

    Open questions at the time
    • Identity of the recycling-dependent affinity change unresolved
    • Specific ubiquitin ligase not yet assigned in this study
  5. 2009 High

    Placed DLL1 in a tissue pathway by showing it activates NOTCH1 to maintain arterial endothelial identity through downstream VEGF/NRP1 and COUP-TFII control.

    Evidence Endothelial-specific conditional knockout mice with immunofluorescence, in situ, and Notch reporter assays

    PMID:19144989

    Open questions at the time
    • Direct vs indirect regulation of all downstream markers not fully separated
  6. 2010 High

    Distinguished DLL1 signaling range, showing it can activate Notch across expression-domain boundaries in the spinal cord and compensate for JAG1 loss.

    Evidence Single and double neuroepithelium-specific conditional knockouts with neuronal subtype quantification

    PMID:21124801

    Open questions at the time
    • Molecular basis for differential signaling range vs JAG1 unknown
  7. 2011 High

    Mapped multiple regulatory inputs and tissue roles: Cdx transcriptional control, HuR-mediated mitotic mRNA stabilization, MT1-MMP shedding, and redundancy with DLL4 in intestinal stem-cell maintenance.

    Evidence ChIP and Cdx KO; RIP and Elavl1 mouse; MT1-MMP co-IP and synthetic-peptide cleavage; inducible gut-specific double KO with lineage tracing

    PMID:21238454 PMID:21346194 PMID:21572390 PMID:22015720

    Open questions at the time
    • Interplay among these regulatory layers not integrated
    • Cdx and shedding findings are single-lab
  8. 2013 High

    Resolved whether the intracellular domain signals in reverse and revealed asymmetric DLL1 segregation in neural stem cells, plus SYNJ2BP as a stabilizing PDZ partner.

    Evidence Ubiquitous DICD transgenic mice and nuclear-localization assays; conditional Dll1 KO with live imaging; yeast two-hybrid and stability assays for SYNJ2BP

    PMID:23695674 PMID:24025447 PMID:24167636

    Open questions at the time
    • DICD result is a negative in vivo conclusion that does not exclude subtle context-specific roles
    • SYNJ2BP finding single-lab
  9. 2014 High

    Linked surface stability, shedding, and phosphorylation, and separated cis-inhibition from trans-activation as a source of DLL1/DLL4 functional divergence.

    Evidence Mass spectrometry phosphosite mapping with mutants and knock-in mice; transactivation co-culture and DLL1-to-DLL4 knock-in mice

    PMID:24449764 PMID:26114479

    Open questions at the time
    • Phospho-deficient mice develop normally, indicating in vivo compensation not understood
    • Kinase identity (PKB priming) inferred, not directly proven
  10. 2016 High

    Defined ectodomain structure-function by showing every EGF repeat contributes to activity and that Mib1 promotes DLL1 endocytosis via dynamin-2/Snx18 recruitment.

    Evidence Systematic EGF-repeat mutagenesis with knock-in allelic series; Co-IP and endocytosis assays for Mib1/dynamin-2/Snx18

    PMID:26801181 PMID:26923255

    Open questions at the time
    • How individual EGF repeats map to receptor contacts not structurally resolved
    • Mib1/Snx18 mechanism single-lab
  11. 2017 Medium

    Established trafficking and tissue requirements: Arp2/3-dependent vesicular transport to the surface, and DLL1-Notch control of osteoblast maturation.

    Evidence shRNA epistasis with soluble-DLL1 rescue and transport imaging; osteoblast-specific transgenic mice with histomorphometry

    PMID:27735989 PMID:28380416

    Open questions at the time
    • Arp2/3 requirement inferred from trafficking block, mechanism indirect
    • Osteoblast phenotype from overexpression, not loss-of-function
  12. 2018 High

    Defined receptor-selectivity determinants in the ectodomain and identified estrogen and stem-cell niche cross-talk as regulators of DLL1 stability and function.

    Evidence Chimeric ligand and biochemical binding studies with knock-in mice; ubiquitination/stability assays in ERα+ cells; conditional KO with mammary transplantation and macrophage co-culture

    PMID:29773667 PMID:30289388 PMID:30442981

    Open questions at the time
    • Estrogen-to-ubiquitination link mechanistic intermediary unknown
    • Selectivity element between N-terminus and EGF3 not structurally mapped
  13. 2021 Medium

    Identified MyoD as a direct muscle transcriptional activator of Dll1 and characterized DLL1 cancer roles driving NF-κB chemoresistance and CAF-mediated Wnt/β-catenin radioresistance.

    Evidence ChIP, E-box mutant knock-in mice, and CRISPRi in human cells; conditional KO/reporter mice with RNA-seq, ATAC-seq, and pharmacological pathway inhibition

    PMID:33462238 PMID:34370738 PMID:36007109

    Open questions at the time
    • NF-κB and CAF cancer mechanisms single-lab
    • Directness of NF-κB activation downstream of DLL1 not fully dissected
  14. 2022 Medium

    Expanded the regulatory network with NF-κB/APE1 and N-Myc/HUWE1 transcriptional control of DLL1, and showed DLL1 supports T-cell development via both NOTCH1 and NOTCH2.

