LFNG (Lunatic fringe) is a Golgi-resident, single-pass type II membrane glycosyltransferase of the Fringe family (GT31; EC 2.4.1.222). Using UDP-GlcNAc and a Mn2+-dependent DxD active site, it transfers beta1,3-linked N-acetylglucosamine onto O-linked fucose (added by POFUT1) on specific EGF-like repeats of Notch receptor ectodomains, initiating elongation of the O-fucose glycan. This modification changes ligand selectivity of Notch: it enhances NOTCH1 activation by Delta-like ligands (DLL1) and reduces activation by Jagged ligands (e.g. JAG1-NOTCH2 binding and signaling). Oscillating LFNG expression is a core component of the vertebrate segmentation clock, and LFNG is also required for boundary formation, T-cell and marginal-zone B-cell development in mouse. Biallelic loss-of-function variants cause spondylocostal dysostosis type 3 with vertebral segmentation defects.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Golgi apparatus/Golgi membrane localization. Reason: Fringe acts in the Golgi on Notch during its secretion; type II Golgi membrane protein. Supporting Evidence: file:human/LFNG/LFNG-uniprot.txt Golgi apparatus membrane |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-5096538 | ACCEPT | Summary: Golgi apparatus/Golgi membrane localization. Reason: Fringe acts in the Golgi on Notch during its secretion; type II Golgi membrane protein. Supporting Evidence: file:human/LFNG/LFNG-uniprot.txt Golgi apparatus membrane |
| GO:0001756 somitogenesis | ISS GO_REF:0000024 | ACCEPT | Summary: LFNG is an essential oscillating component of somite segmentation; human loss causes SCDO3. Reason: Well-supported developmental process in which LFNG-mediated Notch modulation is a mechanistic step of the segmentation clock. Supporting Evidence: file:human/LFNG/LFNG-uniprot.txt Essential mediator of somite segmentation and patterning PMID:19061953 mutation of the LUNATIC FRINGE (LFNG) gene, which causes SCD type 3. |
| GO:0002315 marginal zone B cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Lymphocyte (MZ B / T cell) development (mouse Lfng). Reason: Lfng enhances DLL-NOTCH1/2 interactions in thymus and spleen; tissue-level role, non-core. Supporting Evidence: file:human/LFNG/LFNG-uniprot.txt resulting in inhibition of NOTCH1 activation by JAG1 and enhancement of NOTCH1 activation by DLL1 via an increase in its binding to DLL1 |
| GO:0002315 marginal zone B cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Lymphocyte (MZ B / T cell) development (mouse Lfng). Reason: Lfng enhances DLL-NOTCH1/2 interactions in thymus and spleen; tissue-level role, non-core. Supporting Evidence: file:human/LFNG/LFNG-uniprot.txt resulting in inhibition of NOTCH1 activation by JAG1 and enhancement of NOTCH1 activation by DLL1 via an increase in its binding to DLL1 |
| GO:0005576 extracellular region | NAS PMID:10341080 Genomic structure, mapping, and expression analysis of the m... | MARK AS OVER ANNOTATED | Summary: Extracellular region based on the 'secretory protein' description. Reason: Although Fringe can be secreted when overexpressed, its function is Golgi-resident modification of Notch. Supporting Evidence: PMID:10341080 Fringe genes encode pioneer secretory proteins with weak similarity to glycosyltransferases. file:human/LFNG/LFNG-uniprot.txt Golgi apparatus membrane |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | ACCEPT | Summary: Golgi apparatus/Golgi membrane localization. Reason: Fringe acts in the Golgi on Notch during its secretion; type II Golgi membrane protein. Supporting Evidence: file:human/LFNG/LFNG-uniprot.txt Golgi apparatus membrane |
| GO:0005794 Golgi apparatus | ISS GO_REF:0000024 | ACCEPT | Summary: Golgi apparatus/Golgi membrane localization. Reason: Fringe acts in the Golgi on Notch during its secretion; type II Golgi membrane protein. Supporting Evidence: file:human/LFNG/LFNG-uniprot.txt Golgi apparatus membrane |
| GO:0007389 pattern specification process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Pattern specification (InterPro). Reason: Fringe proteins act in boundary formation and patterning; broad, non-core. Supporting Evidence: PMID:10341080 Both expression patterns and functional studies support an important role for Fringe genes in patterning during embryonic development |
