Affinage

DLK1

Protein delta homolog 1 · UniProt P80370

Length
383 aa
Mass
41.3 kDa
Annotated
2026-04-28
100 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DLK1 (Pref-1) is a paternally expressed, imprinted transmembrane protein containing six EGF-like repeats that functions as a gatekeeper of progenitor cell identity, inhibiting terminal differentiation of adipocytes, osteoblasts, myoblasts, and hematopoietic cells while regulating proliferation in a context- and isoform-dependent manner (PMID:8500166, PMID:15068508, PMID:22801971, PMID:22891218). Proteolytic cleavage releases a soluble ectodomain that inhibits adipogenesis by activating MEK/ERK signaling to sustain Sox9 expression, thereby suppressing C/EBPβ/δ (PMID:9001251, PMID:19541743, PMID:30355480), whereas the membrane-bound form additionally inhibits preadipocyte and hematopoietic stem cell proliferation through cell-autonomous mechanisms (PMID:22891218, PMID:22801971); DLK1 directly interacts with NOTCH1 via its EGF domains 5–6 to modulate Notch signaling outputs in a cell-type-specific manner (PMID:26791579, PMID:17320900). Under hypoxia, ADAM17/HIF-dependent cleavage generates a nuclear-translocating intracellular fragment that promotes stem-like and invasive phenotypes in glioma (PMID:32205867). Paternally inherited loss-of-function mutations in DLK1 cause familial central precocious puberty with undetectable serum DLK1 (PMID:28324015).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1993 High

    Identification of DLK1 as an EGF-repeat transmembrane protein that blocks adipogenesis established the first functional role for this gene as a negative regulator of differentiation.

    Evidence cDNA cloning and constitutive overexpression in 3T3-L1 preadipocytes with differentiation assay

    PMID:8500166

    Open questions at the time
    • receptor or binding partner unknown
    • mechanism of differentiation inhibition uncharacterized
    • in vivo relevance not tested
  2. 1997 High

    Demonstration that DLK1 is proteolytically cleaved to release a biologically active soluble ectodomain, and that alternative splicing governs whether cleavage occurs, resolved how DLK1 can function in both juxtacrine and paracrine modes.

    Evidence In vitro cleavage assays, recombinant ectodomain addition and antibody neutralization in 3T3-L1 cells, splice-form analysis

    PMID:9001251

    Open questions at the time
    • identity of the protease performing cleavage unknown
    • whether membrane-bound vs. soluble forms have distinct downstream signaling not yet tested
  3. 1998 High

    Mapping of a cis-regulatory SAD element required for transcriptional silencing of DLK1 during differentiation revealed how DLK1 expression is shut off to permit adipogenesis.

    Evidence 5'-deletion reporter constructs, gel shift, UV cross-linking, and mutagenesis in 3T3-L1 cells

    PMID:9822638

    Open questions at the time
    • identity of the ~63 kDa SAD-binding protein unknown
    • whether this element operates in non-adipose lineages untested
  4. 1999 High

    Demonstration that dexamethasone promotes adipogenesis by transcriptionally repressing DLK1 connected glucocorticoid signaling to the DLK1 regulatory axis.

    Evidence Nuclear run-on, mRNA stability assays, and antisense transfection in 3T3-L1 cells

    PMID:10212243

    Open questions at the time
    • glucocorticoid receptor binding at DLK1 promoter not directly shown
    • relevance to in vivo glucocorticoid-induced obesity not tested
  5. 2004 High

    DLK1 was shown to maintain bipotential mesenchymal progenitor identity by inhibiting both osteoblast and adipocyte differentiation, broadening its role beyond adipogenesis; separately, DLK1 was established as the causal gene for callipyge muscular hypertrophy.

    Evidence Retroviral overexpression in human MSCs with cytochemistry, FACS, and ex vivo calvaria culture; transgenic DLK1 expression in mouse skeletal muscle and IHC in callipyge sheep

    PMID:15068508 PMID:15498495

    Open questions at the time
    • molecular mechanism of osteoblast inhibition not dissected
    • downstream myogenic signaling targets unknown
  6. 2006 Medium

    Showing that DLK1's extracellular domain inhibits Notch signaling in mesenchymal cells provided the first direct link between DLK1 and the Notch pathway, though the outcome (pro- vs. anti-adipogenic) proved cell-type-dependent.

    Evidence Domain-deletion constructs, co-culture, ERK1/2 activation, and Notch1 knockdown in C3H10T1/2 cells

    PMID:17320900

    Open questions at the time
    • direct physical interaction between DLK1 and Notch1 not yet demonstrated
    • basis for cell-type-specific divergent outcomes unclear
  7. 2009 Medium

    Consolidation of the MEK/ERK–Sox9–C/EBPβ/δ signaling axis downstream of soluble DLK1 provided a coherent molecular mechanism for adipogenesis inhibition.

