Agrin is a large extracellular proteoglycan that couples cell-surface signaling to basement-membrane attachment. Secreted agrin binds laminin through its N-terminal domain and dystroglycan through C-terminal laminin G-like domains. Neuronal splice forms activate the LRP4-MuSK receptor system, inducing acetylcholine-receptor clustering and supporting neuromuscular synapse formation and maintenance. An alternative N terminus produces transmembrane agrin, which promotes neuronal filopodia and synaptic organization. The independent C-terminal splice choices alter receptor and glycan interactions; forms lacking a z insert can also signal in non-muscle contexts. Agrin is abundant in several human basement membranes and has additional tissue-dependent roles in cell differentiation, endothelial junction organization and repair signaling.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Agrin has membrane-associated secreted and transmembrane forms. Reason: The PAINT placement is compatible with the conserved cell-surface biology. Human UniProt distinguishes secreted LN agrin from the type II transmembrane isoform; receptor-bound secreted protein also associates with the cell surface. The annotation does not require every isoform to span the membrane. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002309037 SUPPORTS TRANSFER PAINT ancestral-node assertion; the human annotation follows inheritance from this node. Target biology supports the inferred scope; descendant number or self-inclusion is not treated as circularity. The complete node-by-node experimental reconstruction was not repeated. Supporting Evidence: file:human/AGRN/AGRN-uniprot.txt Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. file:human/AGRN/AGRN-uniprot.txt Component of the AGRN-LRP4 receptor complex that induces the phosphorylation and activation of MUSK. |
| GO:0007165 signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: Agrin transmits extracellular signals through receptor complexes. Reason: Agrin itself acts as the extracellular signal: LRP4 binding activates MuSK, and additional receptor contexts occur outside muscle. This is direct signaling participation, not merely a consequence of altered synapse development. The broad process accommodates those contexts. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002309037 SUPPORTS TRANSFER PAINT ancestral-node assertion; the human annotation follows inheritance from this node. Target biology supports the inferred scope; descendant number or self-inclusion is not treated as circularity. The complete node-by-node experimental reconstruction was not repeated. Supporting Evidence: PMID:18848351 Here, we report that Lrp4, a member of the LDLR family, is a receptor for Agrin, forms a complex with MuSK, and mediates MuSK activation by Agrin. |
| GO:0005604 basement membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Secreted agrin is anchored in basement membranes. Reason: Human glomerular immunoelectron microscopy and laminin-mediated basal-lamina anchoring independently support the PAINT localization. This applies to the secreted forms and does not erase transmembrane isoform biology. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008557712 SUPPORTS TRANSFER PAINT ancestral-node assertion; the human annotation follows inheritance from this node. Target biology supports the inferred scope; descendant number or self-inclusion is not treated as circularity. The complete node-by-node experimental reconstruction was not repeated. Supporting Evidence: PMID:9405491 In immunoelectron microscopy, agrin showed a linear distribution along the GBM and was present throughout the width of the GBM. file:human/AGRN/AGRN-uniprot.txt This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain. |
| GO:0007268 chemical synaptic transmission | IBA GO_REF:0000033 | MODIFY | Summary: Agrin modulates synaptic excitability and transmission. Reason: GO:0007268 describes the transmitter-release, receptor-activation and postsynaptic-response sequence. Agrin binding to neuronal alpha3 Na+/K+-ATPase changes membrane depolarization and action-potential frequency; the competitive fragment also changes native neuronal activity in PMID:16630822. This positive modulatory mechanism is better represented by GO:0050804 than by assigning agrin the transmission sequence itself. The refinement concerns the role expressed by the ancestral annotation, not donor count or an asserted human-specific loss. The neutral modulation term is retained because the measured readout is excitability/action-potential frequency, not a direct measurement of increased synaptic transmission strength. The historical MGI mouse IDA chain resolves to PMID:8653788, whose accessible abstract reports mutant NMJ organization; it does not by itself resolve the exact transmission assay behind that donor annotation. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN008557735 UNRESOLVED PTN008557735 is the PAINT ancestral assertion. The historical MGI graph (2023-03-10) links mouse chemical synaptic transmission IDA to J:33098/PMID:8653788; its abstract establishes NMJ organizational defects. The precise transmission assay and full ancestral experimental reconstruction remain unresolved. Independent agrin physiology supports the term-role refinement without asserting human-specific loss. Proposed replacements: modulation of chemical synaptic transmission Supporting Evidence: file:human/AGRN/AGRN-uniprot.txt Functions differentially in the central nervous system (CNS) by inhibiting the alpha(3)-subtype of Na+/K+-ATPase and evoking depolarization at CNS synapses. PMID:16630822 Agrin inhibition of alpha3NKA activity results in membrane depolarization and increased action potential frequency in cortical neurons in culture and acute slice. PMID:8653788 postsynaptic AChR aggregates are markedly reduced in number, size, and density in muscles of agrin-deficient mutant mice. |
| GO:0007399 nervous system development | IBA GO_REF:0000033 | ACCEPT | Summary: Agrin organizes developing neuromuscular and neuronal synapses. Reason: Synapse development is a direct function of agrin signaling, so the broader developmental term includes a core role. It is not rejected simply because more specific neuromuscular annotations coexist. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008557712 SUPPORTS TRANSFER PAINT ancestral-node assertion; the human annotation follows inheritance from this node. Target biology supports the inferred scope; descendant number or self-inclusion is not treated as circularity. The complete node-by-node experimental reconstruction was not repeated. Supporting Evidence: PMID:18848351 Here, we report that Lrp4, a member of the LDLR family, is a receptor for Agrin, forms a complex with MuSK, and mediates MuSK activation by Agrin. file:human/AGRN/AGRN-uniprot.txt Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. |
| GO:0007528 neuromuscular junction development | IBA GO_REF:0000033 | ACCEPT | Summary: Agrin signaling organizes the neuromuscular junction. Reason: Agrin supplies the nerve-derived ligand that activates the LRP4-MuSK pathway and promotes postsynaptic differentiation. This is a conserved mechanistic contribution, supported independently of disease necessity alone. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008557735 SUPPORTS TRANSFER PAINT ancestral-node assertion; the human annotation follows inheritance from this node. Target biology supports the inferred scope; descendant number or self-inclusion is not treated as circularity. The complete node-by-node experimental reconstruction was not repeated. Supporting Evidence: PMID:18848351 Here, we report that Lrp4, a member of the LDLR family, is a receptor for Agrin, forms a complex with MuSK, and mediates MuSK activation by Agrin. PMID:15340048 We also report that a single 5-min agrin pulse, followed by extensive washing, triggered long-lasting MuSK and AChR phosphorylation and efficient AChR clustering. |
| GO:0030297 transmembrane receptor protein tyrosine kinase activator activity | IBA GO_REF:0000033 | ACCEPT | Summary: Agrin activates the MuSK receptor tyrosine kinase through LRP4. Reason: The molecular function describes agrin as an activator, not as a kinase. LRP4 recognizes agrin and couples it to MuSK activation; z-insert splicing strongly affects this activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008557735 SUPPORTS TRANSFER PAINT ancestral-node assertion; the human annotation follows inheritance from this node. Target biology supports the inferred scope; descendant number or self-inclusion is not treated as circularity. The complete node-by-node experimental reconstruction was not repeated. Supporting Evidence: PMID:18848351 Here, we report that Lrp4, a member of the LDLR family, is a receptor for Agrin, forms a complex with MuSK, and mediates MuSK activation by Agrin. file:human/AGRN/AGRN-uniprot.txt Component of the AGRN-LRP4 receptor complex that induces the phosphorylation and activation of MUSK. |
| GO:0030548 acetylcholine receptor regulator activity | IBA GO_REF:0000033 | UNDECIDED | Summary: AChR organization is established; regulation of the active receptor fraction remains unresolved. Reason: GO:0030548 explicitly permits direct or indirect interaction, so agrin binding LRP4 rather than AChR does not disqualify this activity. Its definition nevertheless requires changing the proportion of receptors in the active form. The recovered pulse experiment measures MuSK/AChR phosphorylation and receptor clustering; organization, abundance and stabilization do not by themselves resolve that active-state fraction. The historical MGI mouse IDA links to J:86639/PMID:14622576, whose accessible abstract reports GGT-dependent AChR clustering and NMJ development. That positive donor pathway result does not resolve the active-state fraction without the full assay details; the PAINT placement itself was not reconstructed. Retain uncertainty without denying indirect AChR regulation or the established agrin-LRP4-MuSK organizing mechanism. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN008557735 UNRESOLVED PTN008557735 identifies the ancestral assertion. The historical MGI graph (2023-03-10) identifies a mouse IDA descendant, J:86639, mapped by MouseMine to PMID:14622576. Its accessible abstract reports agrin/MuSK-GGT signaling and clustering; the exact active-AChR-fraction experiment remains unresolved. Donor count or self-inclusion is not a propagation error. Supporting Evidence: PMID:15340048 We also report that a single 5-min agrin pulse, followed by extensive washing, triggered long-lasting MuSK and AChR phosphorylation and efficient AChR clustering. PMID:14622576 Agrin causes a rapid increase in tyrosine phosphorylation of the alpha(G/F) subunit of GGT and in GGT activity. |
