DLK1 (delta-like non-canonical Notch ligand 1, also called fetal antigen 1 or preadipocyte factor 1) is a single-pass type I membrane glycoprotein of the Delta/Serrate/LAG-2 family whose extracellular region consists of six EGF-like repeats but lacks the DSL motif required for canonical Notch activation, so it acts as a non-canonical, generally inhibitory modulator of Notch signalling. It is expressed from the paternally inherited allele of the imprinted DLK1-DIO3 locus, is abundant in fetal tissues, placenta, adrenal cortex, pancreatic islet beta cells and preadipocytes, and is re-expressed in neuroblastoma, small cell lung carcinoma, hepatoblastoma, hepatocellular carcinoma and other tumours, which makes its exposed ectodomain an antibody and CAR-T target. A juxtamembrane region is cleaved by ADAM17, releasing a soluble ectodomain (circulating FA1) that retains activity, so DLK1 signals both as a membrane protein in trans and as a secreted factor. Functionally it keeps progenitor cells undifferentiated, inhibiting adipogenesis and osteoblast differentiation while promoting osteoclastogenesis and bone resorption.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Calcium ion binding mapped from the calcium-binding EGF-like domain signature. Reason: The assignment is a domain-based inference; calcium binding by the EGF repeats is a structural property rather than a demonstrated function of DLK1, and no experimental support was found. Supporting Evidence: file:human/DLK1/DLK1-uniprot.txt DOMAIN 24..55 PMID:7925474 FA1 has six well conserved epidermal-growth-factor motifs |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Interactions with progranulin and SPRED1 from a neurodegeneration interactome map. Reason: Generic protein binding from a systematic screen with no follow-up defining a DLK1 function; uninformative. Removal does not assert the interactions are false. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Interactions with progranulin and SPRED1 from a neurodegeneration interactome map. Reason: Generic protein binding from a systematic screen with no follow-up defining a DLK1 function; uninformative. Removal does not assert the interactions are false. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains |
| GO:0005576 extracellular region | IDA PMID:25093684 The proteins DLK1 and DLK2 modulate NOTCH1-dependent prolife... | ACCEPT | Summary: The DLK1 ectodomain is shed and circulates as soluble fetal antigen 1. Reason: FA1 was purified from human amniotic fluid and shown to be the DLK1 ectodomain; the soluble form is biologically active, so the extracellular location is genuine and not merely contamination. Supporting Evidence: PMID:7925474 The present paper describes the primary structure, glycosylation and tissue localization of fetal antigen 1 (FA1) isolated from second-trimester human amniotic fluid PMID:25093684 The proteins DLK1 and DLK2 modulate NOTCH1-dependent proliferation and oncogenic potential of human SK-MEL-2 melanoma cells |
| GO:0005576 extracellular region | IDA PMID:7925474 Protein structure of fetal antigen 1 (FA1). A novel circulat... | ACCEPT | Summary: The DLK1 ectodomain is shed and circulates as soluble fetal antigen 1. Reason: FA1 was purified from human amniotic fluid and shown to be the DLK1 ectodomain; the soluble form is biologically active, so the extracellular location is genuine and not merely contamination. Supporting Evidence: PMID:7925474 The present paper describes the primary structure, glycosylation and tissue localization of fetal antigen 1 (FA1) isolated from second-trimester human amniotic fluid PMID:25093684 The proteins DLK1 and DLK2 modulate NOTCH1-dependent proliferation and oncogenic potential of human SK-MEL-2 melanoma cells |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Cytoplasm localization transferred from the mouse orthologue. Reason: DLK1 has a 56-residue cytoplasmic tail and transits the secretory pathway, so cytoplasmic signal is plausible, but its functional pools are the plasma membrane and the shed ectodomain; retained as non-core. Supporting Evidence: file:human/DLK1/DLK1-uniprot.txt SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane protein. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cytoplasm localization transferred from the mouse orthologue. Reason: DLK1 has a 56-residue cytoplasmic tail and transits the secretory pathway, so cytoplasmic signal is plausible, but its functional pools are the plasma membrane and the shed ectodomain; retained as non-core. Supporting Evidence: file:human/DLK1/DLK1-uniprot.txt SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane protein. |
