Affinage

AGRN

Agrin · UniProt O00468

Length
2068 aa
Mass
217.3 kDa
Annotated
2026-06-09
100 papers in source corpus 41 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Agrin is a heparan sulfate proteoglycan secreted by motor neurons that serves as the master organizer of postsynaptic differentiation at the neuromuscular junction (NMJ), where its loss in vivo markedly reduces postsynaptic AChR aggregates (PMID:8653788, PMID:2846587). Its synaptogenic activity is conferred by alternatively spliced C-terminal isoforms: a 33-bp B-site insertion present in neuronal agrin is required for AChR-aggregating activity (PMID:1314620, PMID:1314621), and this activity localizes to a C-terminal G-like domain fragment that is functionally separable from the protein's heparin-binding domains (PMID:7860635). Agrin signals through the co-receptor LRP4, which binds agrin directly and recruits the receptor tyrosine kinase MuSK; agrin/LRP4 assemble into a tetrameric complex dependent on the neuronal z8 loop (PMID:22302937), and within an arc-shaped LRP4 central cavity agrin and MuSK are brought together in a 1:1:1 ternary complex that activates MuSK (PMID:18848351, PMID:18957220, PMID:37252960). Downstream, MuSK activation drives tyrosine phosphorylation of the AChR beta subunit—required for clustering and for cytoskeletal anchoring of receptors (PMID:8603924, PMID:11285269)—and activation of the Rho-family GTPases Rac and Cdc42 (PMID:10893268). Distinct agrin isoforms partition functionally: a long-N-terminus isoform is deposited in the basal lamina and is required for NMJ formation, whereas a short-N-terminus form remains cell-associated (PMID:11018052), and proper processing of the SEA domain is needed to sustain NMJ integrity postnatally (PMID:21890498). Beyond the NMJ, agrin functions as a mechanosensing extracellular matrix proteoglycan that stabilizes YAP and antagonizes Hippo signaling through integrin-ILK-PAK1 and Lrp4/MuSK pathways (PMID:28273460), promotes cardiomyocyte division and cardiac regeneration via dystrophin-glycoprotein complex disassembly and YAP/ERK signaling (PMID:28581497), and drives osteochondral regeneration through CREB activation and WNT suppression (PMID:32878982). Agrin also engages diverse cell-type-specific receptors—binding alpha-dystroglycan (PMID:8043271), inhibiting the alpha3 Na+/K+-ATPase to regulate CNS neuronal excitability (PMID:16630822), and activating EphB1 on erythroblasts (PMID:26990660).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1988 Medium

    Established the cellular origin and secretory route of the synapse-organizing factor, showing motor neurons synthesize, concentrate in the Golgi, and release agrin-like molecules that aggregate AChR/AChE on myotubes.

    Evidence Anti-agrin monoclonal staining of motor neuron cell bodies plus AChR/AChE aggregation bioassay

    PMID:2846587

    Open questions at the time
    • Did not identify the molecular receptor mediating aggregation
    • Did not resolve which agrin isoform carries the activity
  2. 1992 High

    Defined the molecular basis of agrin's synaptogenic specificity by showing a 33-bp B-site insertion is required for AChR/AChE aggregating activity, distinguishing active neuronal from inactive isoforms.

    Evidence Expression of alternatively spliced chick cDNAs with functional aggregation assay (two concurrent papers)

    PMID:1314620 PMID:1314621

    Open questions at the time
    • Mechanism by which the B-site insertion confers activity not defined
    • Receptor for the active isoform unknown
  3. 1994 High

    Identified alpha-dystroglycan as the major high-affinity agrin-binding membrane protein, but showed it is not required for neural-agrin-induced AChR clustering, decoupling agrin binding from clustering signaling.

    Evidence Binding assays with purified alpha-dystroglycan, affinity measurement, and antibody blocking in Torpedo/C2 membranes

    PMID:8043271

    Open questions at the time
    • The clustering-competent receptor remained unidentified
    • Functional role of high-affinity dystroglycan binding unresolved
  4. 1995 High

    Mapped the AChR-aggregating activity to a C-terminal G-like fragment and separated it from heparin binding, establishing modular domain functions and a quantitative potency scale.