| GO:0043113 receptor clustering | IBA GO_REF:0000033 | ACCEPT | Summary: Agrin directly induces receptor clustering through receptor signaling. Reason: A brief agrin pulse is sufficient to initiate a sustained signaling cascade and subsequent AChR clustering. The ligand executes a signaling step in the clustering mechanism. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008557735 SUPPORTS TRANSFER PAINT ancestral-node assertion; the human annotation follows inheritance from this node. Target biology supports the inferred scope; descendant number or self-inclusion is not treated as circularity. The complete node-by-node experimental reconstruction was not repeated. Supporting Evidence: PMID:15340048 We also report that a single 5-min agrin pulse, followed by extensive washing, triggered long-lasting MuSK and AChR phosphorylation and efficient AChR clustering. |
| GO:0045202 synapse | IBA GO_REF:0000033 | ACCEPT | Summary: Agrin acts at synapses as a matrix-associated or membrane-associated protein. Reason: Synaptic basal-lamina anchoring and neuronal transmembrane agrin support the inherited synaptic localization. Isoform and tissue context determine the physical form. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008557712 SUPPORTS TRANSFER PAINT ancestral-node assertion; the human annotation follows inheritance from this node. Target biology supports the inferred scope; descendant number or self-inclusion is not treated as circularity. The complete node-by-node experimental reconstruction was not repeated. Supporting Evidence: file:human/AGRN/AGRN-uniprot.txt This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain. file:human/AGRN/AGRN-uniprot.txt Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: A calcium-binding EGF-like domain supports the InterPro mapping. Reason: The proximate source is IPR001881, the calcium-binding EGF-like domain. This domain inference is distinct from the experimentally measured calcium binding of the chick G3 domain. Calcium dependence of AChR clustering alone would not demonstrate direct binding; independent donor biochemistry supplies that distinction. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR001881 SUPPORTS TRANSFER Calcium-binding EGF-like domain mapping. This is distinct from chick G3 thermodynamic binding and from downstream calcium-dependent clustering. |
| GO:0005576 extracellular region | IEA GO_REF:0000117 | ACCEPT | Summary: Secreted agrin occupies the extracellular region. Reason: The broad location is correct for secreted agrin in basal lamina and extracellular matrix. ARBA rule predicates were not separately reconstructed; human tissue localization independently supports the judgment. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00027128 UNRESOLVED Rule identifier traced from GOA; its full predicates were not independently inspected. The annotation-level biological judgment uses the cited independent evidence, not an asserted audit of rule internals. Supporting Evidence: PMID:9405491 In immunoelectron microscopy, agrin showed a linear distribution along the GBM and was present throughout the width of the GBM. PMID:9652404 In this study we present the cDNA sequence of human agrin, and demonstrate a high agrin content in adult basement membranes. |
| GO:0005604 basement membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Agrin localizes to basement membranes. Reason: The combined mapping and mouse donor record agree with direct human GBM and adult lung/kidney localization. This is a physiological site of agrin function. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00027708 UNRESOLVED Rule identifier traced from GOA; its full predicates were not independently inspected. The annotation-level biological judgment uses the cited independent evidence, not an asserted audit of rule internals. UniProtKB:M0QWP1 UNRESOLVED Mouse UniProt/Ensembl source pair traced from GOA; the exact experimental-to-automated transfer chain was not reconstructed. Direct human localization or conserved agrin signaling independently supports the retained/refined term. Ensembl:ENSMUSP00000137931 UNRESOLVED Mouse UniProt/Ensembl source pair traced from GOA; the exact experimental-to-automated transfer chain was not reconstructed. Direct human localization or conserved agrin signaling independently supports the retained/refined term. Supporting Evidence: PMID:9405491 In immunoelectron microscopy, agrin showed a linear distribution along the GBM and was present throughout the width of the GBM. PMID:9652404 In this study we present the cDNA sequence of human agrin, and demonstrate a high agrin content in adult basement membranes. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Agrin is associated with the plasma membrane. Reason: The combined ARBA/subcellular-location mapping is consistent with the transmembrane isoform and extracellular receptor interactions. No claim that all secreted agrin is an integral membrane protein is needed. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00027801 UNRESOLVED Rule identifier traced from GOA; its full predicates were not independently inspected. The annotation-level biological judgment uses the cited independent evidence, not an asserted audit of rule internals. UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER Independent functional evidence supports the mapped biological scope described in the annotation rationale. Supporting Evidence: file:human/AGRN/AGRN-uniprot.txt Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. file:human/AGRN/AGRN-uniprot.txt Component of the AGRN-LRP4 receptor complex that induces the phosphorylation and activation of MUSK. |
| GO:0007010 cytoskeleton organization | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Agrin signaling organizes actin-rich neuronal protrusions and postsynaptic structures. Reason: Transmembrane agrin promotes actin-rich neuronal protrusions through extracellular signaling. The human UniProt synthesis supports the conserved role, and PMID:19940118 directly maps process induction to extracellular follistatin-like domains using chick TM-agrin in chick neurons and heterologous cell hosts. These data support cytoskeleton organization without making agrin a structural filament constituent. Retain this CNS protrusion-organizing branch as a non-core, isoform- and cellular-context-dependent function alongside the central matrix-anchoring and neuromuscular receptor-organizing functions. This classification reflects the experimental biological context, not merely absence from the compact core list. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00026736 UNRESOLVED Rule identifier traced from GOA; its full predicates were not independently inspected. The annotation-level biological judgment uses the cited independent evidence, not an asserted audit of rule internals. Supporting Evidence: file:human/AGRN/AGRN-uniprot.txt Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. PMID:19940118 Mapping of the process-inducing activity in neurons and non-neuronal cells demonstrates that the cytoplasmic part of transmembrane agrin is dispensable and that the extracellular region is necessary for process formation. |
| GO:0007399 nervous system development | IEA GO_REF:0000117 | ACCEPT | Summary: Synaptic development is part of agrin nervous-system function. Reason: The broad developmental mapping includes the established ligand-driven formation of neuromuscular synapses and the neuronal filopodial/synapse role. Breadth alone does not make it peripheral. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00027428 UNRESOLVED Rule identifier traced from GOA; its full predicates were not independently inspected. The annotation-level biological judgment uses the cited independent evidence, not an asserted audit of rule internals. Supporting Evidence: PMID:18848351 Here, we report that Lrp4, a member of the LDLR family, is a receptor for Agrin, forms a complex with MuSK, and mediates MuSK activation by Agrin. file:human/AGRN/AGRN-uniprot.txt Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. |
| GO:0008582 regulation of synaptic assembly at neuromuscular junction | IEA GO_REF:0000107 | MODIFY | Summary: Agrin positively promotes neuromuscular synaptic assembly. Reason: The transferred regulation term can be refined to its established positive direction: agrin activates receptor signaling and induces postsynaptic organization. The donor mapping is retained as provenance, while the positive direction is independently supported by functional assays. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB:M0QWP1 UNRESOLVED Mouse UniProt/Ensembl source pair traced from GOA; the exact experimental-to-automated transfer chain was not reconstructed. Direct human localization or conserved agrin signaling independently supports the retained/refined term. Ensembl:ENSMUSP00000137931 UNRESOLVED Mouse UniProt/Ensembl source pair traced from GOA; the exact experimental-to-automated transfer chain was not reconstructed. Direct human localization or conserved agrin signaling independently supports the retained/refined term. Proposed replacements: positive regulation of synaptic assembly at neuromuscular junction Supporting Evidence: PMID:18848351 Here, we report that Lrp4, a member of the LDLR family, is a receptor for Agrin, forms a complex with MuSK, and mediates MuSK activation by Agrin. PMID:15340048 We also report that a single 5-min agrin pulse, followed by extensive washing, triggered long-lasting MuSK and AChR phosphorylation and efficient AChR clustering. |
| GO:0030154 cell differentiation | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: Agrin participates in context-dependent cell differentiation as an extracellular ligand. Reason: The keyword mapping is biologically supported beyond a developmental-expression correlation. Human y(0)z(0) agrin is modeled as a receptor ligand in the cached chondrocyte GO-CAM; PMID:26290588 reports human chondrocyte loss-of-function and bovine gain-of-function/receptor experiments. Retain the broad process as a context-dependent role rather than infer a universal differentiation program. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-KW:KW-0221 SUPPORTS TRANSFER Independent functional evidence supports the mapped biological scope described in the annotation rationale. |
