Anosmin-1 is a secreted extracellular glycoprotein containing a cysteine-rich region, a WAP domain and four fibronectin type III domains. It associates with cell-surface glycosaminoglycans and extracellular matrix, binds FGFR1, and modulates assembly and activity of FGF receptor signaling complexes. These interactions contribute to cell adhesion, neuronal differentiation and context-dependent neuronal migration and axon guidance during olfactory-system development. Loss of ANOS1 function causes the X-linked form of Kallmann syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:19696444 Novel mechanisms of fibroblast growth factor receptor 1 regu... | MODIFY | Summary: Direct FGFR1 binding refines the generic interaction annotation. Reason: The original study directly measures binding to the FGFR1 ectodomain. It also reports weaker FGFR2IIIc binding and negligible FGFR3IIIc binding, supporting type 1 fibroblast growth factor receptor binding as the refinement. Order-dependent FGF2/FGFR1/heparin assembly establishes modulation, not an independently sufficient receptor agonist or an equivalent interaction with every FGFR. Proposed replacements: type 1 fibroblast growth factor receptor binding Supporting Evidence: PMID:19696444 Here, we show that anosmin-1 directly binds to FGFR1 with high affinity. PMID:19696444 anosmin-1 binds to FGFR2IIIc with much lower affinity and displays negligible binding to FGFR3IIIc. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The ANOS1–NCALD screen interaction has not been resolved at the pair level. Reason: The preserved IPI assertion names NCALD (UniProtKB:P61601). The HuRI article is available, but the target-specific construct, assay and supplementary interaction record have not been adjudicated. The generic term gives no established functional refinement. This is an evidence boundary, not a claim that the interaction is false; cellular-compartment differences alone cannot refute it. Under the explicit action criteria, lack of functional specificity alone does not establish that this experimentally curated assertion is incorrect. UNDECIDED preserves the unresolved pair evidence. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The ANOS1–UBQLN1 screen interaction has not been resolved at the pair level. Reason: The preserved IPI assertion names UBQLN1 (UniProtKB:Q9UMX0). The HuRI article is available, but the target-specific construct, assay and supplementary interaction record have not been adjudicated. The generic term gives no established functional refinement. This is an evidence boundary, not a claim that the interaction is false; cellular-compartment differences alone cannot refute it. Under the explicit action criteria, lack of functional specificity alone does not establish that this experimentally curated assertion is incorrect. UNDECIDED preserves the unresolved pair evidence. |
| GO:0005576 extracellular region | IDA PMID:8842728 The Kallmann syndrome gene product expressed in COS cells is... | ACCEPT | Summary: Anosmin-1 is secreted and associates with extracellular cell surfaces. Reason: The original abstract explicitly distinguishes human and chick constructs from the COS expression host and reports a diffusible processed component. Together with extracellular FGFR1/heparin binding, this supports extracellular localization without assigning a membrane-spanning topology. Supporting Evidence: PMID:8842728 By overexpressing both the human and chick KAL cDNAs in eukaryotic cells, we now provide evidence that KAL is a glycosylated peripheral membrane protein PMID:19696444 Here, we show that anosmin-1 directly binds to FGFR1 with high affinity. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic extracellular assignment agrees with experimental localization. Reason: The combined ARBA, InterPro and UniProt-location mapping is corroborated by the human/chick processing study and extracellular receptor/glycosaminoglycan interactions. Acceptance of this location does not validate the separate WAP-domain peptidase-inhibitor inference. Supporting Evidence: PMID:8842728 By overexpressing both the human and chick KAL cDNAs in eukaryotic cells, we now provide evidence that KAL is a glycosylated peripheral membrane protein PMID:19696444 Here, we show that anosmin-1 directly binds to FGFR1 with high affinity. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654514 | ACCEPT | Summary: The FGFR1c binding event occurs extracellularly. Reason: The cached Reactome event places anosmin-1 binding to FGFR1c outside the cell, consistent with the directly studied FGFR1/FGF2/heparin system. It is a location assertion; it does not establish autonomous ligand activity or every downstream developmental effect. Supporting Evidence: Reactome:R-HSA-5654514 PMID:19696444 Here, we show that anosmin-1 directly binds to FGFR1 with high affinity. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654515 | ACCEPT | Summary: The heparan sulfate binding event occurs extracellularly. Reason: The cached Reactome event places anosmin-1 binding to heparan sulfate outside the cell, consistent with the directly studied FGFR1/FGF2/heparin system. It is a location assertion; it does not establish autonomous ligand activity or every downstream developmental effect. Supporting Evidence: Reactome:R-HSA-5654515 PMID:19696444 Here, we show that anosmin-1 directly binds to FGFR1 with high affinity. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Anosmin-1 associates peripherally with the plasma membrane surface. Reason: The UniProt subcellular-location mapping is compatible with the original peripheral membrane localization and extracellular glycosaminoglycan attachment. Plasma-membrane location does not imply that anosmin-1 is an integral transmembrane protein. Supporting Evidence: PMID:8842728 By overexpressing both the human and chick KAL cDNAs in eukaryotic cells, we now provide evidence that KAL is a glycosylated peripheral membrane protein |
| GO:0006935 chemotaxis | TAS PMID:8842728 The Kallmann syndrome gene product expressed in COS cells is... | ACCEPT | Summary: Anosmin-1 modulates neuronal chemotaxis in a signaling-context-dependent manner. Reason: The 1996 source proposed a diffusible chemoattractant mechanism rather than directly testing it. The later PMID:19696444 human-neuronal Transwell experiments independently support chemotactic modulation, with opposing effects depending on complex assembly. Retain the original TAS provenance without attributing the later assay to that early paper or implying invariably positive attraction. The protein participates as an extracellular cue and receptor-complex modulator; it is not asserted to be the moving cell. Supporting Evidence: PMID:19696444 Transwell migration assays where anosmin-1 was shown to induce opposing effects during chemotaxis of human neuronal cells. |
| GO:0007155 cell adhesion | TAS PMID:1913827 The candidate gene for the X-linked Kallmann syndrome encode... | ACCEPT | Summary: Anosmin-1 provides a glycosaminoglycan-dependent adhesive surface. Reason: The 1991 identification paper inferred adhesion from sequence similarity. Independent PMID:9730987 coated-protein and producer-cell experiments subsequently demonstrated adhesion; its original Results explicitly identify human KAL-1 cDNA expressed in CHO cells. Preserve the early TAS reference, distinguish protein species from assay host, and ground acceptance in the later direct evidence rather than gene-disease necessity alone. Supporting Evidence: PMID:9730987 cell adhesion to anosmin-1 is dependent on the presence of heparan sulfate and chondroitin sulfate glycosaminoglycans at the cell surface. |
| GO:0007155 cell adhesion | TAS PMID:1922361 A gene deleted in Kallmann's syndrome shares homology with n... | ACCEPT | Summary: Anosmin-1 provides a glycosaminoglycan-dependent adhesive surface. Reason: The 1991 identification paper inferred adhesion from sequence similarity. Independent PMID:9730987 coated-protein and producer-cell experiments subsequently demonstrated adhesion; its original Results explicitly identify human KAL-1 cDNA expressed in CHO cells. Preserve the early TAS reference, distinguish protein species from assay host, and ground acceptance in the later direct evidence rather than gene-disease necessity alone. Supporting Evidence: PMID:9730987 cell adhesion to anosmin-1 is dependent on the presence of heparan sulfate and chondroitin sulfate glycosaminoglycans at the cell surface. |
| GO:0007411 axon guidance | TAS PMID:1922361 A gene deleted in Kallmann's syndrome shares homology with n... | ACCEPT | Summary: Human anosmin-1 acts as an extracellular guidance cue for developing olfactory axons. Reason: The original 1991 source is sequence-based. Independent PMID:12007408 now supplies resolved human KAL-1 construct evidence: producer CHO cells attract E15 rat olfactory-bulb axons, with a tandem assay separating directionality from general growth. Human protein, expression host and neuronal responders are distinct. Preserve the original TAS provenance and the developmental assay limits; this is cue participation, not a disease-necessity inference. Supporting Evidence: PMID:12007408 anosmin-1-producing CHO cells demonstrate that anosmin-1 is a chemoattractant for the axons of these neurons file:human/ANOS1/ANOS1-notes.md Figure 1A/B (p. 219) explicitly identifies “Purified anosmin-1 produced by CHO cells transfected with the human KAL-1 cDNA”. |