    Evidence Recombinant truncation series with EC50 measurements and heparin binding assays in chick myotubes; enzymatic demonstration of heparan sulfate chains

    PMID:7852425 PMID:7860635

    Open questions at the time
    • Did not identify the receptor engaging the active fragment
    • Role of heparan sulfate chains in signaling not defined
  5. 1996 High

    Provided in vivo proof that agrin is essential for postsynaptic differentiation and demonstrated that AChR clustering requires tyrosine phosphorylation, linking agrin to a kinase-dependent signaling step.

    Evidence Agrin-null mouse phenotyping; phosphotyrosine immunoblotting of AChR beta subunit with kinase inhibitors in C2 myotubes

    PMID:8603924 PMID:8653788

    Open questions at the time
    • The receptor kinase activated by agrin was not identified
    • Connection between phosphorylation and physical clustering unresolved
  6. 2000 High

    Placed Rho-family GTPases Rac and Cdc42 as critical intracellular transducers downstream of agrin and resolved isoform-specific N-terminal targeting that governs basal lamina deposition required for NMJ formation.

    Evidence Dominant-negative/constitutively active Rac/Cdc42 with GTPase assays; gene-trap ablation of LN-agrin isoform with localization analysis

    PMID:10893268 PMID:11018052

    Open questions at the time
    • How GTPase activation links to AChR cytoskeletal anchoring not fully mapped
    • Upstream receptor connecting agrin to GTPases not defined
  7. 2001 High

    Showed AChR beta-subunit phosphorylation occurs on surface receptors and regulates cytoskeletal anchoring, mechanistically connecting phosphorylation to cluster stability.

    Evidence Tyrosine-minus beta subunit expression, detergent extractability, and clustering quantification in Sol8 myotubes

    PMID:11285269

    Open questions at the time
    • The kinase phosphorylating beta subunit not identified in this study
    • Other phosphorylation substrates not addressed
  8. 2002 Medium

    Dissected calcium requirements, showing extracellular calcium is needed for MuSK complex formation while intracellular calcium acts downstream for beta-subunit phosphorylation and clustering.

    Evidence Differential chelation (EGTA vs BAPTA) with MuSK phosphorylation and AChR clustering assays

    PMID:11748634

    Open questions at the time
    • Molecular target of intracellular calcium not identified
    • Source of intracellular calcium not defined
  9. 2008 High

    Identified LRP4 as the direct agrin receptor that complexes with and activates MuSK, resolving the long-missing receptor link, and showed MuSK endocytosis (regulated by NSF) is required for signaling.

    Evidence Reciprocal Co-IP, heterologous expression, siRNA in myotubes (two labs); MuSK endocytosis and NSF binding/inhibition assays

    PMID:18272689 PMID:18848351 PMID:18957220

    Open questions at the time
    • Structural basis of the agrin-LRP4-MuSK assembly not yet resolved
    • How endocytosis promotes downstream signaling not detailed
  10. 2012 High

    Provided the structural mechanism of agrin-LRP4 recognition, showing tetrameric assembly driven by the neuronal z8 loop is essential for AChR clustering.

    Evidence X-ray crystallography of agrin-LRP4 complex with z8-loop mutagenesis and clustering assays

    PMID:22302937

    Open questions at the time
    • MuSK was not part of this structure
    • How tetramerization triggers MuSK activation unresolved
  11. 2023 High

    Completed the structural model by capturing the agrin/LRP4/MuSK ternary complex, showing arc-shaped LRP4 recruits both agrin and MuSK to enable a direct agrin-MuSK contact that activates the kinase.

    Evidence Cryo-EM of the extracellular ternary complex with defined 1:1:1 stoichiometry

    PMID:37252960

    Open questions at the time
    • Conformational dynamics of activation not resolved
    • Single structural study; transmembrane/intracellular activation steps not visualized