    Evidence Synthesis of MAPK assays, Sox9 overexpression/knockdown, and C/EBP reporter assays from multiple studies

    PMID:19541743

    Open questions at the time
    • direct receptor for soluble DLK1 upstream of MEK/ERK not identified
    • pathway validated mainly in 3T3-L1 model
  8. 2010 High

    Conditional knockout revealed that Dlk1 is required for normal skeletal muscle development and satellite cell regulation, and that CTCF-bound insulator elements control imprinted DLK1 expression with loss of imprinting in AML.

    Evidence Muscle-specific Dlk1 KO/OE in mice with satellite cell culture; allele-specific expression, methylation, and CTCF ChIP in AML samples

    PMID:20089961 PMID:21124733

    Open questions at the time
    • downstream targets of Dlk1 in satellite cells beyond NF-κB not defined
    • functional consequence of biallelic expression in AML not directly tested
  9. 2012 High

    Isoform-specific dissection revealed that membrane-bound DLK1 uniquely inhibits preadipocyte and hematopoietic stem cell proliferation, whereas soluble DLK1 primarily inhibits differentiation, establishing that cleavage status dictates functional mode.

    Evidence Independent isoform manipulation in preadipocytes with cell cycle analysis and DLK1-null mice; Dlk1 KO/OE mice and stromal co-cultures for hematopoietic readouts

    PMID:22801971 PMID:22891218

    Open questions at the time
    • mechanism by which membrane-bound DLK1 arrests G1/S progression unknown
    • whether isoform-specific effects extend to other tissues untested
  10. 2014 High

    Multiple studies mapped DLK1 function in diverse contexts: Pref-1+ cells were placed as the earliest mesenchymal adipose precursors preceding Zfp423+ and PPARγ+ cells; DLK1 overexpression was shown to cause pituitary IGF1 resistance and shift metabolism toward lipid oxidation; and DLK1 was linked to Notch inhibition in salivary gland organogenesis.

    Evidence Lineage tracing with Pref-1 promoter and inducible cell ablation in mice; transgenic DLK1 overexpression with metabolic and endocrine phenotyping; organotypic gland cultures with DLK1 and DAPT

    PMID:24828459 PMID:25088414 PMID:25349437

    Open questions at the time
    • receptor mediating DLK1 metabolic effects in liver/pituitary not identified
    • how DLK1 interacts with GH axis mechanistically unclear
  11. 2016 High

    Direct physical interaction between DLK1 EGF domains 5–6 and NOTCH1 EGF domains 10–15 was mapped, providing the structural basis for DLK1-mediated Notch inhibition.

    Evidence Mammalian two-hybrid domain deletion mapping, Notch1 activation comparison in Dlk1+/+ vs Dlk1−/− E16.5 tissues, siRNA in cell lines

    PMID:26791579

    Open questions at the time
    • no biophysical or structural characterization of the interaction
    • whether DLK1 competes with canonical Notch ligands at these domains not directly tested
  12. 2017 High

    Human genetics established that paternally inherited DLK1 loss-of-function causes familial central precocious puberty with undetectable serum DLK1, linking DLK1 to neuroendocrine pubertal timing control.

    Evidence Linkage analysis, whole-genome sequencing of affected families, serum DLK1 ELISA, DLK1 expression in mouse hypothalamus and kisspeptin neuron cell lines

    PMID:28324015

    Open questions at the time
    • molecular mechanism by which DLK1 regulates GnRH/kisspeptin axis unknown
    • whether Notch inhibition mediates the pubertal phenotype untested
  13. 2020 High

    Discovery of a hypoxia-driven, ADAM17/HIF-dependent cleavage event that releases a DLK1 intracellular fragment translocating to the nucleus revealed a non-canonical signaling mode promoting stemness and invasion in glioma.

    Evidence ADAM17 inhibitors, HIF siRNA, cleavable vs. non-cleavable DLK1 constructs, nuclear immunofluorescence, PDGFB-induced glioma mouse model

    PMID:32205867

    Open questions at the time
    • nuclear targets of the DLK1 intracellular fragment not identified
    • whether this mechanism operates outside glioma unknown
    • structural determinants of intracellular fragment release vs. ectodomain shedding unclear
  14. 2021 Medium

    Biallelic expression of Dlk1 in the hippocampal subgranular zone, escaping canonical imprinting, was shown to be required for normal adult neurogenesis and spatial discrimination, demonstrating tissue-specific regulation of imprinting.