| GO:0043113 receptor clustering | IEA GO_REF:0000120 | ACCEPT | Summary: Agrin induces AChR clustering. Reason: The combined ARBA/IPR004850 mapping is consistent with direct agrin-pulse assays and the LRP4-MuSK pathway. The mapping does not establish identical potency for every splice form. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00084392 UNRESOLVED Rule identifier traced from GOA; its full predicates were not independently inspected. The annotation-level biological judgment uses the cited independent evidence, not an asserted audit of rule internals. InterPro:IPR004850 SUPPORTS TRANSFER Agrin domain/family mapping, independently corroborated by receptor-clustering or conserved NtA/laminin-binding evidence as appropriate. Supporting Evidence: PMID:15340048 We also report that a single 5-min agrin pulse, followed by extensive washing, triggered long-lasting MuSK and AChR phosphorylation and efficient AChR clustering. PMID:18848351 Here, we report that Lrp4, a member of the LDLR family, is a receptor for Agrin, forms a complex with MuSK, and mediates MuSK activation by Agrin. |
| GO:0043236 laminin binding | IEA GO_REF:0000120 | ACCEPT | Summary: The N-terminal agrin domain binds laminin. Reason: IPR004850 and the ARBA rule are supported independently by the NtA binding experiments and conserved human domain. The direct 1997 experiments use chick constructs; the source should not be described as a purified human binding assay. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00086571 UNRESOLVED Rule identifier traced from GOA; its full predicates were not independently inspected. The annotation-level biological judgment uses the cited independent evidence, not an asserted audit of rule internals. InterPro:IPR004850 SUPPORTS TRANSFER Agrin domain/family mapping, independently corroborated by receptor-clustering or conserved NtA/laminin-binding evidence as appropriate. Supporting Evidence: PMID:9151673 In the current report we show that an NH2-terminal fragment of agrin containing these 130 amino acids is sufficient to bind to Matrigel and that the binding to this preparation is mediated by laminin-1. file:human/AGRN/AGRN-uniprot.txt This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain. |
| GO:0045202 synapse | IEA GO_REF:0000044 | ACCEPT | Summary: Agrin is a synaptic protein. Reason: The UniProt SL-0258 mapping is supported by synaptic basal-lamina anchoring and the neuronal transmembrane form. Both support a synaptic location without specifying one membrane topology. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0258 SUPPORTS TRANSFER Independent functional evidence supports the mapped biological scope described in the annotation rationale. Supporting Evidence: file:human/AGRN/AGRN-uniprot.txt This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain. file:human/AGRN/AGRN-uniprot.txt Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | MODIFY | Summary: Calcium is the supported metal ligand. Reason: Refine the keyword-derived metal-ion binding to calcium-ion binding, supported by the calcium-binding domain mapping and chick G3 binding measurements. This is a molecular substrate refinement; it does not license narrower localization claims for unrelated compartment annotations. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB-KW:KW-0479 SUPPORTS TRANSFER Independent functional evidence supports the mapped biological scope described in the annotation rationale. Proposed replacements: calcium ion binding |
| GO:0050808 synapse organization | IEA GO_REF:0000117 | ACCEPT | Summary: Agrin organizes and maintains synapses. Reason: Agrin is a signaling and anchoring molecule in synaptic organization. Human disease and recombinant-variant experiments further distinguish maintenance from initial AChR-clustering potency. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00029184 UNRESOLVED Rule identifier traced from GOA; its full predicates were not independently inspected. The annotation-level biological judgment uses the cited independent evidence, not an asserted audit of rule internals. Supporting Evidence: PMID:18848351 Here, we report that Lrp4, a member of the LDLR family, is a receptor for Agrin, forms a complex with MuSK, and mediates MuSK activation by Agrin. file:human/AGRN/AGRN-uniprot.txt This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain. |
| GO:0061024 membrane organization | IEA GO_REF:0000117 | ACCEPT | Summary: Agrin organizes receptor-rich membrane domains. Reason: Postsynaptic receptor clustering is an established organizing function of agrin and supports this broad membrane-organization annotation. PMID:15340048 measures agrin-triggered AChR clustering. The independent lymphocyte lipid-microdomain findings in PMID:11349136 illustrate an additional cellular context; the core judgment does not depend on classifying lymphocyte signaling as a central neuromuscular function. The compact core lists the receptor-organizing mechanism rather than every true process ancestor. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00028824 UNRESOLVED Rule identifier traced from GOA; its full predicates were not independently inspected. The annotation-level biological judgment uses the cited independent evidence, not an asserted audit of rule internals. Supporting Evidence: PMID:15340048 We also report that a single 5-min agrin pulse, followed by extensive washing, triggered long-lasting MuSK and AChR phosphorylation and efficient AChR clustering. PMID:11349136 Our data show that agrin induces the aggregation of signaling proteins and the creation of signaling domains in both immune and nervous systems through a common lipid raft pathway. |
| GO:0099536 synaptic signaling | IEA GO_REF:0000117 | ACCEPT | Summary: Agrin provides extracellular signals at synapses. Reason: The term accommodates the LRP4-MuSK signal and CNS excitability effects. These mechanisms support synaptic signaling even though agrin is neither the AChR agonist nor a neurotransmitter-producing enzyme. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00026596 UNRESOLVED Rule identifier traced from GOA; its full predicates were not independently inspected. The annotation-level biological judgment uses the cited independent evidence, not an asserted audit of rule internals. Supporting Evidence: PMID:18848351 Here, we report that Lrp4, a member of the LDLR family, is a receptor for Agrin, forms a complex with MuSK, and mediates MuSK activation by Agrin. file:human/AGRN/AGRN-uniprot.txt Functions differentially in the central nervous system (CNS) by inhibiting the alpha(3)-subtype of Na+/K+-ATPase and evoking depolarization at CNS synapses. |
| GO:0005515 protein binding | IPI PMID:21078624 Comparison of an expanded ataxia interactome with patient me... | REMOVE | Summary: The ATXN7 interaction does not specify a useful molecular function. Reason: The source is an interaction-network study and the UniProt record independently lists AGRN-ATXN7. Generic protein binding gives no informative activity, and no specific functional replacement follows from this pair. Removal is a curation-specificity decision, not a claim that the interaction is false or that an inaccessible supplement lacks AGRN. Supporting Evidence: file:human/AGRN/AGRN-uniprot.txt O00468; O15265: ATXN7; NbExp=2; IntAct=EBI-947482, EBI-708350; |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2467665 | ACCEPT | Summary: Agrin is an extracellular ligand and matrix component. Reason: The cached event, AGRN binds Beta amyloid fibril via GAG chains, places an extracellular agrin interaction in a receptor/matrix context. Independent human localization establishes the broad extracellular location. Supporting Evidence: Reactome:R-HSA-2467665 Several agrin (AGRN) ligands require the presence of heparan-sulfate GAG sidechains and probably represent interactions with them. PMID:9405491 In immunoelectron microscopy, agrin showed a linear distribution along the GBM and was present throughout the width of the GBM. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9914537 | ACCEPT | Summary: Agrin is an extracellular ligand and matrix component. Reason: The cached event, DGC complex binds AGRN and HSPG2, places an extracellular agrin interaction in a receptor/matrix context. Independent human localization establishes the broad extracellular location. Supporting Evidence: Reactome:R-HSA-9914537 Alpha-dystroglycan (DAG1(30-653)) binds G domain-like sequences in other extracellular matrix molecules such as AGRN (agrin) (Gee et al. PMID:9405491 In immunoelectron microscopy, agrin showed a linear distribution along the GBM and was present throughout the width of the GBM. |
| GO:0005576 extracellular region | TAS Reactome:R-NUL-2467431 | ACCEPT | Summary: Agrin is an extracellular ligand and matrix component. Reason: The cached event, Agrin binds Integrin alphaVbeta1 (alpha1beta1), places an extracellular agrin interaction in a receptor/matrix context. Independent human localization establishes the broad extracellular location. R-NUL-2467431 is a Gallus gallus event; it is comparative support, not a human experiment. Supporting Evidence: Reactome:R-NUL-2467431 Agrin is a large (>400 kDa) multi-domain heparan sulfate proteoglycan found in basement membranes. PMID:9405491 In immunoelectron microscopy, agrin showed a linear distribution along the GBM and was present throughout the width of the GBM. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-1667005 | UNDECIDED | Summary: The cited heparanase event resolves a lysosomal step, not this Golgi location. Reason: The cached event explicitly describes lysosomal HPSE cleavage. Agrin biosynthesis plausibly passes through the Golgi, but the particular source-to-Golgi assertion is not resolved by this event summary. Preserve uncertainty rather than use a degradation event as direct evidence for the Golgi compartment. Supporting Evidence: Reactome:R-HSA-1667005 Heparanase (HPSE) is an endoglycosidase that cleaves heparan sulfate (HS) chains from its HS proteoglycan (HSPG), by selectively cleaving the linkage between a glucuronic acid (GlcA) unit and an N-sulfo glucosamine unit (GlcNACS, Toyoshima & Nakajima 1999; Okada et al. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-1878002 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event XYLTs transfer Xyl to core protein concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. Supporting Evidence: Reactome:R-HSA-1878002 Xylosyltransferases (XYLT1, XYLT2) catalyse the initial step in the tetrasaccharide linkage required forglycosaminoglycan biosynthesis. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-1889955 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event B3GAT dimers transfer GlcA to tetrasaccharide linker concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. Supporting Evidence: Reactome:R-HSA-1889955 Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 3 (B3GAT3) (Ouzzine et al. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-1889978 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event B3GALT6 transfers Gal to the tetrasaccharide linker concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. Supporting Evidence: Reactome:R-HSA-1889978 Beta-1,3-galactosyltransferase 6 (B3GALT6) transfers a second galactose to the tetrasaccharide linker. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-1889981 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event B4GALT7 transfers Gal group to xylosyl-unit of the tetrasaccharide linker concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. Supporting Evidence: Reactome:R-HSA-1889981 Beta-1,4-galactosyltransferase 7 (B4GALT7) adds galactose (Gal) to beta-xyloside in a beta-1,4 linkage creating the second unit in the formation of the tetrasaccharide linker, the precursor required for glycosaminoglycan (GAG) synthesis (Almeida et al. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-2022851 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event EXT1:EXT2 transfers GlcNAc to the heparan chain concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. Supporting Evidence: Reactome:R-HSA-2022851 The EXT2 subunit of the EXT1:EXT2 complex transfers an N-acetylglucosamine moiety from UDP-GlcNAc to the growing heparan chain of HSPGs. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-2022856 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event EXT1:EXT2 transfers GlcA to heparan concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. Supporting Evidence: Reactome:R-HSA-2022856 The EXT1 subunit of the EXT1:EXT2 complex transfers a glucuronyl (GlcA) moiety from UDP-GlcA to the growing heparan chain of HSPGs. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-2022860 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event NDST1-4 can sulfate a glucosamine residue in heparan to form heparan sulfate (HS) concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. Supporting Evidence: Reactome:R-HSA-2022860 The bifunctional enzymes heparan sulfate N-deacetylases/N-sulfotransferases 1-4 (NDST1-4) catalyse both the N-deacetylation and the N-sulfation of N-acetylglucosamine (GlcNAc) of heparan (Dixon et al. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-2022887 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event NDST1-4 N-deacetylates GlcNAc residues in heparan concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. Supporting Evidence: Reactome:R-HSA-2022887 The bifunctional enzymes heparan sulfate N-deacetylase/N-sulfotransferase 1-4 (NDST1-4) catalyse both the N-deacetylation and the N-sulfation of N-acetylglucosamine (GlcNAc) of heparan (Dixon et al. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-2024108 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event Some HSPGs are secreted to the plasma membrane concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. Supporting Evidence: Reactome:R-HSA-2024108 Depending on the nature of the core protein HS-GAGs are attached to, they will either translocate to the cell surface or be secreted into the extracellular matrix (ECM). |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-2076383 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event HS3ST1 sulfates GlcN at C3 in heparan sulfate concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. Supporting Evidence: Reactome:R-HSA-2076383 Heparan sulfate 3-O-sulfotransferase1 (HS3ST1) transfers sulfate to the 3-OH position on glucosamine (GlcN) residues of heparan sulfate (HS) to form 3-O-sulfated HS. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-2076392 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event EXT1:EXT2 transfers GlcA to heparan concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. Supporting Evidence: Reactome:R-HSA-2076392 The EXT1 subunit of the EXT1:EXT2 complex transfers a glucuronyl (GlcA) moiety from UDP-GlcA to the growing heparan chain of HSPGs. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-2076419 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event HS6STs sulfate GlcN at C6 in heparan sulfate/heparin concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. Supporting Evidence: Reactome:R-HSA-2076419 Heparan-sulfate 6-O-sulfotransferases 1 and 2 (HS3ST1-2) (Habuchi et al. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-2076508 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event HS2ST1 trimer sulfates IdoA at C2 in heparan sulfate concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. Supporting Evidence: Reactome:R-HSA-2076508 Human heparan sulfate L-iduronyl 2-O-sulfotransferase 1 (HS2ST1) trimer mediates the transfer of sulfate from PAPS to the C2-position of iduronate (and glucuronate with lesser preference) (Smeds et al. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-2076611 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event HS3ST2-6 sulfate GlcN at C3 in heparan sulfate concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. Supporting Evidence: Reactome:R-HSA-2076611 Heparan sulfate 3-O-sulfotransferases (HS3ST2-6), associated with the Golgi membrane, transfer sulfate to the 3-OH position on glucosamine (GlcN) residues of heparan sulfate (HS) to form 3-O-sulfated HS (Shworak et al. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-3560802 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event Defective B3GAT3 does not transfer GlcA to tetrasaccharide linker concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. The defective enzyme in this event is the named glycan-pathway enzyme, not an agrin catalytic mutant. Supporting Evidence: Reactome:R-HSA-3560802 B3GAT3 (Ouzzine et al. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-3560804 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event Defective B4GALT7 does not transfer Gal to xylosyl-unit of the tetrasaccharide linker concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. The defective enzyme in this event is the named glycan-pathway enzyme, not an agrin catalytic mutant. Supporting Evidence: Reactome:R-HSA-3560804 Beta 1,4 galactosyltransferase 7 (B4GALT7) adds galactose (Gal) to beta-xyloside in a beta-1,4-linkage creating the second unit in the tetrasaccharide linker sequence in proteoglycans, the precursor required for extension of glycosaminoglycan (GAG) chains (Almeida et al. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-3656254 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event Defective EXT2 (in EXT1:EXT2) does not transfer GlcNAc to the heparan chain concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. The defective enzyme in this event is the named glycan-pathway enzyme, not an agrin catalytic mutant. Supporting Evidence: Reactome:R-HSA-3656254 Exostosin 1 and 2 (EXT1 and 2) are dual-specific glycosyltransferases required to form heparan sulfate (HS) which is involved in regulating various body functions during development, homeostasis and pathology including blood clotting, angiogenesis and metastasis of cancer cells. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-3656257 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event Defective EXT1 (in EXT1:EXT2) does not transfer GlcA to heparan concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. The defective enzyme in this event is the named glycan-pathway enzyme, not an agrin catalytic mutant. Supporting Evidence: Reactome:R-HSA-3656257 Exostosin 1 and 2 (EXT1 and 2) are dual-specific glycosyltransferases required to form heparan sulfate (HS) which is involved in regulating various body functions during development, homeostasis and pathology including blood clotting, angiogenesis and metastasis of cancer cells. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-3656261 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event Defective EXT1 (in EXT1:EXT2) does not transfer GlcNAc to the heparan chain concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. The defective enzyme in this event is the named glycan-pathway enzyme, not an agrin catalytic mutant. Supporting Evidence: Reactome:R-HSA-3656261 Exostosin 1 and 2 (EXT1 and 2) are dual-specific glycosyltransferases required to form heparan sulfate (HS) which is involved in regulating variousbody functions during development, homeostasis and pathology including blood clotting, angiogenesis and metastasis of cancer cells. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-3656267 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event Defective EXT2 (in EXT1:EXT2) does not transfer GlcA to heparan concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. The defective enzyme in this event is the named glycan-pathway enzyme, not an agrin catalytic mutant. Supporting Evidence: Reactome:R-HSA-3656267 Exostosin 1 and 2 (EXT1 and 2) are dual-specific glycosyltransferases required to form heparan sulfate (HS) which is involved in regulating various body functions during development, homeostasis and pathology including blood clotting, angiogenesis and metastasis of cancer cells. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-4420365 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event Defective B3GALT6 does not transfer Gal to the tetrasaccharide linker concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. The defective enzyme in this event is the named glycan-pathway enzyme, not an agrin catalytic mutant. Supporting Evidence: Reactome:R-HSA-4420365 Beta-1,3-galactosyltransferase 6 (B3GALT6) normally transfers a second galactose to the tetrasaccharide linker, an initiator sequence required for the biosynthesis of chondroitin sulfate, dermatan sulfate and heparans. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-9036285 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event Defective EXT1 (in EXT1:EXT2) does not transfer GlcA to heparan concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. The defective enzyme in this event is the named glycan-pathway enzyme, not an agrin catalytic mutant. Supporting Evidence: Reactome:R-HSA-9036285 Exostosin 1 and 2 (EXT1 and 2) are dual-specific glycosyltransferases required to form heparan sulfate (HS) which is involved in regulating various body functions during development, homeostasis and pathology including blood clotting, angiogenesis and metastasis of cancer cells. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-9036289 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event Defective EXT2 (in EXT1:EXT2) does not transfer GlcA to heparan concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. The defective enzyme in this event is the named glycan-pathway enzyme, not an agrin catalytic mutant. Supporting Evidence: Reactome:R-HSA-9036289 Exostosin 1 and 2 (EXT1 and 2) are dual-specific glycosyltransferases required to form heparan sulfate (HS) which is involved in regulating various body functions during development, homeostasis and pathology including blood clotting, angiogenesis and metastasis of cancer cells. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-9940993 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event PXYLP1 dephosphorylates Xyl moiety concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. Supporting Evidence: Reactome:R-HSA-9940993 2-Phosphoxylose phosphatase 1 (PXYLP1) dephosphorylates the xylose (Xyl) moiety of the GAG linker glycan chain of proteoglycans, making the chain available for the biosynthesis of heparan/chondoitin/dermatan (Koike et al., 2014; reviewed in Nowicka & GrΔda, 2019). |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-9941039 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event FAM20B phosphorylates Xyl moiety concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. Supporting Evidence: Reactome:R-HSA-9941039 Glycosaminoglycan xylosylkinase FAM20B phosphorylates the xylose (Xyl) moiety of the GAG linker glycan chain of proteoglycans, making the chain unavailable for the biosynthesis of heparan/chondoitin/dermatan (Koike et al., 2009; reviewed in Nowicka & GrΔda, 2019). |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-9953259 | KEEP AS NON CORE | Summary: Golgi transit accompanies agrin glycan maturation and secretion. Reason: The event EXTL3 dimer transfers GlcNAc to the GAG linker concerns glycan maturation or secretory trafficking of HSPG participants. Agrin is a glycosylated substrate or transported cargo in this setting; the compartment annotation can be retained without assigning it the glycosyltransferase or sulfotransferase activity. Supporting Evidence: Reactome:R-HSA-9953259 Exostosin-like 2 (EXTL2) and Exostosin-like 3 (EXTL3) dimer transfer an N-acetylglucosamine moiety from UDP-GlcNAc to a GlcA-Gal-Gal-Xyl moiety, which is the GAG-linker chain on HS-/DS-/CS-proteoglycans (Kitagawa et al., 1999; Kim et al., 2001; Wilson et al., 2022). |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1678694 | ACCEPT | Summary: Agrin has a physiological cell-surface pool. Reason: The event Heparanase 2 (HPSE2) binds heparan sulfate proteoglycans contains a cell-surface HSPG participant. Agrin membrane association is independently supported by its transmembrane form and cell-surface receptor interactions; the broad location does not imply a new catalytic function. Supporting Evidence: Reactome:R-HSA-1678694 Heparanase 2 (HPSE2) (McKenzie et al. file:human/AGRN/AGRN-uniprot.txt Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2024084 | ACCEPT | Summary: Agrin has a physiological cell-surface pool. Reason: The event HS-GAGs translocate to the lysosome for degradation contains a cell-surface HSPG participant. Agrin membrane association is independently supported by its transmembrane form and cell-surface receptor interactions; the broad location does not imply a new catalytic function. Supporting Evidence: Reactome:R-HSA-2024084 As part of the natural turnover of GAGs, extracellular HSPGs are endocytosed to the lysosome to be degraded (Winchester 2005). file:human/AGRN/AGRN-uniprot.txt Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2024108 | ACCEPT | Summary: Agrin has a physiological cell-surface pool. Reason: The event Some HSPGs are secreted to the plasma membrane contains a cell-surface HSPG participant. Agrin membrane association is independently supported by its transmembrane form and cell-surface receptor interactions; the broad location does not imply a new catalytic function. Supporting Evidence: Reactome:R-HSA-2024108 Depending on the nature of the core protein HS-GAGs are attached to, they will either translocate to the cell surface or be secreted into the extracellular matrix (ECM). file:human/AGRN/AGRN-uniprot.txt Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2404131 | ACCEPT | Summary: Agrin has a physiological cell-surface pool. Reason: The event LRPs transport extracellular CR:atREs:HSPG:apoE to cytosol contains a cell-surface HSPG participant. Agrin membrane association is independently supported by its transmembrane form and cell-surface receptor interactions; the broad location does not imply a new catalytic function. The retinoid/chylomicron event is not evidence that agrin catalyzes retinoid metabolism. Supporting Evidence: Reactome:R-HSA-2404131 When the low-density lipoprotein receptor (LDLR) is missing, saturated or inhibited, chylomicron remnants (CRs) containing all-trans-retinyl esters (atREs) can be cleared from circulation by interaction with cell-surface heparan sulfate proteoglycan (HSPG) and secreted apolipoprotein E (apoE). file:human/AGRN/AGRN-uniprot.txt Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2423785 | ACCEPT | Summary: Agrin has a physiological cell-surface pool. Reason: The event CR:atREs binds apoE and HSPG contains a cell-surface HSPG participant. Agrin membrane association is independently supported by its transmembrane form and cell-surface receptor interactions; the broad location does not imply a new catalytic function. The retinoid/chylomicron event is not evidence that agrin catalyzes retinoid metabolism. Supporting Evidence: Reactome:R-HSA-2423785 When the low-density lipoprotein receptor (LDLR) is missing, saturated or inhibited, chylomicron remnants (CRs) containing all-trans-retinyl esters (atREs) bind apolioprotein E (apoE). file:human/AGRN/AGRN-uniprot.txt Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2429643 | ACCEPT | Summary: Agrin has a physiological cell-surface pool. Reason: The event NREH hydrolyses atREs (HSPG:apoE) to atROL and FAs contains a cell-surface HSPG participant. Agrin membrane association is independently supported by its transmembrane form and cell-surface receptor interactions; the broad location does not imply a new catalytic function. The retinoid/chylomicron event is not evidence that agrin catalyzes retinoid metabolism. Supporting Evidence: Reactome:R-HSA-2429643 Once inside liver parenchymal cells, all-trans-retinyl esters (atREs), are hydrolysed to all-trans-retinol (atROL) and fatty acids (FAs) by a neutral, all-trans-retinyl ester hydrolase (NREH). file:human/AGRN/AGRN-uniprot.txt Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9694579 | ACCEPT | Summary: Agrin has a physiological cell-surface pool. Reason: The event Spike glycoprotein of SARS-CoV-2 binds ACE2 on host cell contains a cell-surface HSPG participant. Agrin membrane association is independently supported by its transmembrane form and cell-surface receptor interactions; the broad location does not imply a new catalytic function. Generic HSPG membership in this viral event does not independently demonstrate an AGRN-specific viral-entry mechanism. Supporting Evidence: Reactome:R-HSA-9694579 SARS-CoV-2 spike protein trimer (S3), as a component of the S3:M:E:encapsidated SARS coronavirus-2 genomic RNA: 7a:O-glycosyl 3a tetramer complex, binds to glycosylated angiotensin converting enzyme 2 (ACE2) associated with the human host cell plasma membrane (Zhang et al, 2020; Raghuvamsi et al, 2021; reviewed by Jackson et al, 2022). file:human/AGRN/AGRN-uniprot.txt Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9694661 | ACCEPT | Summary: Agrin has a physiological cell-surface pool. Reason: The event TMPRSS2 Mediated SARS-CoV-2 Spike Protein Cleavage and Endocytosis contains a cell-surface HSPG participant. Agrin membrane association is independently supported by its transmembrane form and cell-surface receptor interactions; the broad location does not imply a new catalytic function. Generic HSPG membership in this viral event does not independently demonstrate an AGRN-specific viral-entry mechanism. Supporting Evidence: Reactome:R-HSA-9694661 Transmembrane protease serine 2 (TMPRSS2), associated with the plasma membrane of the host cell, mediates the hydrolytic cleavage of SARS-CoV-2 Spike (S) protein component of the viral membrane-associate S3:M:E:encapsidated SARS coronavirus genomic RNA: 7a:O-glycosyl 3a tetramer complex associated with ACE2 (Xia et al, 2020; Bestle et al, 2020; Koch et al, 2021).<br><br>Neuropilin-1 (NRP1) is a receptor expressed in a broad range of cells from human organ systems including respiratory, urinary, digestive, reproductive, and immune systems. file:human/AGRN/AGRN-uniprot.txt Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9698988 | ACCEPT | Summary: Agrin has a physiological cell-surface pool. Reason: The event Direct Host Cell Membrane Membrane Fusion and Release of SARS-CoV-2 Nucleocapsid contains a cell-surface HSPG participant. Agrin membrane association is independently supported by its transmembrane form and cell-surface receptor interactions; the broad location does not imply a new catalytic function. Generic HSPG membership in this viral event does not independently demonstrate an AGRN-specific viral-entry mechanism. Supporting Evidence: Reactome:R-HSA-9698988 SARS-CoV-2 virions attached to the host cell surface via a complex involving viral spike (S) protein and host angiotensin-converting enzyme 2 (ACE2) can directly fuse their membrane with the host cell membrane, releasing the uncoated virion nucleocapsid into the cytoplasm. file:human/AGRN/AGRN-uniprot.txt Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9699007 | ACCEPT | Summary: Agrin has a physiological cell-surface pool. Reason: The event FURIN Mediated SARS-CoV-2 Spike Protein Cleavage and Endocytosis contains a cell-surface HSPG participant. Agrin membrane association is independently supported by its transmembrane form and cell-surface receptor interactions; the broad location does not imply a new catalytic function. Generic HSPG membership in this viral event does not independently demonstrate an AGRN-specific viral-entry mechanism. Supporting Evidence: Reactome:R-HSA-9699007 In a SARS-CoV-2 infection the cellular protease furin cleaves the spike protein at the S1/S2 site and that cleavage is essential for S-protein-mediated cell-cell fusion and entry into human lung cells. file:human/AGRN/AGRN-uniprot.txt Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9836899 | ACCEPT | Summary: Agrin has a physiological cell-surface pool. Reason: The event sG binds to