Open questions

Synthesis pass · forward-looking unresolved questions
  • How agrin's many non-NMJ receptor systems (alpha-dystroglycan, alpha3 Na+/K+-ATPase, EphB1, Lrp4-Ror2, NOTCH1) are mechanistically coordinated and whether they share the LRP4-dependent logic of the NMJ remains unresolved.
  • No unifying receptor-engagement model across tissues
  • Several non-NMJ mechanisms rest on single-lab studies without reconstitution
  • Relative contribution of heparan sulfate vs protein-domain interactions across contexts unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0048018 receptor ligand activity 3 GO:0005198 structural molecule activity 1 GO:0008289 lipid binding 1
Localization
GO:0005576 extracellular region 3 GO:0005794 Golgi apparatus 2 GO:0005886 plasma membrane 2 GO:0031012 extracellular matrix 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-112316 Neuronal System 3 R-HSA-1474244 Extracellular matrix organization 3
Partners
ATP1A3DAG1EPHB1LRP4MUSKNCAM1NSFROR2
Complex memberships
agrin/LRP4/MuSK ternary complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Agrin-deficient mutant mice show markedly reduced postsynaptic AChR aggregates in number, size, and density, establishing agrin as a critical organizer of postsynaptic differentiation at the neuromuscular junction in vivo. Genetic knockout (agrin-null mice) with histological and electrophysiological phenotypic readout Cell High 8653788
2008 LRP4 is a direct receptor for agrin and forms a complex with MuSK, mediating MuSK activation and AChR clustering; LRP4 enables agrin binding and MuSK signaling in otherwise non-responsive cells and becomes tyrosine-phosphorylated upon agrin stimulation. Co-immunoprecipitation, pulldown, heterologous expression of LRP4, siRNA knockdown in myotubes, MuSK phosphorylation assay Cell / Neuron High 18848351 18957220
2012 Crystal structure of the agrin-LRP4 complex reveals two agrin-LRP4 heterodimers forming a tetramer; the z8 loop unique to neuronal agrin is required for initial binary complex formation and promotes tetrameric assembly through additional interfaces, which is essential for AChR clustering. X-ray crystallography of agrin-LRP4 complex, mutagenesis of z8 loop, AChR clustering functional assay Genes & development High 22302937
2023 Cryo-EM structure of the agrin/LRP4/MuSK ternary complex (1:1:1 stoichiometry) reveals that arc-shaped LRP4 simultaneously recruits both agrin and MuSK to its central cavity, promoting a direct agrin-MuSK interaction that activates MuSK. Cryo-EM structural determination of extracellular ternary complex Proceedings of the National Academy of Sciences of the United States of America High 37252960
1994 Alpha-dystroglycan is the major agrin-binding protein in Torpedo electric organ and C2 myotube membranes, binding both nerve and muscle agrin isoforms with approximately nanomolar affinity; however, blocking alpha-dystroglycan binding with antibodies did not block AChR clustering by neural agrin. Pulldown/binding assays with purified alpha-dystroglycan, antibody blocking experiments, nanomolar affinity binding measurements Neuron High 8043271
1995 The active site for agrin-induced AChR aggregation maps to a C-terminal fragment containing splice site B and the most C-terminal G-like domain; the B8-containing 45 kDa fragment is sufficient for high activity (EC50 ~130 pM), whereas a smaller 21 kDa fragment retains activity but requires higher concentrations and no longer binds heparin, indicating distinct domains for heparin binding and AChR aggregation. Recombinant truncation mutants and isoform EC50 measurements in chick myotube AChR clustering assay, heparin binding assay The Journal of cell biology High 7860635
1996 Agrin induces rapid tyrosine phosphorylation of the AChR beta subunit prior to cluster formation; inhibition of this phosphorylation by herbimycin or staurosporine blocks agrin-induced AChR clustering, establishing that AChR clustering in mammalian muscle requires tyrosine phosphorylation. Phosphotyrosine immunoblotting of AChR beta subunit, pharmacological kinase inhibitors (herbimycin, staurosporine), AChR clustering assay in mouse C2 myotubes The Journal of cell biology High 8603924