    Evidence Allele-specific expression analysis, maternal/paternal/biallelic Dlk1 mutant mice with behavioral and neurogenesis quantification

    PMID:33712542

    Open questions at the time
    • mechanism of imprint escape in hippocampus not defined
    • downstream neurogenic targets of Dlk1 in subgranular zone unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of the cell-surface receptor that transduces soluble DLK1 signaling to MEK/ERK and AMPK pathways remains unknown, and the nuclear targets of the DLK1 intracellular fragment have not been identified.
  • no receptor for soluble DLK1 identified
  • nuclear binding partners/targets of DLK1 ICD unknown
  • structural basis of DLK1–NOTCH1 interaction not resolved at atomic level

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005576 extracellular region 5 GO:0005886 plasma membrane 5 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1266738 Developmental Biology 4 R-HSA-1430728 Metabolism 2
Partners
ADAM17CTCFNOTCH1SOX9

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Pref-1 (DLK1) is synthesized as a transmembrane protein with six tandem EGF-like repeats and functions as a negative regulator of adipocyte differentiation; constitutive expression in preadipocytes blocks adipogenesis. cDNA cloning, constitutive overexpression in 3T3-L1 preadipocytes with differentiation assay Cell High 8500166
1997 Membrane-associated Pref-1 (DLK1) is cleaved in the juxtamembrane region to generate a soluble ~50 kDa ectodomain that is biologically active and inhibits adipocyte differentiation; only the two largest alternatively spliced isoforms undergo this cleavage, establishing that alternative splicing governs juxtacrine vs. paracrine modes of Pref-1 action. In vitro cleavage assays, addition of recombinant ectodomain to 3T3-L1 cells, antibody neutralization, alternate splice-form analysis Molecular and cellular biology High 9001251
1999 Dexamethasone promotes adipogenesis by transcriptionally repressing the Pref-1 (DLK1) gene; nuclear run-on assays showed reduced Pref-1 transcription, and antisense Pref-1 transfection enhanced adipogenesis at low dexamethasone concentrations, placing Pref-1 downregulation as a key mechanism of glucocorticoid-driven adipoconversion. Nuclear run-on transcription assay, actinomycin D mRNA stability assay, stable antisense transfection with differentiation assay The Journal of biological chemistry High 10212243
1998 A specific cis-element in the Pref-1 (DLK1) promoter, the SAD (suppression in adipocyte differentiation) element (core sequence -183AAAGA-179), is required for differentiation-dependent transcriptional suppression of the Pref-1 gene; an ~63 kDa nuclear protein binds this element. Stable transfection of 5'-deletion reporter constructs, gel mobility shift assay, UV cross-linking, base-substitution mutagenesis The Journal of biological chemistry High 9822638
2004 Constitutive overexpression of DLK1/Pref-1 in human mesenchymal stem cells inhibits both osteoblast and adipocyte differentiation without affecting proliferation, identifying DLK1 as a regulator that maintains the bipotential progenitor pool. Retroviral overexpression in hMSC-TERT cells, cytochemical staining, FACS, real-time PCR, ex vivo calvaria organ culture Journal of bone and mineral research High 15068508
2004 Ectopic expression of DLK1 protein in skeletal muscle of callipyge sheep (+(MAT)/CLPG(PAT)) causes muscular hypertrophy; transgenic mice expressing DLK1 in skeletal muscle develop generalized muscular hypertrophy, establishing DLK1 as the causal agent of the callipyge phenotype. Immunohistochemistry in sheep muscle, transgenic mouse model with skeletal muscle-specific DLK1 expression Current biology : CB High 15498495
2006 The EGF-like extracellular domain of DLK1 inhibits Notch signaling in mesenchymal C3H10T1/2 cells, but this Notch inhibition paradoxically potentiates adipogenesis in these cells (unlike 3T3-L1 cells); the effect requires Notch1 expression and is mediated by the extracellular, not the intracellular, domain of DLK1. Overexpression of full-length vs. domain-deletion DLK1 constructs, co-culture assay, ERK1/2 activation measurement, Notch1 knockdown Journal of molecular biology Medium 17320900
2009 Soluble Pref-1 (DLK1) activates the MEK/ERK pathway; ERK activation by Pref-1 prevents downregulation of Sox9, which in turn suppresses C/EBPβ and C/EBPδ expression and blocks adipogenesis. Pref-1 also induces Sox9 to promote chondrogenic lineage commitment while inhibiting chondrocyte maturation and osteoblast differentiation. Review synthesizing signaling pathway data from multiple mechanistic studies (MAPK assays, Sox9 overexpression/knockdown, C/EBP reporter assays) Molecular endocrinology (Baltimore, Md.) Medium 19541743