HSPGs contains a cell-surface HSPG participant. Agrin membrane association is independently supported by its transmembrane form and cell-surface receptor interactions; the broad location does not imply a new catalytic function. Generic HSPG membership in this viral event does not independently demonstrate an AGRN-specific viral-entry mechanism. Supporting Evidence: Reactome:R-HSA-9836899 The secreted soluble isoform of hRSV G protein (sG) binds to proteoglycans on the surface of host cells (Escribano-Romero et al, 2004). file:human/AGRN/AGRN-uniprot.txt Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-1667005 | KEEP AS NON CORE | Summary: Agrin can enter the lysosomal compartment during turnover. Reason: The event Heparanase (HPSE) cleaves heparan sulfate from its proteoglycan (lysosome) concerns HSPG transport or degradation. This is a cargo/substrate location, compatible with turnover of extracellular or membrane-associated agrin; it is not a core site of agrin receptor signaling. Supporting Evidence: Reactome:R-HSA-1667005 Heparanase (HPSE) is an endoglycosidase that cleaves heparan sulfate (HS) chains from its HS proteoglycan (HSPG), by selectively cleaving the linkage between a glucuronic acid (GlcA) unit and an N-sulfo glucosamine unit (GlcNACS, Toyoshima & Nakajima 1999; Okada et al. |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-2024084 | KEEP AS NON CORE | Summary: Agrin can enter the lysosomal compartment during turnover. Reason: The event HS-GAGs translocate to the lysosome for degradation concerns HSPG transport or degradation. This is a cargo/substrate location, compatible with turnover of extracellular or membrane-associated agrin; it is not a core site of agrin receptor signaling. Supporting Evidence: Reactome:R-HSA-2024084 As part of the natural turnover of GAGs, extracellular HSPGs are endocytosed to the lysosome to be degraded (Winchester 2005). |
| GO:0046847 filopodium assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transmembrane agrin promotes dendritic filopodium assembly. Reason: The human UniProt synthesis describes transmembrane agrin-induced dendritic filopodia, and the rat donor P25304 is correctly identified. Independent PMID:19940118 measures process induction by chick TM-agrin in chick tectal neurons and heterologous cells, with extracellular domain-mutant controls. It corroborates a conserved signaling role but does not reconstruct the precise rat ISS donor experiment or assay human AGRN merely because HEK293 is a host. Retain this CNS protrusion-assembly activity as a non-core function of the transmembrane context; the positive activity is preserved rather than denied or treated as a generic consequence of losing neuromuscular synapses. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P25304 UNRESOLVED Rat agrin donor identified; precise original donor experiment not reconstructed. The human UniProt functional synthesis independently describes transmembrane agrin-induced dendritic filopodia. Supporting Evidence: file:human/AGRN/AGRN-uniprot.txt Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. PMID:19940118 Mapping of the process-inducing activity in neurons and non-neuronal cells demonstrates that the cytoplasmic part of transmembrane agrin is dispensable and that the extracellular region is necessary for process formation. |
| GO:0031012 extracellular matrix | HDA PMID:23658023 Comparative proteomic analysis of supportive and unsupportiv... | ACCEPT | Summary: Human stem-cell-associated extracellular matrix contains agrin. Reason: The full cached proteomic table identifies AGRN in HUES1-derived matrix (10.0 in the reported spectral-count units), while the listed feeder conditions are ND for this row. Retain ECM localization without claiming agrin was detected in every supportive feeder matrix or shown individually to maintain pluripotency. Supporting Evidence: PMID:20551380 In particular, three glycoproteins (podocan, sclerostin, and agrin) were identified for the first time in human aortas at the protein level. |
| GO:0031012 extracellular matrix | IDA PMID:17628813 MLC1 is associated with the dystrophin-glycoprotein complex ... | ACCEPT | Summary: Agrin is directly localized in human brain extracellular matrix. Reason: The full cached study includes anti-agrin immunostaining around vessels and extracellular-matrix colocalization experiments. Its headline MLC1-Kir4.1 interaction is a separate result and does not make the agrin localization a paralog error. Supporting Evidence: PMID:17628813 In control tissue, agrin (Fig. 4k) and Ξ±βdystroglycan (Fig. 4m) were seen in the perivascular extracellular matrix, whereas these proteins were observed both in the perivascular extracellular matrix and within cells in MLC tissue (Fig. 4l, n). |
| GO:0005201 extracellular matrix structural constituent | RCA PMID:28675934 Characterization of the Extracellular Matrix of Normal and D... | ACCEPT | Summary: Agrin is a structural extracellular-matrix proteoglycan. Reason: The RCA assertion combines a protocol for normal and diseased ECM proteomics with protein-class/function knowledge. Matrix anchoring through laminin and dystroglycan provides independent mechanistic support for a structural contribution. These proteomic studies do not by themselves measure compression resistance, tissue modulus, or renal charge filtration. Their classifications should not be described as direct biomechanical assays. Supporting Evidence: file:human/AGRN/AGRN-uniprot.txt This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain. PMID:9417121 In adult kidney and lung, agrin co-purified and co-immunoprecipitated with dystroglycan, and both molecules were co-localized in embryonic tissue. |
| GO:0031012 extracellular matrix | HDA PMID:28675934 Characterization of the Extracellular Matrix of Normal and D... | ACCEPT | Summary: Agrin is detected in extracellular matrix. Reason: The curated HDA assertion concerns agrin detection in the ECM isolation/proteomics protocol. The location is independently corroborated by human aortic identification and basement-membrane staining. Where the AGRN-specific supplementary peptide row is absent from the cached extraction, that gap does not establish contamination or a wrong-gene annotation. Supporting Evidence: PMID:20551380 In particular, three glycoproteins (podocan, sclerostin, and agrin) were identified for the first time in human aortas at the protein level. PMID:9405491 In immunoelectron microscopy, agrin showed a linear distribution along the GBM and was present throughout the width of the GBM. |
| GO:0005201 extracellular matrix structural constituent | RCA PMID:27068509 Extracellular matrix remodelling in response to venous hyper... | ACCEPT | Summary: Agrin is a structural extracellular-matrix proteoglycan. Reason: The RCA assertion combines human varicose-vein ECM proteomics with protein-class/function knowledge. Matrix anchoring through laminin and dystroglycan provides independent mechanistic support for a structural contribution. These proteomic studies do not by themselves measure compression resistance, tissue modulus, or renal charge filtration. Their classifications should not be described as direct biomechanical assays. Supporting Evidence: file:human/AGRN/AGRN-uniprot.txt This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain. PMID:9417121 In adult kidney and lung, agrin co-purified and co-immunoprecipitated with dystroglycan, and both molecules were co-localized in embryonic tissue. |
| GO:0005201 extracellular matrix structural constituent | RCA PMID:27559042 Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin... | ACCEPT | Summary: Agrin is a structural extracellular-matrix proteoglycan. Reason: The RCA assertion combines human atrial glycoproteomics with protein-class/function knowledge. Matrix anchoring through laminin and dystroglycan provides independent mechanistic support for a structural contribution. These proteomic studies do not by themselves measure compression resistance, tissue modulus, or renal charge filtration. Their classifications should not be described as direct biomechanical assays. Supporting Evidence: file:human/AGRN/AGRN-uniprot.txt This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain. PMID:9417121 In adult kidney and lung, agrin co-purified and co-immunoprecipitated with dystroglycan, and both molecules were co-localized in embryonic tissue. |
| GO:0005201 extracellular matrix structural constituent | RCA PMID:20551380 Proteomics characterization of extracellular space component... | ACCEPT | Summary: Agrin is a structural extracellular-matrix proteoglycan. Reason: The RCA assertion combines human aortic ECM proteomics with protein-class/function knowledge. Matrix anchoring through laminin and dystroglycan provides independent mechanistic support for a structural contribution. These proteomic studies do not by themselves measure compression resistance, tissue modulus, or renal charge filtration. Their classifications should not be described as direct biomechanical assays. Supporting Evidence: file:human/AGRN/AGRN-uniprot.txt This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain. PMID:9417121 In adult kidney and lung, agrin co-purified and co-immunoprecipitated with dystroglycan, and both molecules were co-localized in embryonic tissue. |
| GO:0031012 extracellular matrix | HDA PMID:27068509 Extracellular matrix remodelling in response to venous hyper... | ACCEPT | Summary: Agrin is detected in extracellular matrix. Reason: The curated HDA assertion concerns agrin detection in human varicose-vein matrix fractions. The location is independently corroborated by human aortic identification and basement-membrane staining. Where the AGRN-specific supplementary peptide row is absent from the cached extraction, that gap does not establish contamination or a wrong-gene annotation. Aggrecan is a prominent focus of the paper, but that does not exclude agrin from its broader proteomic dataset. Supporting Evidence: PMID:20551380 In particular, three glycoproteins (podocan, sclerostin, and agrin) were identified for the first time in human aortas at the protein level. PMID:9405491 In immunoelectron microscopy, agrin showed a linear distribution along the GBM and was present throughout the width of the GBM. |