| GO:0016020 membrane | IBA GO_REF:0000033 | MODIFY | Summary: DLK1 is a single-pass type I membrane protein. Reason: Membrane is correct but less specific than the evidence supports; the protein is at the plasma membrane with its six EGF-like repeats (residues 24-303) exposed extracellularly, which is where it modulates Notch on neighbouring cells and from where the ectodomain is shed. Proposed replacements: plasma membrane Supporting Evidence: PMID:8095043 This protein is a putative transmembrane protein belonging to the epidermal growth factor-like superfamily file:human/DLK1/DLK1-uniprot.txt TOPO_DOM 24..303 |
| GO:0016020 membrane | IEA GO_REF:0000044 | MODIFY | Summary: DLK1 is a single-pass type I membrane protein. Reason: Membrane is correct but less specific than the evidence supports; the protein is at the plasma membrane with its six EGF-like repeats (residues 24-303) exposed extracellularly, which is where it modulates Notch on neighbouring cells and from where the ectodomain is shed. Proposed replacements: plasma membrane Supporting Evidence: PMID:8095043 This protein is a putative transmembrane protein belonging to the epidermal growth factor-like superfamily file:human/DLK1/DLK1-uniprot.txt TOPO_DOM 24..303 |
| GO:0016020 membrane | TAS PMID:8095043 dlk, a putative mammalian homeotic gene differentially expre... | MODIFY | Summary: DLK1 is a single-pass type I membrane protein. Reason: Membrane is correct but less specific than the evidence supports; the protein is at the plasma membrane with its six EGF-like repeats (residues 24-303) exposed extracellularly, which is where it modulates Notch on neighbouring cells and from where the ectodomain is shed. Proposed replacements: plasma membrane Supporting Evidence: PMID:8095043 This protein is a putative transmembrane protein belonging to the epidermal growth factor-like superfamily file:human/DLK1/DLK1-uniprot.txt TOPO_DOM 24..303 |
| GO:0030154 cell differentiation | IEA GO_REF:0000107 | MODIFY | Summary: DLK1 keeps progenitor cells undifferentiated. Reason: True but general; the experimentally supported specific claims in this review are negative regulation of osteoblast differentiation and of ossification, with positive regulation of osteoclast differentiation. Proposed replacements: negative regulation of osteoblast differentiation negative regulation of ossification Supporting Evidence: PMID:21308776 is a transmembrane protein belonging to the Notch/Delta family that acts as a membrane-associated or a soluble protein to regulate regeneration of a number of adult tissues |
| GO:0030279 negative regulation of ossification | IDA PMID:21308776 DLK1 is a novel regulator of bone mass that mediates estroge... | ACCEPT | Summary: DLK1 inhibits osteoblast differentiation and reduces bone formation. Reason: Osteoblast-specific DLK1 overexpression reduces bone mineral density and bone volume, with matching cellular readouts; the soluble and membrane forms both act on the progenitors. Supporting Evidence: PMID:21308776 Col1-Dlk1 mice displayed growth retardation and significantly reduced total body weight and bone mineral density (BMD) PMID:21308776 Micro-computed tomographis (µCT) scanning revealed a reduced trabecular and cortical bone volume fraction |
| GO:0045596 negative regulation of cell differentiation | IEA GO_REF:0000117 | MODIFY | Summary: DLK1 keeps progenitor cells undifferentiated. Reason: True but general; the experimentally supported specific claims in this review are negative regulation of osteoblast differentiation and of ossification, with positive regulation of osteoclast differentiation. Proposed replacements: negative regulation of osteoblast differentiation negative regulation of ossification Supporting Evidence: PMID:21308776 is a transmembrane protein belonging to the Notch/Delta family that acts as a membrane-associated or a soluble protein to regulate regeneration of a number of adult tissues |
| GO:0045668 negative regulation of osteoblast differentiation | IDA PMID:21308776 DLK1 is a novel regulator of bone mass that mediates estroge... | ACCEPT | Summary: DLK1 inhibits osteoblast differentiation and reduces bone formation. Reason: Osteoblast-specific DLK1 overexpression reduces bone mineral density and bone volume, with matching cellular readouts; the soluble and membrane forms both act on the progenitors. Supporting Evidence: PMID:21308776 Col1-Dlk1 mice displayed growth retardation and significantly reduced total body weight and bone mineral density (BMD) PMID:21308776 Micro-computed tomographis (µCT) scanning revealed a reduced trabecular and cortical bone volume fraction |
| GO:0045672 positive regulation of osteoclast differentiation | IDA PMID:21308776 DLK1 is a novel regulator of bone mass that mediates estroge... | KEEP AS NON CORE | Summary: DLK1 increases osteoclast numbers and bone resorption. Reason: Supported by the same overexpression study and relevant to the estrogen-deficiency bone phenotype, but the effect on osteoclasts is exerted indirectly, through cytokines produced by DLK1-expressing osteoblastic cells; retained as non-core. Supporting Evidence: PMID:21308776 DLK1 is a novel regulator of bone mass that mediates estrogen deficiency-induced bone loss in mice |