    Evidence ChIP and redox-inhibitor experiments; Co-IP and ubiquitination assays with xenografts; conditional Dll4 KO with Dll1 rescue and Notch-receptor-deficient chimeras

    PMID:35371023 PMID:35750470 PMID:35848447

    Open questions at the time
    • Cancer transcriptional axes single-lab
    • Receptor-usage context dependence not mechanistically explained
  15. 2025 Medium

    Connected NOTCH1 glycosylation to ligand binding and added Usp11 deubiquitination and immunosuppressive macrophage recruitment to the DLL1 functional repertoire.

    Evidence Mass spectrometry glycan mapping with mutagenesis; Co-IP/ubiquitination assays with Usp11 KO mice; conditional KO with antibody blockade and patient-derived explants

    PMID:39904982 PMID:41129232 PMID:41191774

    Open questions at the time
    • Glycan finding not independently replicated
    • Usp11 and macrophage-axis findings single-lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple post-translational layers (recycling, phosphorylation, shedding, competing ubiquitination/deubiquitination) are integrated to set DLL1 signaling output in a given cell, and the structural basis of ectodomain receptor selectivity, remain unresolved.
  • No integrated quantitative model of DLL1 surface activation
  • No structure of DLL1 ectodomain bound to NOTCH1 vs NOTCH2
  • Compensation masking phospho-mutant phenotypes in vivo unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 2
Partners
MAGI1MIB1MMP14NOTCH1NOTCH2SYNJ2BPUSP11