2010 Dlk1 is required for normal skeletal muscle development and regeneration; muscle-specific Dlk1 knockout reduces myofiber number and MyoD expression, impairs regeneration with augmented NF-κB and inflammatory cytokine signaling, and promotes satellite cell self-renewal; conversely, Dlk1 overexpression inhibits satellite cell proliferation and enhances differentiation. Conditional knockout and overexpression in mice, satellite cell single-fiber culture, immunofluorescence, gene expression analysis PloS one High 21124733
2012 Membrane-bound DLK1 (DLK1-M), but not soluble DLK1, inhibits G1-to-S-phase cell cycle progression and preadipocyte proliferation; DLK1-null mice show increased preadipocyte replication and higher fat mass, establishing a dual inhibitory role of DLK1 on both proliferation and differentiation in adipogenesis. Independent manipulation of DLK1 isoform levels in preadipocytes, cell cycle analysis, in vivo analysis of DLK1-null mice Diabetes High 22891218
2012 The membrane-bound form of Dlk1, but not soluble Dlk1, is required for its negative regulatory effect on hematopoietic stem and progenitor cell activity in the aorta-gonad-mesonephros region; this was demonstrated in Dlk1 KO and overexpressing mice and recapitulated in co-cultures with stromal cells expressing different Dlk1 levels. Dlk1 knockout and overexpression mouse models, co-culture experiments, FACS-based hematopoietic stem cell quantification Haematologica High 22801971
2012 DLK1 is expressed predominantly as a soluble protein (cleaved extracellular domain) in adult mouse hypothalamus and localizes to soma and dendrites of arginine-vasopressin and oxytocin neurons in multiple hypothalamic nuclei, suggesting a neuroendocrine role. Western blot of hypothalamic fractions, immunohistochemistry, in situ hybridization PloS one Medium 22563444
2014 DLK1 promotes lung cancer cell invasion by upregulating MMP9 expression through activation of Notch signaling (NOTCH1/NICD nuclear translocation, HES1); γ-secretase inhibitor (GSI) blocked DLK1-induced MMP9 upregulation. DLK1 overexpression/knockdown in lung cancer cell lines, transwell invasion assay, Western blot, gelatin zymography, GSI pharmacological inhibition PloS one Medium 24621612
2014 Membrane-bound Dlk1 promotes myogenic hypertrophy and fusion in C2C12 cells, whereas soluble Dlk1 inhibits myotube formation, demonstrating isoform-specific opposing roles in myogenesis. C2C12 cell lines stably expressing membrane-bound vs. soluble Dlk1, fusion index quantification, gene expression analysis FEBS letters Medium 24582655
2014 DLK1/Pref-1 overexpression causes reduced fat stores, pituitary IGF1 resistance, impaired GH feedback regulation, and increased circulating GH, which shifts whole-body fuel metabolism toward peripheral lipid oxidation and reduces hepatic steatosis; these effects were demonstrated by overexpressing Dlk1 from endogenous control elements in mice. Transgenic mouse overexpression from endogenous elements, metabolic phenotyping, hormone measurements, glucose/insulin tolerance tests Proceedings of the National Academy of Sciences of the United States of America High 25349437
2014 Pref-1+ cells are very early mesenchymal adipose precursors that precede Zfp423+ and PPARγ+ cells in the adipogenic hierarchy; ablation of Pref-1-marked cells prevents embryonic white adipose tissue development and adult adipose expansion upon high-fat feeding. Transgenic mouse lineage tracing with Pref-1 promoter-driven fluorescent labels and inducible cell ablation Cell reports High 25088414
2015 Exogenous soluble DLK1 (Fc-DLK1 fusion) reduces hepatic steatosis and hyperglycemia in db/db mice by activating AMPK and ACC phosphorylation, suppressing SREBP-1c, lowering PEPCK/G6Pase expression, and inducing AKT-mediated cytosolic translocation of FOXO1; the gluconeogenic effect was blocked by an AMPK inhibitor. Recombinant soluble DLK1 treatment of db/db mice and primary hepatocytes, AMPK inhibitor co-administration, Western blot, glucose production assay International journal of obesity (2005) Medium 26315841
2016 DLK1 directly interacts with NOTCH1 in mammals; the interaction occurs between EGF domains 5 and 6 of DLK1 and EGF domains 10-15 of NOTCH1, demonstrated by mammalian two-hybrid system; DLK1 reduces NOTCH1 activation in Dlk1+/+ vs Dlk1-/- embryos and in siRNA-manipulated cell lines. Mammalian two-hybrid system, domain deletion mapping, comparison of NOTCH1 activation in Dlk1+/+ vs Dlk1-/- E16.5 mouse tissues, siRNA knockdown in mammalian cell line Cellular signalling High 26791579