| GO:0008593 regulation of Notch signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: LFNG regulates Notch signaling by glycosylating Notch receptors, shifting ligand preference (PTN000087518). Reason: Core process: direction-neutral term appropriate because Fringe both enhances Delta-like and inhibits Jagged signaling. Supporting Evidence: file:human/LFNG/LFNG-uniprot.txt resulting in inhibition of NOTCH1 activation by JAG1 and enhancement of NOTCH1 activation by DLL1 via an increase in its binding to DLL1 PMID:11346656 We also found that both fringe proteins reduced Jagged1-triggered Notch2 signaling, whereas neither affected Delta1-triggered Notch2 signaling. PMID:10935626 We obtained biological evidence that Fringe-dependent elongation of O-linked fucose on Notch modulates Notch signalling by using co-culture assays in mammalian cells |
| GO:0008593 regulation of Notch signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: LFNG regulates Notch signaling by glycosylating Notch receptors, shifting ligand preference (PTN000087518). Reason: Core process: direction-neutral term appropriate because Fringe both enhances Delta-like and inhibits Jagged signaling. Supporting Evidence: file:human/LFNG/LFNG-uniprot.txt resulting in inhibition of NOTCH1 activation by JAG1 and enhancement of NOTCH1 activation by DLL1 via an increase in its binding to DLL1 PMID:11346656 We also found that both fringe proteins reduced Jagged1-triggered Notch2 signaling, whereas neither affected Delta1-triggered Notch2 signaling. PMID:10935626 We obtained biological evidence that Fringe-dependent elongation of O-linked fucose on Notch modulates Notch signalling by using co-culture assays in mammalian cells |
| GO:0008593 regulation of Notch signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: LFNG regulates Notch signaling by glycosylating Notch receptors, shifting ligand preference (PTN000087518). Reason: Core process: direction-neutral term appropriate because Fringe both enhances Delta-like and inhibits Jagged signaling. Supporting Evidence: file:human/LFNG/LFNG-uniprot.txt resulting in inhibition of NOTCH1 activation by JAG1 and enhancement of NOTCH1 activation by DLL1 via an increase in its binding to DLL1 PMID:11346656 We also found that both fringe proteins reduced Jagged1-triggered Notch2 signaling, whereas neither affected Delta1-triggered Notch2 signaling. PMID:10935626 We obtained biological evidence that Fringe-dependent elongation of O-linked fucose on Notch modulates Notch signalling by using co-culture assays in mammalian cells |
| GO:0009887 animal organ morphogenesis | NAS PMID:10341080 Genomic structure, mapping, and expression analysis of the m... | MARK AS OVER ANNOTATED | Summary: Animal organ morphogenesis (NAS). Reason: Very broad inference from expression; not informative. Supporting Evidence: PMID:10341080 Both expression patterns and functional studies support an important role for Fringe genes in patterning during embryonic development |
| GO:0014807 regulation of somitogenesis | IMP PMID:19061953 Mutation of the fucose-specific beta1,3 N-acetylglucosaminyl... | ACCEPT | Summary: LFNG is an essential oscillating component of somite segmentation; human loss causes SCDO3. Reason: Well-supported developmental process in which LFNG-mediated Notch modulation is a mechanistic step of the segmentation clock. Supporting Evidence: file:human/LFNG/LFNG-uniprot.txt Essential mediator of somite segmentation and patterning PMID:19061953 mutation of the LUNATIC FRINGE (LFNG) gene, which causes SCD type 3. |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: Membrane (InterPro). Reason: Correct; Golgi membrane is more specific. Supporting Evidence: file:human/LFNG/LFNG-uniprot.txt Golgi apparatus membrane |
| GO:0016757 glycosyltransferase activity | IEA GO_REF:0000002 | ACCEPT | Summary: Glycosyltransferase activity (InterPro). Reason: Correct parent of the specific O-fucosylpeptide GlcNAc-transferase activity. Supporting Evidence: file:human/LFNG/LFNG-uniprot.txt Glycosyltransferase that initiates the elongation of O-linked fucose residues attached to EGF-like repeats in the extracellular domain of Notch molecules. |
| GO:0030217 T cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Lymphocyte (MZ B / T cell) development (mouse Lfng). Reason: Lfng enhances DLL-NOTCH1/2 interactions in thymus and spleen; tissue-level role, non-core. Supporting Evidence: file:human/LFNG/LFNG-uniprot.txt resulting in inhibition of NOTCH1 activation by JAG1 and enhancement of NOTCH1 activation by DLL1 via an increase in its binding to DLL1 |