2001 Agrin-induced phosphorylation of the AChR beta subunit occurs only on cell-surface AChR; phosphorylated AChR is preferentially linked to the cytoskeleton (less detergent-extractable), and mutation of the beta subunit tyrosine residues reduces agrin-induced AChR clustering, establishing that beta subunit phosphorylation regulates cytoskeletal anchoring and contributes to clustering. Expression of tagged tyrosine-minus AChR beta subunit in mouse Sol8 myotubes, detergent extractability assay, AChR clustering quantification The Journal of cell biology High 11285269
2000 Agrin causes muscle-specific activation of the Rho-family GTPases Rac and Cdc42; dominant-interfering mutants of either block agrin-induced AChR clustering, while constitutively active mutants aggregate AChRs in the absence of agrin, placing Rac/Cdc42 activation as a critical step downstream of agrin in AChR clustering. Biochemical GTPase activity assays, dominant-negative and constitutively active Rac/Cdc42 expression in myotubes, AChR clustering assay The Journal of cell biology High 10893268
1992 A 33 bp insertion in the chick agrin cDNA (corresponding to the alternatively spliced B site) is required for AChR/AChE aggregating activity; isoforms lacking this insert are inactive. cDNA isolation from chick brain library, expression of recombinant proteins, AChR/AChE aggregation activity assay, in situ hybridization and PCR of motor neuron fractions Neuron High 1314620 1314621
1995 Agrin is a heparan sulfate proteoglycan (HSPG); treatment with heparitinase or nitrous acid shifts its apparent molecular weight, and it binds tightly to anion exchange resins; agrin also interacts with neural cell adhesion molecule (NCAM). Western blotting with enzyme treatment (heparitinase, nitrous acid), anion exchange chromatography, immunocytochemistry, HSPG purification and antibody cross-reactivity The Journal of biological chemistry High 7852425
2000 The murine agrin gene generates two protein isoforms with distinct N-termini (SN-agrin, 49 aa N-term; LN-agrin, 150 aa N-term) that differ in subcellular localization and function: LN-agrin is incorporated into basal laminae and is required for NMJ formation, while SN-agrin remains cell-associated; 'gene trap' ablation of LN-agrin abolishes basal lamina agrin and impairs NMJ formation as severely as full agrin knockout. Gene trap mutagenesis, immunostaining for basal lamina localization, in vitro bioactivity assays, NMJ morphology analysis The Journal of cell biology High 11018052
2006 Agrin binds the alpha3 subunit of the Na+/K+-ATPase (alpha3NKA) in CNS neurons; this interaction inhibits alpha3NKA activity, leading to membrane depolarization and increased action potential frequency in cortical neurons; an agrin fragment acting as competitive antagonist depresses action potential frequency, demonstrating that endogenous agrin regulates native alpha3NKA function. Biochemical binding assays (Co-IP), colocalization at synapses, pharmacological inhibition with agrin fragment as competitive antagonist, electrophysiology in cortical neuron culture and acute slices Cell High 16630822
2017 Agrin promotes cardiomyocyte division through a mechanism involving disassembly of the dystrophin-glycoprotein complex and activation of Yap- and ERK-mediated signaling; recombinant agrin administered in vivo promotes cardiac regeneration after myocardial infarction in adult mice. Recombinant agrin treatment of iPSC-derived cardiomyocytes, western blotting for dystrophin-glycoprotein complex components, YAP/ERK signaling assays, myocardial infarction mouse model with single agrin dose Nature High 28581497
2017 Agrin transduces matrix and cellular rigidity signals to enhance stability and mechanoactivity of YAP by antagonizing focal adhesion assembly of core Hippo components (Merlin and LATS1/2) through ILK-PAK1 signaling, acting through both integrin-focal adhesion and Lrp4/MuSK receptor pathways. Knockdown/overexpression of Agrin in cell lines, YAP nuclear localization assays, LATS1/2 phosphorylation assays, ILK-PAK1 pathway inhibition, traction force microscopy Cell reports Medium 28273460
2001 Agrin is expressed in lymphocytes and induces aggregation of signaling proteins in lipid raft microdomains, reorganizing the immunological synapse and setting the threshold for T cell signaling through a lipid raft pathway. Immunofluorescence/confocal microscopy of lipid raft redistribution, T cell activation assays, agrin expression analysis in lymphocytes Science Medium 11349136