2017 Loss-of-function genomic defects in DLK1 (paternally inherited) cause familial central precocious puberty; affected individuals have undetectable serum DLK1 and Dlk1 is expressed in mouse hypothalamus and kisspeptin neuron-derived cell lines, implicating DLK1 in the neuroendocrine control of pubertal timing. Linkage analysis, whole-genome sequencing, serum DLK1 ELISA, in situ hybridization in mouse hypothalamus, Dlk1 expression in kisspeptin cell lines The Journal of clinical endocrinology and metabolism High 28324015
2018 Soluble DLK1 (extracellular domain) stimulates angiogenesis by activating Notch1/Akt/eNOS/Hes-1 signaling in endothelial cells; γ-secretase inhibitor or Notch1 knockdown/antibody neutralization reversed DLK1-EC-induced endothelial migration and angiogenesis. Recombinant DLK1-EC treatment of endothelial cells and aorta ring sprouting assay, corneal neovascularization in rats, Western blot/luciferase reporter for Notch1 pathway, pharmacological and siRNA inhibition of Notch1 Angiogenesis Medium 29383634
2018 Sox9 inactivation in Pref-1+ cells converts them to PDGFRα+ cells expressing early adipogenic markers, demonstrating that Sox9 maintains the Pref-1+ early precursor state and that Sox9 inactivation is required for white adipose tissue expansion; Pref-1+ cells precede PDGFRα+ cells in the adipogenic hierarchy. Pref-1 promoter-rtTA system for inducible Sox9 inactivation in mice, lineage tracing, FACS, gene expression Cell reports High 30355480
2020 Hypoxia induces ADAM17-dependent cleavage of DLK1 and release of an intracellular fragment that translocates to the nucleus in glioma cells; HIF-1α/HIF-2α are required for this cleavage. Expression of cleavable DLK1 promotes colony formation, stem cell marker expression, PI3K-pathway-mediated metabolic shift, and invasion; non-cleavable DLK1 does not replicate these effects. Immunofluorescence of DLK1 nuclear translocation, ADAM17 inhibitors and HIF siRNA to block cleavage, cleavable vs. non-cleavable DLK1 constructs, PDGFB-induced glioma mouse model Oncogene High 32205867
2021 Dlk1 is expressed biallelically (loss of canonical imprinting) in the subgranular zone of the hippocampus; both parental alleles are required for normal adult neurogenesis and cognitive function (spatial discrimination), demonstrated by allele-specific Dlk1 mutant mice. Allele-specific expression analysis, maternal/paternal/biallelic Dlk1 mutant mouse behavioral battery, adult neurogenesis quantification Proceedings of the National Academy of Sciences of the United States of America Medium 33712542
2005 Intracellular domain interactions of DLK1 are critical for inhibiting differentiation and proliferation of hematopoietic HL-60 cells; unlike in preadipocytes, proteolytic release of the extracellular domain is not required for DLK1 function in hematopoietic cells. Ectopic expression of DLK1 with domain mutations in HL-60 cells, differentiation and proliferation assays Oncogene Medium 15806146
2014 DLK1 loss-of-function in neuroblastoma xenografts enhances tumor cell differentiation likely by increasing basal MEK/ERK phosphorylation; DLK1+ cells are preferentially located in hypoxic tumor regions. Loss-of-function DLK1 mutants in neuroblastoma xenografts, MEK/ERK phosphorylation analysis, hypoxia immunostaining Cancer letters Medium 22142700
2014 DLK1 inhibits branching morphogenesis of submandibular salivary glands and parasympathetic innervation of epithelial end buds through inhibition of NOTCH signaling; soluble DLK1 and the γ-secretase inhibitor DAPT phenocopied each other in organotypic cultures, reducing branching, increasing epithelial apoptosis, and impairing parasympathetic ganglion outgrowth. Organotypic submandibular gland cultures with soluble DLK1 or DAPT treatment, rescue with carbachol, immunohistochemistry Biology of the cell Medium 24828459
2024 DLK1 is robustly expressed on the cell surface of neuroblastoma cells; shRNA-mediated silencing of DLK1 in neuroblastoma cells increases cellular differentiation; a DLK1-targeting antibody-drug conjugate (ADCT-701) shows potent cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Proteogenomic analysis, immunofluorescence, flow cytometry, IHC, shRNA silencing with differentiation assay, ADC xenograft efficacy study Cancer cell Medium 39454577
2010 An insulator element 18 kb upstream of DLK1, bound by CTCF, regulates monoallelic (imprinted) DLK1 expression; hypermethylation of this region on both alleles in AML disrupts CTCF binding and results in biallelic DLK1 overexpression. SNP allele-specific expression analysis, quantitative methylation analysis, allele-specific methylation analysis, chromatin immunoprecipitation for CTCF Blood Medium 20089961