| GO:0031012 extracellular matrix | HDA PMID:27559042 Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin... | ACCEPT | Summary: Agrin is detected in extracellular matrix. Reason: The curated HDA assertion concerns agrin detection in human atrial extracellular glycoproteins. The location is independently corroborated by human aortic identification and basement-membrane staining. Where the AGRN-specific supplementary peptide row is absent from the cached extraction, that gap does not establish contamination or a wrong-gene annotation. Supporting Evidence: PMID:20551380 In particular, three glycoproteins (podocan, sclerostin, and agrin) were identified for the first time in human aortas at the protein level. PMID:9405491 In immunoelectron microscopy, agrin showed a linear distribution along the GBM and was present throughout the width of the GBM. |
| GO:0031012 extracellular matrix | HDA PMID:20551380 Proteomics characterization of extracellular space component... | ACCEPT | Summary: Agrin is detected in extracellular matrix. Reason: The curated HDA assertion concerns agrin detection in human aortic ECM. The location is independently corroborated by human aortic identification and basement-membrane staining. Where the AGRN-specific supplementary peptide row is absent from the cached extraction, that gap does not establish contamination or a wrong-gene annotation. Supporting Evidence: PMID:20551380 In particular, three glycoproteins (podocan, sclerostin, and agrin) were identified for the first time in human aortas at the protein level. PMID:9405491 In immunoelectron microscopy, agrin showed a linear distribution along the GBM and was present throughout the width of the GBM. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: Agrin is reported in an extracellular-vesicle preparation. Reason: The source describes proteomic analysis of expressed prostatic secretions in urine. Retain the curator-supported fraction association as non-core; the available extraction does not resolve the AGRN peptide/vesicle-topology details. It does not support an agrin-specific vesicle-biogenesis activity, but lack of that activity is not evidence that detection was contamination. |
| GO:0070062 extracellular exosome | HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid... | KEEP AS NON CORE | Summary: Agrin is reported in an extracellular-vesicle preparation. Reason: The source describes proteomic analysis of human parotid saliva. Retain the curator-supported fraction association as non-core; the available extraction does not resolve the AGRN peptide/vesicle-topology details. It does not support an agrin-specific vesicle-biogenesis activity, but lack of that activity is not evidence that detection was contamination. |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: Agrin is reported in an extracellular-vesicle preparation. Reason: The source describes proteomic analysis of B-cell-derived exosomes. Retain the curator-supported fraction association as non-core; the available extraction does not resolve the AGRN peptide/vesicle-topology details. It does not support an agrin-specific vesicle-biogenesis activity, but lack of that activity is not evidence that detection was contamination. |
| GO:0002162 dystroglycan binding | ISS GO_REF:0000024 | ACCEPT | Summary: Agrin binds dystroglycan as a matrix-to-cell-surface interaction. Reason: The chick and rat agrin donors are consistent with conserved LG-domain binding. PMID:9417121 reports solid-phase ligand binding, copurification and coimmunoprecipitation; the human UniProt domain annotation independently supports this specific molecular interaction. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P31696 SUPPORTS TRANSFER Independent functional evidence supports the mapped biological scope described in the annotation rationale. UniProtKB:P25304 SUPPORTS TRANSFER Independent functional evidence supports the mapped biological scope described in the annotation rationale. Supporting Evidence: file:human/AGRN/AGRN-uniprot.txt Both laminin G-like 2 (G2) and laminin G-like 3 (G3) domains are required for alpha-dystroglycan/DAG1 binding. PMID:9417121 In adult kidney and lung, agrin co-purified and co-immunoprecipitated with dystroglycan, and both molecules were co-localized in embryonic tissue. |
| GO:0035374 chondroitin sulfate binding | ISS GO_REF:0000024 | UNDECIDED | Summary: Covalent chondroitin-sulfate attachment does not resolve noncovalent binding. Reason: The mouse Agrn donor was traced through the historical MGI comparative GO graph to PMID:12773545. The recovered primary Methods and Results test GAG attachment to recombinant chick agrin using glycosidases and serine-cluster substitutions. Those assays establish covalent modification, while the annotated molecular function concerns ligand binding. Additional donor evidence for noncovalent chondroitin-sulfate recognition remains unresolved; do not infer that agrin universally cannot bind this glycan. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:A2ASQ1 UNRESOLVED Mouse Agrn comparative GO graph traces glycan terms to PMID:12773545. The recovered primary experiments map covalent GAG attachment; noncovalent ligand binding is not resolved by those assays. |
| GO:0043395 heparan sulfate proteoglycan binding | ISS GO_REF:0000024 | MODIFY | Summary: The G3 domain binds heparan sulfate; distinguish the glycan from an intact proteoglycan. Reason: PMID:17649979 directly measures noncovalent heparan-sulfate/heparin binding by chick agrin G3 using calorimetry and NMR. This provides positive conserved-domain support for heparan sulfate binding in human agrin, rather than requiring a human direct assay for an ISS judgment. GO:1904399 names that measured glycan ligand; GO:0043395 instead names a heparan-sulfate proteoglycan. The mouse PMID:12773545 attachment experiments do not establish noncovalent recognition of an intact proteoglycan. Refine the ligand scope without equating covalent glycosylation with binding or claiming intact-proteoglycan binding is impossible. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB:A2ASQ1 UNRESOLVED Mouse Agrn comparative GO graph traces glycan terms to PMID:12773545. The recovered primary experiments map covalent GAG attachment; noncovalent ligand binding is not resolved by those assays. UniProtKB:P31696 UNRESOLVED Chick agrin G3 directly binds heparan sulfate/heparin in PMID:17649979. This independent positive evidence supports the glycan-binding refinement by conserved-domain inference; it does not resolve the original whole-proteoglycan source assertion. Proposed replacements: heparan sulfate binding Supporting Evidence: PMID:17649979 By contrast, the glycosaminoglycans heparin and heparan sulfate bind independently of Ca2+. Binding is endothermic, and the binding site spans about 12 saccharide units. |
| GO:0005509 calcium ion binding | ISS GO_REF:0000024 | ACCEPT | Summary: Agrin G3 directly binds calcium in the chick donor experiments. Reason: The P31696 donor is chick agrin. PMID:17649979 reports direct thermodynamic calcium-binding measurements on isolated G3 splice variants, supporting the conserved biochemical capacity independently of the calcium requirement of receptor clustering. Human affinity and domain-specific occupancy are not measured by that experiment. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P31696 SUPPORTS TRANSFER Chick agrin P31696; primary G3 thermodynamic study PMID:17649979 measures calcium or calcium-dependent sialic-acid binding. Human affinity and physiological ligand usage are not directly measured. |
| GO:0033691 sialic acid binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Agrin G3 has experimentally measured sialic-acid binding. Reason: Chick G3 calorimetry/NMR in PMID:17649979 reports calcium-dependent binding with approximately millimolar affinity under the tested conditions. Preserve the biochemical capacity as non-core; this preparation does not establish a dominant human physiological sialic-acid receptor function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P31696 SUPPORTS TRANSFER Chick agrin P31696; primary G3 thermodynamic study PMID:17649979 measures calcium or calcium-dependent sialic-acid binding. Human affinity and physiological ligand usage are not directly measured. Supporting Evidence: file:human/AGRN/AGRN-uniprot.txt Binds sialic acid with a stoichiometry of 1:1 and binding requires calcium ions (By similarity). |
| GO:0045202 synapse | ISS GO_REF:0000024 | ACCEPT | Summary: Agrin has an independently established synaptic location. Reason: The merged source lists rat agrin P25304 and rat ATP1A3 P06687. P06687 is an agrin interaction partner, not an agrin ortholog, so it cannot be described as a pairwise sequence donor. Synaptic agrin localization is nevertheless independently supported by basal-lamina anchoring, rat agrin evidence and the human functional synthesis. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P06687 UNRESOLVED Rat ATP1A3, an agrin interaction partner rather than an agrin ortholog. It is not interpreted as pairwise sequence evidence; synaptic agrin is independently supported. UniProtKB:P25304 SUPPORTS TRANSFER Independent functional evidence supports the mapped biological scope described in the annotation rationale. Supporting Evidence: file:human/AGRN/AGRN-uniprot.txt This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain. file:human/AGRN/AGRN-uniprot.txt Functions differentially in the central nervous system (CNS) by inhibiting the alpha(3)-subtype of Na+/K+-ATPase and evoking depolarization at CNS synapses. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | UNDECIDED | Summary: The precise donor evidence for positive RNA-polymerase-II transcription remains unresolved. Reason: Agrin-MuSK signaling regulates synaptic gene expression, and PMID:10320756 explicitly distinguishes in-vivo transcriptional specialization from neuregulin responses in cultured mouse myotubes. That supports the general regulatory context, but the exact rat P25304 donor experiment underlying this RNA-polymerase-II-specific transfer was not recovered. Do not replace the unresolved source with a different-species experiment or dismiss regulation merely because agrin is extracellular. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P25304 UNRESOLVED Rat agrin donor identified, but its exact RNA-polymerase-II-specific experimental assertion was not recovered; general mouse synaptic transcription evidence is not substituted for this donor chain. |