2008 MuSK undergoes rapid internalization (endocytosis) in response to agrin, which is required for agrin-induced AChR clustering; N-ethylmaleimide sensitive factor (NSF) interacts directly with MuSK with nanomolar affinity and regulates MuSK endocytosis and downstream signaling. MuSK endocytosis assays, NSF-MuSK co-immunoprecipitation and affinity measurement, NSF inhibitor (NEM) and dominant-negative NSF expression, AChR clustering assay The Journal of neuroscience Medium 18272689
1998 Both muscle and neural agrin isoforms increase utrophin mRNA and protein in cultured C2 myotubes via transcriptional activation of the utrophin gene promoter; this mechanism requires an N-box motif in the utrophin promoter and is reproduced by in vivo gene transfer. Northern blotting, Western blotting, utrophin promoter-reporter transfection, site-directed mutagenesis of N-box, in vivo gene transfer in muscle The Journal of biological chemistry Medium 9422725
1996 Substrate-bound (but not soluble) agrin induces expression of AChR epsilon-subunit mRNA in cultured rat myotubes through a transcriptional mechanism, independently of the agrin isoform's AChR-clustering activity. Northern hybridization, epsilon-subunit promoter-reporter assay, comparison of substrate-bound vs. soluble agrin, multiple isoform variants Proceedings of the National Academy of Sciences of the United States of America Medium 8650206
2006 Transmembrane agrin (TM-agrin) overexpression induces filopodia-like processes on hippocampal neuron neurites; siRNA suppression of agrin reduces filopodia number; TM-agrin increases Cdc42 activation downstream, suggesting a signaling role for TM-agrin in filopodia regulation. Overexpression of TM-agrin in hippocampal neurons, siRNA knockdown, time-lapse imaging, Cdc42 activation assay (biochemical pull-down) Molecular and cellular neurosciences Medium 16860570
2009 Transmembrane agrin (TM-agrin)-induced filopodia formation requires partitioning into lipid rafts, activating Src family kinase Fyn and subsequently MAPK; disruption of lipid rafts or inhibition of Fyn/MAPK blocks process formation. Lipid raft fractionation, methyl-beta-cyclodextrin depletion, pharmacological inhibition of Fyn and MAPK, western blotting for kinase phosphorylation The Journal of biological chemistry Medium 19139104
2002 Extracellular calcium is required for agrin-induced MuSK activation (formation of MuSK signaling complex), while intracellular calcium (BAPTA-sensitive) is required downstream for AChR beta-subunit tyrosine phosphorylation and AChR clustering. Calcium chelation (EGTA vs. BAPTA), extracellular calcium removal, MuSK phosphorylation assay, AChR clustering assay in myotubes Journal of neurobiology Medium 11748634
2019 Agrin-Lrp4-Ror2 signaling regulates adult hippocampal neurogenesis: Agrin elevation in hippocampus stimulates NSPC proliferation; Agrn deletion in excitatory neurons decreases NSPC proliferation; Lrp4 on NSPCs interacts with and activates receptor tyrosine kinase Ror2, and Ror2 mutation impairs NSPC proliferation. Conditional genetic deletion of Agrn in excitatory neurons, Lrp4 mutation mice, co-IP of Lrp4-Ror2 interaction, BrdU/EdU incorporation for NSPC proliferation, enriched environment behavioral paradigm eLife Medium 31268420
2011 Agrin is expressed by mesenchymal stem cells and osteoblasts in the hematopoietic niche; Lin-Sca1+c-Kit+ (LSK) hematopoietic stem cells express alpha-dystroglycan as a receptor for agrin; agrin-deficient mice show apoptosis of CD34+CD135- LSK cells and impaired hematopoiesis, both reversed by agrin-sufficient stroma. Agrin knockout mouse analysis, flow cytometry, in vitro agrin-deficient MSC co-culture with Lin-c-Kit+ cells, in vivo rescue with agrin-sufficient stroma Blood Medium 21653324
2016 Agrin induces clustering and activation of EphB1 receptors on developing erythroblasts, leading to activation of alpha5beta1 integrins; agrin knockout mice display severe anemia due to defective erythroblast adhesion to macrophages and impaired erythroid cell maturation. Agrin knockout mouse analysis, EphB1 receptor clustering assay, integrin activation assay, erythroblast-macrophage adhesion assay Cell death and differentiation Medium 26990660