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 DLL1 is a mammalian transmembrane protein with tandem EGF-like repeats in its extracellular domain, closely related to Drosophila Delta, and functions as a ligand for Notch receptors in cell-to-cell signaling during embryogenesis, with expression in paraxial mesoderm and nervous system overlapping with Notch1. Molecular cloning, sequence analysis, in situ hybridization, expression mapping in mouse embryos Development High 7671806
2004 WNT signaling, acting through LEF/TCF transcription factors in cooperation with TBX6, directly activates transcription from the Dll1 promoter in the tailbud and presomitic mesoderm; mutating either T-box or LEF/TCF binding sites in the Dll1 promoter abolishes reporter gene expression in transgenic embryos. Promoter reporter assays in vitro, transgenic mouse embryo reporter analysis, genetic epistasis with Wnt pathway components Genes & Development High 15545628
2005 TBX6 directly binds to at least two of four putative Tbx6 binding sites within a Dll1 paraxial mesoderm enhancer in vitro, establishing Dll1 as a direct transcriptional target of Tbx6 in the presomitic mesoderm. Electrophoretic mobility shift assay (EMSA) for Tbx6 DNA binding, transgenic mouse analysis, genetic interaction studies Genesis Medium 15986483
2005 MAGI1, a scaffolding molecule, directly binds DLL1 and recruits it to cadherin-based adherens junctions (AJs), stabilizing DLL1 on the cell surface; in cultured AJ-forming fibroblasts, MAGI1 localizes DLL1 to AJs through this direct protein-protein interaction. Co-immunoprecipitation, pulldown assays, immunolocalization in developing spinal cord and cultured fibroblasts, surface stability assay Journal of Biological Chemistry High 15908431
2008 Ubiquitination of DLL1 is not required for its endocytosis but is essential for recycling back to the cell surface; recycling is required for DLL1 to acquire high affinity for Notch1. A DLL1-DLL3 chimera (Dll1 ectodomain + Dll3 transmembrane/intracellular domain lacking lysines) can bind Notch1 but cannot induce transendocytosis of the Notch1 extracellular region, demonstrating that transendocytosis is required for Notch activation and depends on the DLL1 intracellular domain. DLL1 partially localizes to lipid microdomains, which are required for Notch signaling activation. Ubiquitination-defective DLL1 mutant analysis, chimeric DLL1-DLL3 construct, endocytosis/recycling assays, Notch1 binding assays, transendocytosis assay, lipid microdomain fractionation PNAS High 18676613
2009 DLL1 is an essential Notch ligand in fetal arterial endothelial cells that activates Notch1 to maintain arterial identity; in the absence of DLL1, VEGFR2 and NRP1 are downregulated and COUP-TFII (a repressor of arterial identity) is upregulated, revealing a DLL1→Notch1→VEGF pathway axis. Endothelial-specific conditional knockout mice, immunofluorescence, in situ hybridization, cell culture Notch reporter assays, Nrp1 promoter RBPJκ-site analysis Blood High 19144989
2011 MT1-MMP (MMP14), expressed on bone marrow stromal cells, directly cleaves DLL1 on the cell surface, reducing Notch signaling in hematopoietic progenitor cells; this cleavage is required for normal B-lymphocyte development. Recombinant MT1-MMP cleaves a synthetic DLL1 peptide at the same site as on the cell surface. Co-culture of MT1-MMP-deficient BMSCs with hematopoietic progenitors, DAPT rescue experiments, Co-IP of MT1-MMP and DLL1, in vitro cleavage of synthetic DLL1 peptide by recombinant MT1-MMP, flow cytometry EMBO Journal High 21572390
2011 DLL1 and DLL4 together are the physiological Notch ligands in the intestinal epithelium; simultaneous inactivation of both leads to complete conversion of proliferating progenitors into goblet cells and loss of intestinal stem cells (Olfm4+, Lgr5+, Ascl2+), while single DLL1 inactivation causes only a moderate increase in goblet cells without loss of stem cells. Inducible gut-specific conditional knockout mice (Vil-Cre-ERT2), lineage tracing, immunofluorescence, in situ hybridization Gastroenterology High 21238454
2011 DLL1 expression in the presomitic mesoderm is regulated by Cdx homeodomain transcription factors; Cdx members occupy the Dll1 promoter both in vivo (ChIP) and in vitro, and Cdx-Dll1 genetic interaction was confirmed in somitogenesis and goblet cell differentiation. Chromatin immunoprecipitation (ChIP), promoter occupancy assays, Cdx conditional knockout mice, genetic interaction analysis Developmental Biology Medium 22015720
2011 Elavl1/HuR binds to the 3' UTR of Dll1 mRNA in neuroepithelial cells during mitosis, stabilizing Dll1 mRNA; RNAi against Elavl1 reduces stability of Dll1-3'UTR-containing transcripts in mitosis-arrested cells and diminishes the capacity of brain precursors to trigger lateral inhibitory Notch signals to neighbors. Elavl1 heterozygous null mice show decreased Dll1 expression in developing brain. RNA immunoprecipitation (RIP), RNAi knockdown, mRNA stability assay, Elavl1 null-heterozygous mouse analysis, in vivo neurogenesis quantification in retina Molecular Biology of the Cell High 21346194
2013 Dll1 protein is induced in activated neural stem cells (NSCs) in the adult subventricular zone, segregates asymmetrically to one daughter cell during mitosis, and is required to maintain quiescent NSCs; Dll1-expressing cells reside in close proximity to quiescent NSCs, suggesting a feedback niche signal from progeny to parent stem cells. Conditional Dll1 knockout mice, live imaging, immunofluorescence for asymmetric protein segregation during mitosis, BrdU/EdU labeling, flow cytometry Nature Communications High 23695674