| GO:0030217 T cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Lymphocyte (MZ B / T cell) development (mouse Lfng). Reason: Lfng enhances DLL-NOTCH1/2 interactions in thymus and spleen; tissue-level role, non-core. Supporting Evidence: file:human/LFNG/LFNG-uniprot.txt resulting in inhibition of NOTCH1 activation by JAG1 and enhancement of NOTCH1 activation by DLL1 via an increase in its binding to DLL1 |
| GO:0033829 O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: LFNG is the fucose-specific beta1,3-GlcNAc-transferase that elongates O-fucose on Notch EGF repeats (PTN000087518 for the IBA). Reason: Core catalytic activity; demonstrated biochemically for mammalian Fringe proteins and confirmed for human LFNG by loss of activity of an SCDO3 DxD-motif variant. Supporting Evidence: PMID:10935626 Drosophila and mammalian Fringe proteins possess a fucose-specific beta1,3 N-acetylglucosaminyltransferase activity that initiates elongation of O-linked fucose residues attached to epidermal growth factor-like sequence repeats of Notch. PMID:30531807 The missense variant was in the DxD motif, an active-site motif of the glycosyltransferase, and its loss of the enzyme function was confirmed by an in vitro enzyme assay. file:human/LFNG/LFNG-uniprot.txt Glycosyltransferase that initiates the elongation of O-linked fucose residues attached to EGF-like repeats in the extracellular domain of Notch molecules. |
| GO:0033829 O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase activity | IDA PMID:10935626 Fringe is a glycosyltransferase that modifies Notch. | ACCEPT | Summary: LFNG is the fucose-specific beta1,3-GlcNAc-transferase that elongates O-fucose on Notch EGF repeats (PTN000087518 for the IBA). Reason: Core catalytic activity; demonstrated biochemically for mammalian Fringe proteins and confirmed for human LFNG by loss of activity of an SCDO3 DxD-motif variant. Supporting Evidence: PMID:10935626 Drosophila and mammalian Fringe proteins possess a fucose-specific beta1,3 N-acetylglucosaminyltransferase activity that initiates elongation of O-linked fucose residues attached to epidermal growth factor-like sequence repeats of Notch. PMID:30531807 The missense variant was in the DxD motif, an active-site motif of the glycosyltransferase, and its loss of the enzyme function was confirmed by an in vitro enzyme assay. file:human/LFNG/LFNG-uniprot.txt Glycosyltransferase that initiates the elongation of O-linked fucose residues attached to EGF-like repeats in the extracellular domain of Notch molecules. |
| GO:0033829 O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: LFNG is the fucose-specific beta1,3-GlcNAc-transferase that elongates O-fucose on Notch EGF repeats (PTN000087518 for the IBA). Reason: Core catalytic activity; demonstrated biochemically for mammalian Fringe proteins and confirmed for human LFNG by loss of activity of an SCDO3 DxD-motif variant. Supporting Evidence: PMID:10935626 Drosophila and mammalian Fringe proteins possess a fucose-specific beta1,3 N-acetylglucosaminyltransferase activity that initiates elongation of O-linked fucose residues attached to epidermal growth factor-like sequence repeats of Notch. PMID:30531807 The missense variant was in the DxD motif, an active-site motif of the glycosyltransferase, and its loss of the enzyme function was confirmed by an in vitro enzyme assay. file:human/LFNG/LFNG-uniprot.txt Glycosyltransferase that initiates the elongation of O-linked fucose residues attached to EGF-like repeats in the extracellular domain of Notch molecules. |
| GO:0033829 O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase activity | ISS GO_REF:0000024 | ACCEPT | Summary: LFNG is the fucose-specific beta1,3-GlcNAc-transferase that elongates O-fucose on Notch EGF repeats (PTN000087518 for the IBA). Reason: Core catalytic activity; demonstrated biochemically for mammalian Fringe proteins and confirmed for human LFNG by loss of activity of an SCDO3 DxD-motif variant. Supporting Evidence: PMID:10935626 Drosophila and mammalian Fringe proteins possess a fucose-specific beta1,3 N-acetylglucosaminyltransferase activity that initiates elongation of O-linked fucose residues attached to epidermal growth factor-like sequence repeats of Notch. PMID:30531807 The missense variant was in the DxD motif, an active-site motif of the glycosyltransferase, and its loss of the enzyme function was confirmed by an in vitro enzyme assay. file:human/LFNG/LFNG-uniprot.txt Glycosyltransferase that initiates the elongation of O-linked fucose residues attached to EGF-like repeats in the extracellular domain of Notch molecules. |