| GO:0009986 cell surface | IBA GO_REF:0000033 | ACCEPT | Summary: Conserved cell-surface association agrees with direct extracellular binding. Reason: The local PAINT slice contains the ancestral PTN000364816 assertion; the full tree and alignment were not reconstructed. Human/chick peripheral localization and human receptor/heparin studies are compatible with inheritance of this function. Preserve the original supporting entities; neither donor count nor a newer local seed list invalidates the IBA. Supporting Evidence: PMID:8842728 By overexpressing both the human and chick KAL cDNAs in eukaryotic cells, we now provide evidence that KAL is a glycosylated peripheral membrane protein PMID:19696444 By contrast, heparin-bound anosmin-1 binds to pre-formed FGF2.FGFR1 complex, generating an anosmin-1.FGFR1.FGF2.heparin complex. |
| GO:0030182 neuron differentiation | IBA GO_REF:0000033 | ACCEPT | Summary: Anosmin-1 contributes to neuronal differentiation through extracellular signaling. Reason: The PTN000364816 PAINT assertion is compatible with the later human olfactory GnRH-neuroblast experiments in PMID:15548653, which measure neurite responses and FGFR1 dependence. This is positive functional support beyond developmental disease phenotypes. Keep the original IBA donors unchanged; no full phylogeny or universal tissue response is claimed. Supporting Evidence: PMID:15548653 In human embryonic GnRH olfactory neuroblasts, wild-type anosmin-1, but not proteins with loss-of-function KS mutations, induces neurite outgrowth |
| GO:0030414 peptidase inhibitor activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: The WAP-domain inhibitor inference exceeds demonstrated anosmin-1 activity. Reason: InterPro:IPR008197 transfers a peptidase-inhibitor function from domain membership. Direct PMID:15324302 assays instead show uPA enhancement and no effect on tested thrombin activity. The WAP fold therefore does not establish inhibition for anosmin-1. Mark this electronic assignment as over-annotated without asserting universal absence of inhibition against untested peptidases. Supporting Evidence: PMID:15324302 Anosmin-1 significantly enhances the amidolytic activity of uPA in vitro file:human/ANOS1/ANOS1-notes.md The same original paper reports enhanced uPA amidolytic activity and “had no effect on thrombin amidolytic activity”. |
| GO:0140149 non-collagenous component of interstitial matrix | IDA PMID:40546398 Comprehensive analysis of anosmin-1 as a potential biomarker... | ACCEPT | Summary: Independent human localization supports interstitial-matrix membership. Reason: PMID:10340754 explicitly reports human basement-membrane and interstitial-matrix localization using immunofluorescence and immunoelectron microscopy. This independently supports the location. Preserve the original PMID:40546398 IDA row, but its accessed gastric-cancer IHC Methods describe cytoplasmic scoring rather than a direct interstitial-matrix assay. This citation-scope caveat does not negate the independent extracellular evidence. Supporting Evidence: PMID:10340754 component of extracellular matrices during organogenesis in man. Anosmin-1 was detected in the basement membranes and/or interstitial matrices |
| GO:0008201 heparin binding | IDA PMID:19696444 Novel mechanisms of fibroblast growth factor receptor 1 regu... | NEW | Summary: Direct heparin binding anchors extracellular anosmin-1 complexes. Reason: The source directly analyzes anosmin-1 binding to heparin and sequential complex assembly. GO:0008201 names this tested ligand; heparan sulfate has a related synonym relationship and a separate term, GO:1904399, rather than being an equivalent definition. The heparin interaction is distinct from FGFR1 binding. The prior NEW annotation is retained; no additional molecular function or biological process is proposed in this follow-up. Supporting Evidence: PMID:19696444 By contrast, heparin-bound anosmin-1 binds to pre-formed FGF2.FGFR1 complex, generating an anosmin-1.FGFR1.FGF2.heparin complex. |
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Download this section (compressed HTML)Q: Which original constructs and pair-level assays establish the ANOS1–NCALD and ANOS1–UBQLN1 HuRI interactions, and do they support a specific molecular role?
Q: Does anosmin-1 inhibit any defined peptidase under physiological conditions, or is the WAP-domain inhibitor mapping overbroad?
Q: Does the uPA-activating biochemical activity generalize to endogenous human anosmin-1 in a physiological setting, and which molecular contacts mediate it?
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