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Pref-1, a protein containing EGF-like repeats, inhibits adipocyte differentiation. Cell 577 8500166
2008 Genomic imprinting at the mammalian Dlk1-Dio3 domain. Trends in genetics : TIG 339 18471925
2000 Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2. Nature cell biology 327 10934472
1998 Delta-1 activation of notch-1 signaling results in HES-1 transactivation. Molecular and cellular biology 283 9819428
2003 Isolation of hepatoblasts based on the expression of Dlk/Pref-1. Journal of cell science 278 12665558
2000 The Dlk1 and Gtl2 genes are linked and reciprocally imprinted. Genes & development 254 10950864
2012 The microRNAs within the DLK1-DIO3 genomic region: involvement in disease pathogenesis. Cellular and molecular life sciences : CMLS 227 22825660
2004 Regulation of human skeletal stem cells differentiation by Dlk1/Pref-1. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 197 15068508
2009 Minireview: Pref-1: role in adipogenesis and mesenchymal cell fate. Molecular endocrinology (Baltimore, Md.) 187 19541743
2003 The Notch ligands, Delta1 and Jagged2, are substrates for presenilin-dependent "gamma-secretase" cleavage. The Journal of biological chemistry 185 12551931
1999 Expression of Delta1 and Serrate1 (Jagged1) in the mouse inner ear. Mechanisms of development 171 10473135
1997 Cleavage of membrane-associated pref-1 generates a soluble inhibitor of adipocyte differentiation. Molecular and cellular biology 170 9001251
2017 Paternally Inherited DLK1 Deletion Associated With Familial Central Precocious Puberty. The Journal of clinical endocrinology and metabolism 147 28324015
2012 Possible roles of DLK1 in the Notch pathway during development and disease. Biochimica et biophysica acta 142 22353464
1999 Autonomous and non-autonomous regulation of mammalian neurite development by Notch1 and Delta1. Current biology : CB 132 10607588
2019 Astragalus polysaccharides (PG2) Enhances the M1 Polarization of Macrophages, Functional Maturation of Dendritic Cells, and T Cell-Mediated Anticancer Immune Responses in Patients with Lung Cancer. Nutrients 131 31547048
1999 Transcriptional repression of pref-1 by glucocorticoids promotes 3T3-L1 adipocyte differentiation. The Journal of biological chemistry 131 10212243
2006 The EGF-like protein dlk1 inhibits notch signaling and potentiates adipogenesis of mesenchymal cells. Journal of molecular biology 113 17320900
2014 Pref-1 marks very early mesenchymal precursors required for adipose tissue development and expansion. Cell reports 107 25088414
2010 Dlk1 is necessary for proper skeletal muscle development and regeneration. PloS one 105 21124733
2004 Ectopic expression of DLK1 protein in skeletal muscle of padumnal heterozygotes causes the callipyge phenotype. Current biology : CB 104 15498495
1999 Delta1 expression during avian hair cell regeneration. Development (Cambridge, England) 95 9927597
2008 Suppression of Th2 cell development by Notch ligands Delta1 and Delta4. Journal of immunology (Baltimore, Md. : 1950) 87 18209061
2008 Human Delta1-pyrroline-5-carboxylate synthase: function and regulation. Amino acids 87 18401542
2000 Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and Notch3 receptors. Biochemical and biophysical research communications 86 11006133
2019 DLK1 Is a Novel Link Between Reproduction and Metabolism. The Journal of clinical endocrinology and metabolism 85 30462238
2012 Regulation of DLK-1 kinase activity by calcium-mediated dissociation from an inhibitory isoform. Neuron 84 23141066
2005 Dlk1 in normal and abnormal hematopoiesis. Leukemia 79 15959531
2006 DLK1: increased expression in gliomas and associated with oncogenic activities. Oncogene 72 16288219
2005 Expression of DLK1 in hematopoietic cells results in inhibition of differentiation and proliferation. Oncogene 71 15806146
2000 Function of pref-1 as an inhibitor of adipocyte differentiation. International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity 71 11126233
2008 Dlk1 influences differentiation and function of B lymphocytes. Stem cells and development 68 18513163
2002 Expression of Notch ligands, Jagged1, 2 and Delta1 in antigen presenting cells in mice. Immunology letters 64 11841846
1998 Transcriptional control of the pref-1 gene in 3T3-L1 adipocyte differentiation. Sequence requirement for differentiation-dependent suppression. The Journal of biological chemistry 64 9822638
2014 DLK1 promotes lung cancer cell invasion through upregulation of MMP9 expression depending on Notch signaling. PloS one 63 24621612