2014 DLL4 but not DLL1 acts as an efficient cis-inhibitor of Notch signaling in cells co-expressing both ligand and receptor; both ligands have similar trans-activation potential, but the differential cis-inhibitory property of DLL4 contributes to context-dependent functional divergence. In vivo, endogenous Dll1 locus DLL4 knock-in mice show dominant somitogenesis defects. Notch transactivation co-culture assays in vitro, conditional overexpression from HPRT locus, DLL1-to-DLL4 knock-in mice (Dll1Dll4ki), vertebral column phenotype analysis PLoS Genetics High 26114479
2014 Serine and threonine phosphorylation sites in the intracellular domain of DLL1 were identified by mass spectrometry; phosphorylation requires membrane association and occurs sequentially, likely primed by protein kinase B. A phosphorylation-deficient DLL1 triple mutant is more stable but has reduced cell-surface levels, is more efficiently cleaved extracellularly, and activates Notch1 significantly less in co-culture assays. However, knock-in mice expressing the phosphorylation-deficient DLL1 develop normally, indicating compensation in vivo. Mass spectrometry phosphosite identification, site-directed mutagenesis, Notch1 co-culture activation assay, knock-in mouse generation, developmental phenotype analysis Molecular and Cellular Biology High 24449764
2013 Over-expression of the DLL1 intracellular domain (DICD) in mouse embryonic stem cells does not block proliferation or stimulate neuronal differentiation, and ubiquitous DICD expression in transgenic mice produces no developmental phenotype, normal Notch target gene expression, and viable fertile adults. Mouse DICD enters the nucleus inefficiently, arguing against a reverse signaling function of the DLL1 intracellular domain in vivo. Transgenic mouse generation with ubiquitous DICD expression, ES cell transfection, Notch target gene analysis, nuclear localization assay PLoS ONE High 24167636
2016 Each individual EGF repeat in the extracellular domain of DLL1 is required for full Notch transactivation activity; mutations disrupting disulfide bridges in each EGF repeat reduce DLL1 activity toward both NOTCH1 and NOTCH2 in co-culture assays. In vivo, an allelic series of knock-in mice shows context-dependent sensitivity: some EGF repeat mutations affect only somite patterning (resembling spondylocostal dysostosis) while others affect multiple processes. EGF-repeat mutagenesis, HPRT single-copy transgene expression, Notch co-culture transactivation assay, knock-in mouse allelic series, vertebral column phenotyping Genetics High 26801181
2016 Mib1 ubiquitin ligase promotes the interaction between dynamin 2 and Snx18 in a ubiquitin ligase activity-dependent manner, thereby facilitating dynamin 2 recruitment to DLL1 and promoting DLL1 endocytosis and Notch signaling efficiency. Co-immunoprecipitation, ubiquitin ligase activity-dependent protein interaction assay, endocytosis assay for DLL1 Genes to Cells Medium 26923255
2013 SYNJ2BP (synaptojanin-2 binding protein) interacts with the PDZ binding motif of DLL1 (and DLL4) intracellular domain, but not with Jagged-1, enhances DLL1 protein stability, promotes Notch signaling in endothelial cells, and inhibits tip cell formation and sprouting angiogenesis. Yeast two-hybrid, Co-IP, DLL1/DLL4 protein stability assay, Notch target gene expression analysis, endothelial cell functional assays (migration, proliferation), in vivo vascular density in immunocompromised mice Circulation Research Medium 24025447
2018 DLL1 is enriched in mammary gland stem cells (MaSCs) and mediates cross-talk with stromal macrophages; MaSC-expressed DLL1 activates Notch signaling in macrophages, increasing their expression of Wnt3, Wnt10A, and Wnt16, which feeds back to promote DLL1-expressing MaSC function. Conditional deletion of Dll1 reduced MaSC numbers and impaired ductal morphogenesis. Conditional Dll1 knockout mice, mammary transplantation assay, immunofluorescence, flow cytometry, Wnt ligand expression analysis in macrophages, co-culture experiments Science High 29773667
2018 Estrogen signaling stabilizes DLL1 protein by preventing its proteasomal and lysosomal degradation and inhibiting DLL1 ubiquitination in ERα+ breast cancer cells. Proteasomal/lysosomal inhibitor treatment, ubiquitination assay, DLL1 protein stability assay, DLL1 conditional knockout in breast cancer mouse models Oncogene Medium 30442981
2018 DLL1 ectodomains dictate selective Notch receptor activation: DLL4 preferentially activates NOTCH1 over NOTCH2, whereas DLL1 is equally effective in activating NOTCH1 and NOTCH2. The discriminating potential lies in the region between the N-terminus and EGF repeat 3. In vivo, ectodomains dictate ligand function during somitogenesis, while during myogenesis even regions C-terminal to EGF3 are interchangeable. Chimeric DLL1/DLL4 ligand analysis, cellular co-culture Notch activation assays, biochemical binding studies, chimeric knock-in mice analysis in vivo eLife High 30289388
2021 MyoD directly activates transcription of Dll1 via E-box motifs in its regulatory region; Dll1 in turn activates Notch signaling in neighboring myoblasts (trans-activation) to prevent premature differentiation, while autonomously inhibiting Notch in Dll1-expressing cells to facilitate their own myogenic program. This MyoD-Dll1-Notch axis was validated by E-box mutant knock-in mice and CRISPR interference in human cells. ChIP for MyoD at Dll1 locus, E-box mutant knock-in mouse model, CRISPR-mediated interference, gain/loss-of-function studies in mouse and human cells, Notch reporter assays PLoS Genetics High 34370738
2021 DLL1+ tumor cells activate Notch signaling in cancer-associated fibroblasts (CAFs), which increases Wnt ligand secretion from CAFs, leading to β-catenin-driven radioresistance and metastasis in breast cancer. Conditional Dll1 knockout and reporter mouse models, co-culture experiments, RNA-seq, ATAC-seq, pharmacological Notch/Wnt pathway inhibition Cancer Research Medium 36007109