| GO:0045887 positive regulation of synaptic assembly at neuromuscular junction | ISS GO_REF:0000024 | ACCEPT | Summary: Agrin positively regulates neuromuscular synaptic assembly. Reason: The mouse Agrn donor agrees with agrin-induced postsynaptic differentiation and conserved human LRP4-MuSK signaling. Agrin performs the ligand step, so this is mechanistic participation rather than necessity alone. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:A2ASQ1 SUPPORTS TRANSFER Independent functional evidence supports the mapped biological scope described in the annotation rationale. Supporting Evidence: PMID:18848351 Here, we report that Lrp4, a member of the LDLR family, is a receptor for Agrin, forms a complex with MuSK, and mediates MuSK activation by Agrin. PMID:15340048 We also report that a single 5-min agrin pulse, followed by extensive washing, triggered long-lasting MuSK and AChR phosphorylation and efficient AChR clustering. |
| GO:0031012 extracellular matrix | TAS PMID:22261194 Proteomics analysis of cardiac extracellular matrix remodeli... | ACCEPT | Summary: The study supports extracellular-matrix localization across cardiac tissues. Reason: The source begins with porcine ischemia/reperfusion proteomics but explicitly includes validation of novel ECM proteins in human left-ventricular tissue. Retain the curator-supported human agrin location; the abstract alone does not resolve every AGRN-specific validation measurement. Supporting Evidence: PMID:22261194 Finally, novel cardiac ECM proteins identified by proteomics were validated in human left ventricular tissue acquired from ischemic cardiomyopathy patients at cardiac transplantation. |
| GO:0005515 protein binding | IPI PMID:9417121 Agrin is a high-affinity binding protein of dystroglycan in ... | MODIFY | Summary: The interaction has a specific dystroglycan-binding function. Reason: Replace generic protein binding with dystroglycan binding, the molecular interaction directly described by the source. Existing ISS evidence for the same term does not make this independent interaction evidence invalid or uninformative once its partner is specified. Proposed replacements: dystroglycan binding Supporting Evidence: PMID:9417121 In adult kidney and lung, agrin co-purified and co-immunoprecipitated with dystroglycan, and both molecules were co-localized in embryonic tissue. |
| GO:0005604 basement membrane | IDA PMID:9405491 Agrin is a major heparan sulfate proteoglycan in the human g... | ACCEPT | Summary: Agrin is a major human glomerular-basement-membrane component. Reason: Human immunostaining, antibody assays and immunoelectron microscopy directly establish the location. The sixfold comparison with perlecan is specific to the crude glomerular extract assay and does not quantify a universal whole-organ fraction. Supporting Evidence: PMID:9405491 In immunoelectron microscopy, agrin showed a linear distribution along the GBM and was present throughout the width of the GBM. |
| GO:0007213 G protein-coupled acetylcholine receptor signaling pathway | TAS PMID:9405491 Agrin is a major heparan sulfate proteoglycan in the human g... | MODIFY | Summary: The cited neuromuscular mechanism is skeletal-muscle AChR clustering. Reason: The complete publisher article PMID:9405491 describes agrin-induced nicotinic AChR clustering at the neuromuscular junction, not a muscarinic G-protein-coupled receptor pathway. GO:0071340 specifies acetylcholine-gated channel clustering in skeletal muscle fibers apposed to nerve terminals and matches that positive source context more precisely than generic receptor clustering. PMID:15340048 independently supports agrin-triggered clustering in myotubes. This is a refinement of an existing assertion, not an additional NEW process. Proposed replacements: skeletal muscle acetylcholine-gated channel clustering Supporting Evidence: PMID:15340048 We also report that a single 5-min agrin pulse, followed by extensive washing, triggered long-lasting MuSK and AChR phosphorylation and efficient AChR clustering. |
| GO:0045162 clustering of voltage-gated sodium channels | TAS PMID:9405491 Agrin is a major heparan sulfate proteoglycan in the human g... | KEEP AS NON CORE | Summary: Agrin-dependent sodium-channel clustering is a reported ancillary synaptic role. Reason: The full PMID:9405491 introduction on page 20 positively attributes sodium-channel aggregation during NMJ development to earlier work, including Sharp and Caldwell (1996), identified in its bibliography on page 27. Retain the TAS scope as a context-dependent postsynaptic organizing effect; the glomerular experiments in this paper are not a direct sodium-channel assay. The short full-text excerpt was verified in the publisher PDF; the copyright notice and article-specific permission route do not provide a license to redistribute the whole article in this repository. The source/page and rights receipt are documented in the notes, without substituting those notes for the original PMID. Supporting Evidence: |
| GO:0043236 laminin binding | TAS PMID:9652404 Primary structure and high expression of human agrin in base... | ACCEPT | Summary: Human agrin retains the laminin-binding N-terminal domain. Reason: The cited human sequence study states that its N-terminal similarity to chick agrin suggests laminin binding. Direct chick domain-binding experiments in PMID:9151673 and the human UniProt domain synthesis corroborate this TAS claim. Do not describe the human sequence paper as a purified-protein binding assay. Supporting Evidence: PMID:9151673 In the current report we show that an NH2-terminal fragment of agrin containing these 130 amino acids is sufficient to bind to Matrigel and that the binding to this preparation is mediated by laminin-1. file:human/AGRN/AGRN-uniprot.txt This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain. |
| GO:0043113 receptor clustering | IDA PMID:15340048 A single pulse of agrin triggers a pathway that acts to clus... | ACCEPT | Summary: Agrin initiates sustained receptor-clustering signaling. Reason: The pulse-and-wash experiment demonstrates that brief agrin exposure can initiate subsequent MuSK/AChR phosphorylation and clustering. This supports an instructive ligand role; continued ligand presence is not required throughout the measured response. Supporting Evidence: PMID:15340048 We also report that a single 5-min agrin pulse, followed by extensive washing, triggered long-lasting MuSK and AChR phosphorylation and efficient AChR clustering. |
| GO:0005200 structural constituent of cytoskeleton | TAS PMID:9652404 Primary structure and high expression of human agrin in base... | UNDECIDED | Summary: The cytoskeletal structural activity cannot be resolved from the accessible source. Reason: GO:0005200 describes contributing to structural integrity of a cytoskeletal structure, which is different from organizing the cytoskeleton through extracellular signaling or matrix attachment. The local human sequence paper is abstract-only and full text was not recovered. Its accessible matrix-localization and NtA-homology results do not settle this exact activity; retain uncertainty rather than categorically reject a curator assertion solely because agrin is extracellular. Agrin also has transmembrane isoforms, and extracellular architecture alone cannot establish that the curator selected an erroneous term; the unresolved issue is the original experimental support for this exact structural activity. Supporting Evidence: PMID:9652404 In this study we present the cDNA sequence of human agrin, and demonstrate a high agrin content in adult basement membranes. |
| GO:0007165 signal transduction | TAS PMID:9652404 Primary structure and high expression of human agrin in base... | ACCEPT | Summary: Agrin supplies an extracellular signal for postsynaptic differentiation. Reason: The TAS source describes the established neuromuscular role, independently mechanistically supported by the LRP4-MuSK study. A broad biological-process signal-transduction annotation is appropriate; it need not be replaced by a molecular-function term from a different GO aspect. Supporting Evidence: PMID:18848351 Here, we report that Lrp4, a member of the LDLR family, is a receptor for Agrin, forms a complex with MuSK, and mediates MuSK activation by Agrin. PMID:9652404 In this study we present the cDNA sequence of human agrin, and demonstrate a high agrin content in adult basement membranes. |
| GO:0043113 receptor clustering | IMP PMID:9151673 Agrin binds to the nerve-muscle basal lamina via laminin | ACCEPT | Summary: Agrin matrix anchoring changes the pattern of receptor clusters. Reason: The full study uses chick agrin fragments and cultured chick myotubes: an N-terminal fragment competes with anchoring and reverses the cluster-size effect of full-length agrin. This is a perturbation of agrin-dependent clustering, not an agrin knockout or a direct human experiment. Conservation of the human NtA domain and independent clustering evidence support retaining the asserted function. Supporting Evidence: PMID:9151673 In the current report we show that an NH2-terminal fragment of agrin containing these 130 amino acids is sufficient to bind to Matrigel and that the binding to this preparation is mediated by laminin-1. PMID:9151673 In addition, we show that the effect of full-length agrin on the size of AChR clusters is reversed in the presence of the NH2-terminal agrin fragment. |
| GO:0050808 synapse organization | TAS PMID:9652404 Primary structure and high expression of human agrin in base... | ACCEPT | Summary: Agrin organizes synapses through signaling and matrix anchoring. Reason: The human sequence/localization paper provides TAS context, while receptor-complex studies and conserved laminin binding identify the underlying organizing functions. Retain the process without upgrading the source into a direct synapse-development experiment. Supporting Evidence: PMID:18848351 Here, we report that Lrp4, a member of the LDLR family, is a receptor for Agrin, forms a complex with MuSK, and mediates MuSK activation by Agrin. file:human/AGRN/AGRN-uniprot.txt This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain. |
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Download this section (compressed HTML)Q: Which primary donor experiments establish noncovalent chondroitin-sulfate or intact heparan-sulfate-proteoglycan binding, separately from covalent GAG attachment and free-glycan binding?
Q: What original rat agrin experiment supports the RNA-polymerase-II-specific transcription annotation, and which synaptic cell context was tested?
Q: Does the human sequence paper support a structural cytoskeletal activity beyond extracellular matrix anchoring and signaling-mediated cytoskeleton organization?
Q: Which PAINT descendant experiment shows that agrin changes the proportion of AChRs in the active form, as required by GO:0030548, separately from receptor clustering, abundance and stabilization? The definition permits indirect interaction.
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