1998 Phospholipase C-delta1 and oxytocin receptor signalling: evidence of its role as an effector. The Biochemical journal 62 9512491
1996 FA1 immunoreactivity in endocrine tumours and during development of the human fetal pancreas; negative correlation with glucagon expression. Histochemistry and cell biology 58 8985741
2016 Regulation of the imprinted Dlk1-Dio3 locus by allele-specific enhancer activity. Genes & development 56 26728555
2014 DLK1/PREF1 regulates nutrient metabolism and protects from steatosis. Proceedings of the National Academy of Sciences of the United States of America 54 25349437
2012 Membrane-tethered delta-like 1 homolog (DLK1) restricts adipose tissue size by inhibiting preadipocyte proliferation. Diabetes 54 22891218
2001 Neurons in the monoaminergic nuclei of the rat and human central nervous system express FA1/dlk. Neuroreport 53 11742219
2020 Heterogeneity of Satellite Cells Implicates DELTA1/NOTCH2 Signaling in Self-Renewal. Cell reports 51 32023464
2005 Phospholipase C-delta1 and -delta3 are essential in the trophoblast for placental development. Molecular and cellular biology 51 16314520
2021 The role of delta-like non-canonical Notch ligand 1 (DLK1) in cancer. Endocrine-related cancer 50 34627131
1997 Molecular mechanisms of adipocyte differentiation and inhibitory action of pref-1. Critical reviews in eukaryotic gene expression 50 9607168
2016 Evidence of non-canonical NOTCH signaling: Delta-like 1 homolog (DLK1) directly interacts with the NOTCH1 receptor in mammals. Cellular signalling 49 26791579
2018 Dlk1-Dio3 locus-derived lncRNAs perpetuate postmitotic motor neuron cell fate and subtype identity. eLife 48 30311912
2002 Pref-1 and ADSF/resistin: two secreted factors inhibiting adipose tissue development. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 48 12660879
2018 Soluble delta-like 1 homolog (DLK1) stimulates angiogenesis through Notch1/Akt/eNOS signaling in endothelial cells. Angiogenesis 47 29383634
2015 Dppa3 expression is critical for generation of fully reprogrammed iPS cells and maintenance of Dlk1-Dio3 imprinting. Nature communications 46 25613421
2020 DLK1, Notch Signaling and the Timing of Puberty. Seminars in reproductive medicine 44 31972862
2012 DLK1 is a somato-dendritic protein expressed in hypothalamic arginine-vasopressin and oxytocin neurons. PloS one 44 22563444
2012 Dlk1 is a negative regulator of emerging hematopoietic stem and progenitor cells. Haematologica 44 22801971
1998 Expression patterns of Notch1, Serrate1, Serrate2 and Delta1 in tissues of the developing chick limb. Mechanisms of development 42 9831652
2010 An upstream insulator regulates DLK1 imprinting in AML. Blood 39 20089961
2007 The calcium channel alpha2/delta1 subunit is involved in extracellular signalling. The Journal of physiology 39 18063658
2021 Emerging Roles of DLK1 in the Stem Cell Niche and Cancer Stemness. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 38 34606325
2020 The Role of Pref-1 during Adipogenic Differentiation: An Overview of Suggested Mechanisms. International journal of molecular sciences 38 32526833
2019 Transcriptional profiling at the DLK1/MEG3 domain explains clinical overlap between imprinting disorders. Science advances 38 30801013
2004 Activation of PLC-delta1 by Gi/o-coupled receptor agonists. American journal of physiology. Cell physiology 38 15525688
2016 Impact of DLK1-DIO3 imprinted cluster hypomethylation in smoker patients with lung cancer. Oncotarget 37 29435111
2019 Astragalus polysaccharide (PG2) Ameliorates Cancer Symptom Clusters, as well as Improves Quality of Life in Patients with Metastatic Disease, through Modulation of the Inflammatory Cascade. Cancers 36 31349728
2018 Sox9-Meis1 Inactivation Is Required for Adipogenesis, Advancing Pref-1+ to PDGFRα+ Cells. Cell reports 36 30355480
2014 RPM-1 uses both ubiquitin ligase and phosphatase-based mechanisms to regulate DLK-1 during neuronal development. PLoS genetics 36 24810406
2006 Atmnd1-delta1 is sensitive to gamma-irradiation and defective in meiotic DNA repair. DNA repair 36 16442857
2020 Striatal glutamate delta-1 receptor regulates behavioral flexibility and thalamostriatal connectivity. Neurobiology of disease 33 31945419
2006 Alternative splicing of delta-like 1 homolog (DLK1) in the pig and human. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 33 16901742
2006 Nucleocytoplasmic shuttling of phospholipase C-delta1: a link to Ca2+. Journal of cellular biochemistry 29 16240320
1996 Characterization of Pref-1 and its inhibitory role in adipocyte differentiation. International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity 29 8680480