2021 DLL1+ breast cancer tumor cells drive a chemoresistant phenotype via NF-κB activation downstream of DLL1; RNA-seq and ATAC-seq using reporter models and patient data showed NF-κB activation is downstream of DLL1. Pharmacological blocking of DLL1 or NF-κB completely sensitizes Dll1+ tumors to chemotherapy. Conditional Dll1 knockout and reporter mouse models, RNA-seq, ATAC-seq, NF-κB pathway inhibition, pharmacological DLL1 blockade Nature Communications Medium 33462238
2022 APE1 redox function activates NF-κB, which directly binds to and induces expression of DLL1 in esophageal adenocarcinoma cells in response to acidic bile salts (reflux conditions); elevated DLL1 then activates NOTCH1 signaling, promoting cancer stem-like properties. NF-κB binding to DLL1 promoter (ChIP), APE1 redox inhibitor experiments, DLL1 knockdown, Notch reporter assays, in vitro and transgenic mouse model validation Gut Medium 35750470
2022 HUWE1 E3 ubiquitin ligase ubiquitinates and degrades N-Myc, which acts as a transcriptional activator of DLL1; thus HUWE1 suppresses the N-Myc→DLL1→NOTCH1 signaling axis to inhibit glioblastoma cell proliferation and invasion. Co-IP, ubiquitination assays, dCas9 synergistic activation, recombinant AAV-mediated HUWE1 overexpression, in vitro and orthotopic xenograft tumor models Cancer Communications Medium 35848447
2022 Dll1 expressed in the thymic epithelium can completely restore T-cell development in Dll4-deficient mice; Dll1 activates both NOTCH1 and NOTCH2 receptors to support T-cell development, in contrast to Dll4 which signals exclusively through NOTCH1 in the thymic environment. Foxn1-Cre conditional Dll4-knockout mice with Dll1 conditional transgenic rescue, bone marrow chimeras with Notch1- or Notch2-deficient hematopoietic cells, flow cytometry Frontiers in Immunology High 35371023
2025 Site-specific O-glucose glycan elongation on NOTCH1 EGF10 (with hexose and Neu5Ac forming a 3'-sialyllactose-like structure, synthesized by B4GALT1 and ST3GAL4) significantly impacts DLL1- and DLL4-dependent NOTCH1 ligand binding and signal transduction; C4-2 position amino acid in the EGF domain is crucial for galactose elongation. Mass spectrometry glycan identification, mutagenesis (C4-2 position), Notch signaling assays, early T-cell development functional assays PNAS Medium 41129232
2025 Usp11 deubiquitinase sustains survival of marginal zone B cells by regulating ubiquitination of Notch ligands DLL1 and JAG2; Co-IP and ubiquitination experiments demonstrated that Usp11 physically interacts with DLL1 and JAG2 and prevents their ubiquitin-mediated degradation. Co-immunoprecipitation, ubiquitination assay, Usp11-/- knockout mice, flow cytometry, single-cell RNA sequencing Cell Death & Disease Medium 39904982
2025 DLL1 recruits immunosuppressive PD-L1+ tumor-associated macrophages through the CCR3/CCL7 axis; tumor cell DLL1-mediated Notch signaling in macrophages maintains cancer stem cell activity. Combination of anti-DLL1 and anti-PD-L1 antibodies with tamoxifen reduced tumor growth and reprogrammed the immunosuppressive tumor microenvironment in mouse models and patient-derived explants. Conditional knockout mouse models, new immunocompetent breast cancer mouse models, antibody blockade experiments, patient-derived explants, flow cytometry, tumor growth analysis Science Translational Medicine Medium 41191774
2010 DLL1 mediates Notch activation across expression domain boundaries in the spinal cord (can signal to progenitors outside its own expression domain), whereas JAG1 can only activate Notch within V1 and dI6 progenitor domains; double Dll1;Jag1 conditional knockout embryos show stronger neurogenic phenotypes than single mutants, confirming functional compensation by Dll1 for Jag1 loss. Single and double conditional knockout mice (neuroepithelium-specific), neuronal subtype quantification, genetic epistasis PLoS ONE High 21124801
2017 DLL1-mediated Notch signaling in osteoblasts promotes proliferation of committed but immature osteoblasts while inhibiting their further differentiation into mature functional osteoblasts; osteoblast-specific DLL1 transgenic mice show severe suppression of bone metabolic turnover due to maturational arrest of osteoblasts impairing osteoblast-osteoclast coupling. Osteoblast-specific DLL1 transgenic mice, bone histomorphometry, osteoblast and osteoclast differentiation assays, bone remodeling marker analysis Journal of Cellular Physiology Medium 27735989
2012 DLL1 activates Notch signaling predominantly through the Notch2 receptor in multiple myeloma cells on bone marrow stromal cells, and this signaling upregulates CYP1A1 (a drug-metabolizing cytochrome P450 enzyme) as a mechanism of bortezomib resistance; CYP1A1 inhibition or siRNA restored bortezomib sensitivity. Co-culture of myeloma cells with Dll1-expressing stromal cells, Notch receptor-specific analysis, CYP1A1 siRNA knockdown, pharmacological inhibition (α-naphthoflavone), in vivo 5T33MM mouse model Biochemical and Biophysical Research Communications Medium 23111325
2017 Arp2/3 complex is required for DLL1 vesicular transport from cytoplasm to cell membrane; inhibition of Arp2/3 impedes DLL1 trafficking to the cell surface, preventing DLL1-mediated Notch1 activation and the maintenance of stem cell phenotype in glioma initiating cells. shRNA knockdown of DLL1 and Arp2/3 components, exogenous soluble DLL1 rescue experiment, vesicular transport imaging, CD133+ cell functional assays, intracranial xenograft model Oncotarget Medium 28380416
2021 C-terminal tagging of DLL1 protein with AcGFPHA or Strep/FLAG tags impairs DLL1 activity in vivo, causing vertebral column defects in homozygous knock-in mice, demonstrating that even small C-terminal additions can reduce DLL1 function during sensitive developmental processes such as somitogenesis. Endogenous knock-in tagging by homologous recombination, developmental phenotype analysis, Western blot protein detection, CHO cell functional assay BMC Research Notes Medium 34583743