| GO:0045746 negative regulation of Notch signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: DLK1 is a non-canonical Notch ligand that inhibits NOTCH1 signalling. Reason: Its EGF-like repeats engage Notch but it lacks the DSL domain needed for activation; in human melanoma cells DLK1 and DLK2 modulate NOTCH1-dependent proliferation, and the inhibitory role is conserved across the family. Supporting Evidence: PMID:25093684 The proteins DLK1 and DLK2 modulate NOTCH1-dependent proliferation and oncogenic potential of human SK-MEL-2 melanoma cells PMID:25093684 NOTCH receptors regulate cell proliferation and survival in several types of cancer cells |
| GO:0045746 negative regulation of Notch signaling pathway | IDA PMID:25093684 The proteins DLK1 and DLK2 modulate NOTCH1-dependent prolife... | ACCEPT | Summary: DLK1 is a non-canonical Notch ligand that inhibits NOTCH1 signalling. Reason: Its EGF-like repeats engage Notch but it lacks the DSL domain needed for activation; in human melanoma cells DLK1 and DLK2 modulate NOTCH1-dependent proliferation, and the inhibitory role is conserved across the family. Supporting Evidence: PMID:25093684 The proteins DLK1 and DLK2 modulate NOTCH1-dependent proliferation and oncogenic potential of human SK-MEL-2 melanoma cells PMID:25093684 NOTCH receptors regulate cell proliferation and survival in several types of cancer cells |
| GO:0045746 negative regulation of Notch signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: DLK1 is a non-canonical Notch ligand that inhibits NOTCH1 signalling. Reason: Its EGF-like repeats engage Notch but it lacks the DSL domain needed for activation; in human melanoma cells DLK1 and DLK2 modulate NOTCH1-dependent proliferation, and the inhibitory role is conserved across the family. Supporting Evidence: PMID:25093684 The proteins DLK1 and DLK2 modulate NOTCH1-dependent proliferation and oncogenic potential of human SK-MEL-2 melanoma cells PMID:25093684 NOTCH receptors regulate cell proliferation and survival in several types of cancer cells |
| GO:0045780 positive regulation of bone resorption | IDA PMID:21308776 DLK1 is a novel regulator of bone mass that mediates estroge... | KEEP AS NON CORE | Summary: DLK1 increases osteoclast numbers and bone resorption. Reason: Supported by the same overexpression study and relevant to the estrogen-deficiency bone phenotype, but the effect on osteoclasts is exerted indirectly, through cytokines produced by DLK1-expressing osteoblastic cells; retained as non-core. Supporting Evidence: PMID:21308776 DLK1 is a novel regulator of bone mass that mediates estrogen deficiency-induced bone loss in mice |
| GO:0045780 positive regulation of bone resorption | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: DLK1 increases osteoclast numbers and bone resorption. Reason: Supported by the same overexpression study and relevant to the estrogen-deficiency bone phenotype, but the effect on osteoclasts is exerted indirectly, through cytokines produced by DLK1-expressing osteoblastic cells; retained as non-core. Supporting Evidence: PMID:21308776 DLK1 is a novel regulator of bone mass that mediates estrogen deficiency-induced bone loss in mice |
| GO:0046850 regulation of bone remodeling | IDA PMID:21308776 DLK1 is a novel regulator of bone mass that mediates estroge... | KEEP AS NON CORE | Summary: DLK1 increases osteoclast numbers and bone resorption. Reason: Supported by the same overexpression study and relevant to the estrogen-deficiency bone phenotype, but the effect on osteoclasts is exerted indirectly, through cytokines produced by DLK1-expressing osteoblastic cells; retained as non-core. Supporting Evidence: PMID:21308776 DLK1 is a novel regulator of bone mass that mediates estrogen deficiency-induced bone loss in mice |
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Download this section (compressed HTML)Q: Does DLK1 inhibit Notch by direct non-productive binding to NOTCH1, by competing with canonical DSL ligands in cis, or by a Notch-independent route in some cell types?
Q: How do membrane-bound DLK1 and the shed FA1 ectodomain differ in potency and range, and which dominates in tumours that are candidate targets for DLK1-directed therapy?
Experiment: Compare Notch reporter activity, progenitor differentiation and tumour cell proliferation in cells expressing wild-type DLK1 versus a cleavage-resistant juxtamembrane mutant, with conditioned-medium transfer to assay the soluble component.
Hypothesis: Shedding by ADAM17 converts DLK1 from a juxtacrine inhibitor into a diffusible one with a different target range.
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