2014 RHGF-1/PDZ-RhoGEF and retrograde DLK-1 signaling drive neuronal remodeling on microtubule disassembly. Proceedings of the National Academy of Sciences of the United States of America 28 25359212
2012 Pref-1 in brown adipose tissue: specific involvement in brown adipocyte differentiation and regulatory role of C/EBPδ. The Biochemical journal 28 22324440
2011 DLK1, delta-like 1 homolog (Drosophila), regulates tumor cell differentiation in vivo. Cancer letters 28 22142700
2008 Instability of Notch1 and Delta1 mRNAs and reduced Notch activity in vertebrate neuroepithelial cells undergoing S-phase. Molecular and cellular neurosciences 28 18289870
2021 Dlk1 dosage regulates hippocampal neurogenesis and cognition. Proceedings of the National Academy of Sciences of the United States of America 27 33712542
2020 Hypoxia-induced release, nuclear translocation, and signaling activity of a DLK1 intracellular fragment in glioma. Oncogene 27 32205867
2016 MicroRNA-409-3p inhibits osteosarcoma cell migration and invasion by targeting catenin-δ1. Gene 27 26992637
2020 Arabidopsis MAPKKK δ-1 is required for full immunity against bacterial and fungal infection. Journal of experimental botany 26 31844896
2015 Exogenous administration of DLK1 ameliorates hepatic steatosis and regulates gluconeogenesis via activation of AMPK. International journal of obesity (2005) 26 26315841
2015 Temple syndrome as a result of isolated hypomethylation of the 14q32 imprinted DLK1/MEG3 region. American journal of medical genetics. Part A 26 26395259
2005 Identification of DLK1 variants in pituitary- and neuroendocrine tumors. Biochemical and biophysical research communications 26 16403460
2022 Epigenome editing reveals core DNA methylation for imprinting control in the Dlk1-Dio3 imprinted domain. Nucleic acids research 25 35544282
2018 A Hearty Dose of Noncoding RNAs: The Imprinted DLK1-DIO3 Locus in Cardiac Development and Disease. Journal of cardiovascular development and disease 25 29996488
2014 DLK1 regulates branching morphogenesis and parasympathetic innervation of salivary glands through inhibition of NOTCH signalling. Biology of the cell 25 24828459
2021 A bipartite element with allele-specific functions safeguards DNA methylation imprints at the Dlk1-Dio3 locus. Developmental cell 24 34710357
2017 DLK1-DIO3 imprinted locus deregulation in development, respiratory disease, and cancer. Expert review of respiratory medicine 24 28715922
1998 Implication of ZOG protein (zona glomerulosa-specific protein) in zone development of the adrenal cortex. Endocrine research 24 9888532
2020 Astragalus Polysaccharide (PG2) Suppresses Macrophage Migration Inhibitory Factor and Aggressiveness of Lung Adenocarcinoma Cells. The American journal of Chinese medicine 23 32924531
2009 Isolation and differentiation of chondrocytic cells derived from human embryonic stem cells using dlk1/FA1 as a novel surface marker. Stem cell reviews and reports 22 20058200
2019 MicroRNA-143-3p suppresses tumorigenesis by targeting catenin-δ1 in colorectal cancer. OncoTargets and therapy 21 31118676
2017 CD146 (MCAM) in human cs-DLK1-/cs-CD34+ adipose stromal/progenitor cells. Stem cell research 21 28549249
2014 Antagonistic roles in fetal development and adult physiology for the oppositely imprinted Grb10 and Dlk1 genes. BMC biology 21 25551289
2007 Expression of ksdD gene encoding 3-ketosteroid-Delta1-dehydrogenase from Arthrobacter simplex in Bacillus subtilis. Letters in applied microbiology 21 17451526
2019 Dysregulation of ncRNAs located at the DLK1‑DIO3 imprinted domain: involvement in urological cancers. Cancer management and research 20 30697070
2014 Membrane-bound delta-like 1 homolog (Dlk1) promotes while soluble Dlk1 inhibits myogenesis in C2C12 cells. FEBS letters 20 24582655
2024 A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma. Cancer cell 19 39454577
2018 Deletion of Dlk1 increases the vulnerability to developing anxiety-like behaviors and ethanol consumption in mice. Biochemical pharmacology 18 30268817
2018 Glutamate delta-1 receptor regulates cocaine-induced plasticity in the nucleus accumbens. Translational psychiatry 18 30315226
2010 Expression of DLK1 and MEG3 genes in porcine tissues during postnatal development. Genetics and molecular biology 18 21637593
2008 Synergistic role of Igf2 and Dlk1 in fetal liver development and hematopoiesis in bi-maternal mice. The Journal of reproduction and development 18 18344616
2007 Expansion and characterization of ventral mesencephalic precursor cells: effect of mitogens and investigation of FA1 as a potential dopaminergic marker. Journal of neuroscience research 18 17471553