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nature cell biology 633 23000963
1995 Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila Delta. Development (Cambridge, England) 406 7671806
2009 DLL1-mediated Notch activation regulates endothelial identity in mouse fetal arteries. Blood 384 19144989
2011 Dll1- and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells. Gastroenterology 352 21238454
2005 The Notch ligands DLL1 and JAG2 act synergistically to regulate hair cell development in the mammalian inner ear. Development (Cambridge, England) 228 16141228
2018 Notch ligand Dll1 mediates cross-talk between mammary stem cells and the macrophageal niche. Science (New York, N.Y.) 164 29773667
2004 WNT signaling, in synergy with T/TBX6, controls Notch signaling by regulating Dll1 expression in the presomitic mesoderm of mouse embryos. Genes & development 147 15545628
2010 Direct comparison of Dll1- and Dll4-mediated Notch activation levels shows differential lymphomyeloid lineage commitment outcomes. Journal of immunology (Baltimore, Md. : 1950) 132 20548034
2013 Dll1 maintains quiescence of adult neural stem cells and segregates asymmetrically during mitosis. Nature communications 114 23695674
2013 Dynamic interactions between intermediate neurogenic progenitors and radial glia in embryonic mouse neocortex: potential role in Dll1-Notch signaling. The Journal of neuroscience : the official journal of the Society for Neuroscience 82 23699523
2018 Estrogen-dependent DLL1-mediated Notch signaling promotes luminal breast cancer. Oncogene 78 30442981
2003 Feedback loops comprising Dll1, Dll3 and Mesp2, and differential involvement of Psen1 are essential for rostrocaudal patterning of somites. Development (Cambridge, England) 77 12900443
2008 The intracellular region of Notch ligands Dll1 and Dll3 regulates their trafficking and signaling activity. Proceedings of the National Academy of Sciences of the United States of America 71 18676613
2021 Dll1+ quiescent tumor stem cells drive chemoresistance in breast cancer through NF-κB survival pathway. Nature communications 60 33462238
2011 Resuscitating cancer immunosurveillance: selective stimulation of DLL1-Notch signaling in T cells rescues T-cell function and inhibits tumor growth. Cancer research 60 21825014
2005 MAGI1 recruits Dll1 to cadherin-based adherens junctions and stabilizes it on the cell surface. The Journal of biological chemistry 58 15908431
2020 Jag1 Modulates an Oscillatory Dll1-Notch-Hes1 Signaling Module to Coordinate Growth and Fate of Pancreatic Progenitors. Developmental cell 57 32059775
2019 Haploinsufficiency of the Notch Ligand DLL1 Causes Variable Neurodevelopmental Disorders. American journal of human genetics 57 31353024
2011 Ptf1a-mediated control of Dll1 reveals an alternative to the lateral inhibition mechanism. Development (Cambridge, England) 55 22096075
2009 Dll1 and Dll4 function sequentially in the retina and pV2 domain of the spinal cord to regulate neurogenesis and create cell diversity. Developmental biology 53 19389377
2014 Spatiotemporal oscillations of Notch1, Dll1 and NICD are coordinated across the mouse PSM. Development (Cambridge, England) 51 25468943
2005 Dll1 is a downstream target of Tbx6 in the paraxial mesoderm. Genesis (New York, N.Y. : 2000) 50 15986483
2021 DLL1 orchestrates CD8+ T cells to induce long-term vascular normalization and tumor regression. Proceedings of the National Academy of Sciences of the United States of America 47 34035167
2018 MiR-34a Enhances Chondrocyte Apoptosis, Senescence and Facilitates Development of Osteoarthritis by Targeting DLL1 and Regulating PI3K/AKT Pathway. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 47 30048987
2017 MiR-34a-5p promotes multi-chemoresistance of osteosarcoma through down-regulation of the DLL1 gene. Scientific reports 46 28281638
2015 Multivalent Forms of the Notch Ligand DLL-1 Enhance Antitumor T-cell Immunity in Lung Cancer and Improve Efficacy of EGFR-Targeted Therapy. Cancer research 45 26404003
2012 Dll1/Notch activation contributes to bortezomib resistance by upregulating CYP1A1 in multiple myeloma. Biochemical and biophysical research communications 45 23111325
2011 MT1-MMP cleaves Dll1 to negatively regulate Notch signalling to maintain normal B-cell development. The EMBO journal 45 21572390
2013 Synaptojanin-2 binding protein stabilizes the Notch ligands DLL1 and DLL4 and inhibits sprouting angiogenesis. Circulation research 39 24025447
2015 Context-Dependent Functional Divergence of the Notch Ligands DLL1 and DLL4 In Vivo. PLoS genetics 35 26114479
2022 Dll1-Mediated Notch Signaling Drives Tumor Cell Cross-talk with Cancer-Associated Fibroblasts to Promote Radioresistance in Breast Cancer. Cancer research 31 36007109
2018 The ectodomains determine ligand function in vivo and selectivity of DLL1 and DLL4 toward NOTCH1 and NOTCH2 in vitro. eLife 31 30289388
2017 Actin cytoskeleton regulator Arp2/3 complex is required for DLL1 activating Notch1 signaling to maintain the stem cell phenotype of glioma initiating cells. Oncotarget 31 28380416
2022 Activation of NOTCH signaling via DLL1 is mediated by APE1-redox-dependent NF-κB activation in oesophageal adenocarcinoma. Gut 30 35750470
2014 Distinct expression patterns of Notch ligands, Dll1 and Dll4, in normal and inflamed mice intestine. PeerJ 29 24860699