| GO:0033829 O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase activity | TAS Reactome:R-HSA-5096538 | ACCEPT | Summary: LFNG is the fucose-specific beta1,3-GlcNAc-transferase that elongates O-fucose on Notch EGF repeats (PTN000087518 for the IBA). Reason: Core catalytic activity; demonstrated biochemically for mammalian Fringe proteins and confirmed for human LFNG by loss of activity of an SCDO3 DxD-motif variant. Supporting Evidence: PMID:10935626 Drosophila and mammalian Fringe proteins possess a fucose-specific beta1,3 N-acetylglucosaminyltransferase activity that initiates elongation of O-linked fucose residues attached to epidermal growth factor-like sequence repeats of Notch. PMID:30531807 The missense variant was in the DxD motif, an active-site motif of the glycosyltransferase, and its loss of the enzyme function was confirmed by an in vitro enzyme assay. file:human/LFNG/LFNG-uniprot.txt Glycosyltransferase that initiates the elongation of O-linked fucose residues attached to EGF-like repeats in the extracellular domain of Notch molecules. |
| GO:0045746 negative regulation of Notch signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of Notch signaling (mouse). Reason: LFNG inhibits Jagged-triggered Notch signaling and periodically inhibits Notch in the segmentation clock, but it also enhances Delta-triggered signaling; the direction-neutral regulation term is core, this one context-specific. Supporting Evidence: PMID:11346656 We also found that both fringe proteins reduced Jagged1-triggered Notch2 signaling, whereas neither affected Delta1-triggered Notch2 signaling. file:human/LFNG/LFNG-uniprot.txt resulting in inhibition of NOTCH1 activation by JAG1 and enhancement of NOTCH1 activation by DLL1 via an increase in its binding to DLL1 |
| GO:0045746 negative regulation of Notch signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of Notch signaling (mouse). Reason: LFNG inhibits Jagged-triggered Notch signaling and periodically inhibits Notch in the segmentation clock, but it also enhances Delta-triggered signaling; the direction-neutral regulation term is core, this one context-specific. Supporting Evidence: PMID:11346656 We also found that both fringe proteins reduced Jagged1-triggered Notch2 signaling, whereas neither affected Delta1-triggered Notch2 signaling. file:human/LFNG/LFNG-uniprot.txt resulting in inhibition of NOTCH1 activation by JAG1 and enhancement of NOTCH1 activation by DLL1 via an increase in its binding to DLL1 |
| GO:1903561 extracellular vesicle | HDA PMID:24769233 Proteomic analysis of cerebrospinal fluid extracellular vesi... | MARK AS OVER ANNOTATED | Summary: Detected in an extracellular-vesicle proteome, but the detection does not establish that this protein is an EV constituent. Reason: Golgi glycosyltransferase. Mainly resident in an intracellular compartment that MISEV2018 (PMID:30637094) lists as not enriched in small EVs of plasma-membrane/endosomal origin (category 4), and its own review keeps no experimental cell-surface or plasma-membrane pool; an exosome annotation from a bulk EV proteome is not supported. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: KEEP_AS_NON_CORE.) Supporting Evidence: PMID:24769233 We report an extensive catalog of 1315 proteins identified in EVs isolated from two different CSF pools by ultracentrifugation |
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Download this section (compressed HTML)Q: Which specific EGF repeats of human NOTCH1 and NOTCH2 are modified by LFNG versus MFNG/RFNG, and how does this map onto ligand-selectivity changes?
Q: Should a direction-specific process (e.g. positive regulation of Delta-Notch signaling) be curated separately for LFNG given its opposing effects on Delta and Jagged?
Experiment: Mass-spectrometric O-glycan site mapping of NOTCH1 from LFNG-knockout versus rescued human cells, coupled with DLL1/JAG1 binding assays.
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