2012 Delta-like ligand (DLL)1 expression in early mouse decidua and its localization to uterine natural killer cells. PloS one 29 23284862
2018 CCN3 and DLL1 co-regulate osteogenic differentiation of mouse embryonic fibroblasts in a Hey1-dependent manner. Cell death & disease 27 30538222
2022 The E3 ubiquitin ligase HUWE1 acts through the N-Myc-DLL1-NOTCH1 signaling axis to suppress glioblastoma progression. Cancer communications (London, England) 26 35848447
2020 DLL1- and DLL4-Mediated Notch Signaling Is Essential for Adult Pancreatic Islet Homeostasis. Diabetes 26 32029480
2016 Effect of Jagged-1 and Dll-1 on osteogenic differentiation by stem cells from human exfoliated deciduous teeth. Archives of oral biology 25 26826998
2015 Increased Serum Levels of the Notch Ligand DLL1 are Associated with Diastolic Dysfunction, Reduced Exercise Capacity, and Adverse Outcome in Chronic Heart Failure. Journal of cardiac failure 25 26211721
2010 Two Notch ligands, Dll1 and Jag1, are differently restricted in their range of action to control neurogenesis in the mammalian spinal cord. PloS one 25 21124801
2015 Dengue virus up-regulates expression of notch ligands Dll1 and Dll4 through interferon-β signalling pathway. Immunology 24 25041739
2014 Divergent and conserved roles of Dll1 signaling in development of craniofacial and trunk muscle. Developmental biology 23 25220152
2021 Feedback regulation of Notch signaling and myogenesis connected by MyoD-Dll1 axis. PLoS genetics 22 34370738
2020 Overexpressing microRNA-34a overcomes ABCG2-mediated drug resistance to 5-FU in side population cells from colon cancer via suppressing DLL1. Journal of biochemistry 21 32044957
2017 DISC1 Regulates the Proliferation and Migration of Mouse Neural Stem/Progenitor Cells through Pax5, Sox2, Dll1 and Neurog2. Frontiers in cellular neuroscience 21 28900388
2013 Sustained vs. oscillating expressions of Ngn2, Dll1 and Hes1: a model of neural differentiation of embryonic telencephalon. Journal of theoretical biology 21 23499991
2011 Stabilization of Dll1 mRNA by Elavl1/HuR in neuroepithelial cells undergoing mitosis. Molecular biology of the cell 21 21346194
2011 Overexpression of Notch ligand Dll1 in B16 melanoma cells leads to reduced tumor growth due to attenuated vascularization. Cancer letters 21 21752535
2017 The Notch Ligands DLL1 and Periostin Are Associated with Symptom Severity and Diastolic Function in Dilated Cardiomyopathy. Journal of cardiovascular translational research 20 28474304
2005 Identification of Dll1 (Delta1) target genes during mouse embryogenesis using differential expression profiling. Gene expression patterns : GEP 20 15979417
2017 Maintenance of Bone Homeostasis by DLL1-Mediated Notch Signaling. Journal of cellular physiology 18 27735989
2009 Dll1 haploinsufficiency in adult mice leads to a complex phenotype affecting metabolic and immunological processes. PloS one 16 19562077
2019 MIR148A family regulates cardiomyocyte differentiation of human embryonic stem cells by inhibiting the DLL1-mediated NOTCH signaling pathway. Journal of molecular and cellular cardiology 15 31233755
2012 Genetic and functional evaluation of the role of DLL1 in susceptibility to visceral leishmaniasis in India. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 14 22561395
2011 Cdx regulates Dll1 in multiple lineages. Developmental biology 14 22015720
2023 The phenotypic spectrum of terminal 6q deletions based on a large cohort derived from social media and literature: a prominent role for DLL1. Orphanet journal of rare diseases 13 36935482
2011 Genetic and functional evidence implicating DLL1 as the gene that influences susceptibility to visceral leishmaniasis at chromosome 6q27. The Journal of infectious diseases 13 21742847
2010 Combination of in silico and in situ hybridisation approaches to identify potential Dll1 associated miRNAs during mouse embryogenesis. Gene expression patterns : GEP 13 20558326
2016 Mib1 modulates dynamin 2 recruitment via Snx18 to promote Dll1 endocytosis for efficient Notch signaling. Genes to cells : devoted to molecular & cellular mechanisms 12 26923255
2016 Context-Dependent Sensitivity to Mutations Disrupting the Structural Integrity of Individual EGF Repeats in the Mouse Notch Ligand DLL1. Genetics 11 26801181
2016 Disruption of Notch signaling aggravates irradiation-induced bone marrow injury, which is ameliorated by a soluble Dll1 ligand through Csf2rb2 upregulation. Scientific reports 11 27188577
2013 Normal development in mice over-expressing the intracellular domain of DLL1 argues against reverse signaling by DLL1 in vivo. PloS one 10 24167636
2021 Terminal 6q deletions cause brain malformations, a phenotype mimicking heterozygous DLL1 pathogenic variants: A multicenter retrospective case series. Prenatal diagnosis 9 34894355
2009 Generation of transgenic mice expressing Cre recombinase under the control of the Dll1 mesoderm enhancer element. Genesis (New York, N.Y. : 2000) 9 19298012
2024 Cooperation of Wnt/β-catenin and Dll1-mediated Notch pathway in Lgr5-positive intestinal stem cells regulates the mucosal injury and repair in DSS-induced colitis mice model. Gastroenterology report 8 39444950
2021 Development of Dl1.72, a Novel Anti-DLL1 Antibody with Anti-Tumor Efficacy against Estrogen Receptor-Positive Breast Cancer. Cancers 8 34439228
2020 The potential mechanism of miR-130b on promotion of the invasion and metastasis of hepatocellular carcinoma by inhibiting Notch-Dll1. Journal of receptor and signal transduction research 8 32019397
2023 MicroRNA-143 acts as a tumor suppressor through Musashi-2/DLL1/Notch1 and Musashi-2/Snail1/MMPs axes in acute myeloid leukemia. Journal of translational medicine 7 37149661
2023 LINC00460 promotes neuroblastoma tumorigenesis and cisplatin resistance by targeting miR-149-5p/DLL1 axis and activating Notch pathway in vitro and in vivo. Drug delivery and translational research 7 38161194
2021 miR-130b suppresses the invasion and migration of prostate cancer via inhibiting DLL1 and regulating the PI3K/Akt pathways. Experimental and therapeutic medicine 7 34976140
2020 Association of DLL1 with type 1 diabetes in patients characterized by low polygenic risk score. Metabolism: clinical and experimental 7 33157082
2022 Dll1 Can Function as a Ligand of Notch1 and Notch2 in the Thymic Epithelium. Frontiers in immunology 6 35371023
2021 MALAT1: A Pivotal lncRNA in the Phenotypic Switch of Gastric Smooth Muscle Cells via the Targeting of the miR-449a/DLL1 Axis in Diabetic Gastroparesis. Frontiers in pharmacology 6 34385927
2014 S/T phosphorylation of DLL1 is required for full ligand activity in vitro but dispensable for DLL1 function in vivo during embryonic patterning and marginal zone B cell development. Molecular and cellular biology 6 24449764
2021 Tamoxifen Downregulates the Expression of Notch1 and DLL1 Genes in MKN-45 Gastric Cancer Cells. Journal of gastrointestinal cancer 5 32901446
2007 [Effect of mutation of chemotaxis signal transduction gene cheA in Pseudomonas putida DLL-1 on its chemotaxis and methyl parathion biodegradation]. Wei sheng wu xue bao = Acta microbiologica Sinica 5 17672308
2022 Dll1 haploinsufficiency causes brain abnormalities with functional relevance. Frontiers in neuroscience 4 36590296
2018 Dll1 Marks Cells of Origin of Ras-Induced Cancer in Mouse Squamous Epithelia. Translational oncology 4 30081298
2017 Glioma cell fate decisions mediated by Dll1-Jag1-Fringe in Notch1 signaling pathway. BMC systems biology 4 28950865
2013 [Up-regulation of DLL1 may promote the chemotherapeutic sensitivity in small cell lung cancer]. Zhongguo fei ai za zhi = Chinese journal of lung cancer 4 23769341
2024 Low-intensity pulsed ultrasound combined with ST36 modulate gastric smooth muscle contractile marker expression via RhoA/Rock and MALAT1/miR-449a/DLL1 signaling in diabetic rats. Neurogastroenterology and motility 3 38873849
2021 Computationally-obtained structural insights into the molecular interactions between Pidilizumab and binding partners DLL1 and PD-1. Journal of biomolecular structure & dynamics 3 33559526
2020 Localization of DLL1- and NICD-positive osteoblasts in cortical bone during postnatal growth in rats. Biochemical and biophysical research communications 3 32703409
2025 Usp11 maintained the survival of marginal zone B cells under ionizing radiation by deubiquitinating DLL1 and JAG2. Cell death & disease 2 39904982
2025 Differential O-glucose elongation on a specific EGF repeat within the canonical ligand-binding domain regulates DLL1/4-NOTCH1 signaling. Proceedings of the National Academy of Sciences of the United States of America 2 41129232
2024 Novel small molecule DMAMCL induces differentiation in rhabdomyosarcoma by downregulating of DLL1. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2 38626518
2012 [Expression of JAG1 and DLL1 genes in colorectal cancer and its clinical significance]. Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery 2 22539391
2025 Soluble DLL1 as an Indicator of acute kidney injury and postoperative delirium following cardiac surgery: a secondary analysis of a prospective study. Perioperative medicine (London, England) 1 40775336
2019 Loss of Pax6 Causes Regional Changes in Dll1 Expression in Developing Cerebral Cortex. Frontiers in cellular neuroscience 1 30894800
2018 A fusion protein composed of the DSL domain of Dll1 and RGD motif protects cryptic stem cells in irradiation injury. Bioscience reports 1 29444821
2017 Differential expression of the Notch1 receptor, and its ligands Dll1, Dll3 and Dll4 in distinct human pituitary adenoma subtypes. Oncology letters 1 28599454
2026 Discovery of guaianolide-eudesmanolide dimers as antihepatoma agents by targeting NEURL1B to disrupt the DLL1/Notch signaling pathway. Bioorganic chemistry 0 41861701
2025 A Serum DLL1 and CRP dual-marker model for bacterial infection detection in patients with decompensated cirrhosis: A dual-cohort diagnostic study. Science progress 0 40629898
2025 DLL1 haploinsufficiency in prenatal brain anomalies: a retrospective analysis of 6q terminal deletions. Frontiers in genetics 0 41190327
2025 DLL1-responsive PD-L1+ tumor-associated macrophages promote endocrine resistance in breast cancer. Science translational medicine 0 41191774
2024 DLL1/NOTCH1 signaling pathway maintain angiogenesis in meniscus development and degeneration. The international journal of biochemistry & cell biology 0 38772475
2024 GMNN and DLL1 mutation-related spondylocarpotarsal synostosis: a case report. Journal of Yeungnam medical science 0 39659197
2021 Activity of the mouse Notch ligand DLL1 is sensitive to C-terminal tagging in vivo. BMC research notes 0 34583743

Missed literature

Know a paper Affinage missed for DLL1? Flag it for the maintainers and the community.

No submissions yet.