2010 The N-terminal follistatin-domain-containing region of agrin (Agrin-Nterm) binds BMP2, BMP4, and TGFbeta1 with affinities in the 10^-8 to 10^-7 M range (KD by SPR); Agrin-Nterm inhibits BMP2 and BMP4 activity in reporter assays (IC50 ~5x10^-7 M) while causing a slight increase in TGFbeta1 activity. Surface plasmon resonance spectroscopy for binding affinities, BMP/TGFbeta reporter assays for functional inhibition PloS one Medium 20505824
2005 Agrin binds alpha-synuclein in a heparan sulfate-dependent manner, induces beta-sheet conformational changes in alpha-synuclein, accelerates protofibril formation, and decreases the half-time of fibril formation; agrin colocalizes with alpha-synuclein in Lewy bodies in the substantia nigra of Parkinson's disease brain. In vitro binding assays (pulldown with heparan sulfate dependency), ThT fluorescence fibril formation kinetics, CD spectroscopy for conformational change, immunohistochemistry/colocalization in PD brain Glycobiology Medium 16037493
2018 Agrin directly interacts with NOTCH1 in lung adenocarcinoma cells, resulting in release of the NOTCH1 intracellular domain and activation of the Notch signaling pathway, which promotes proliferation, migration, invasion, and EMT. Co-immunoprecipitation of AGRN-NOTCH1 interaction, western blotting for NOTCH1 intracellular domain release, Notch pathway inhibitor rescue experiments, in vitro and in vivo tumor assays Pharmacological research Low 37321467
2021 In developing epicardium, agrin promotes epithelial-to-mesenchymal transition (EMT) by decreasing beta-catenin, promoting pFAK localization at focal adhesions, and promoting aggregation of dystroglycan within the Golgi; agrin deletion impairs epicardial EMT and disperses dystroglycan in vivo. Conditional agrin deletion in mice, scanning electron microscopy, immunofluorescence for dystroglycan/pFAK/beta-catenin, human embryonic stem cell-derived epicardial cell assays Development Medium 33969874
2015 Agrin signaling through Lrp4-MuSK forms an oncogenic axis in hepatocellular carcinoma; agrin regulates Arp2/3-dependent ruffling, invadopodia formation, and epithelial-mesenchymal transition through sustained focal adhesion integrity; antibodies targeting agrin reduce oncogenic signaling and tumor growth in vivo. SILAC quantitative proteomics, siRNA knockdown, anti-agrin antibody treatment in mouse xenograft model, focal adhesion integrity assays, invadopodia formation assay Nature communications Medium 25630468
2021 Agrin promotes wound healing by enhancing keratinocyte mechanoperception (augmenting stiffness, traction stress, and fluidic velocity); agrin overhauls cytoskeletal architecture via actomyosin cables upon mechanical stimuli, and Matrix Metalloproteinase-12 (MMP12) is identified as a downstream effector of agrin's mechanoperception pathway. Traction force microscopy, atomic force microscopy for cell stiffness, particle image velocimetry, MMP12 knockdown, agrin recombinant fragment wound healing assay in vivo Nature communications Medium 34732729
1999 BDNF and NT-4 inhibit agrin-induced AChR clustering on cultured myotubes through TrkB receptor activation on muscle cells; direct TrkB activation mimics this inhibition; neutralization of endogenous TrkB ligands increases basal AChR clustering, establishing neurotrophins as physiological regulators of agrin-induced postsynaptic differentiation. AChR clustering assay in myotubes, BDNF/NT-4 treatment, anti-TrkB agonist antibody, TrkB ligand neutralization, dose-response experiments Proceedings of the National Academy of Sciences of the United States of America Medium 9927702
2012 In agrin-deficient mice (lacking agrin everywhere except motor neurons), adult brains show a substantial loss of excitatory synapses, supporting a role for agrin in CNS synapse maintenance; transmembrane agrin is highly expressed in brain and positively regulates dendritic filopodia and excitatory synaptic signaling. Conditional agrin knockout mouse analysis, synapse counting by immunofluorescence, electrophysiology (review citing primary studies) Neurochemistry international Low 22414531
2018 Anti-agrin antibodies are pathogenic: mice immunized with neural agrin (N-agrin) develop myasthenia gravis-like symptoms including muscle weakness, fragmented NMJs, and reduced AChR clustering; anti-N-agrin (but not anti-M-agrin) antibodies block agrin-induced AChR clustering in muscle cells. Active immunization of mice with N-agrin or M-agrin, grip strength and electrophysiology, NMJ morphology, in vitro AChR clustering inhibition assay Neuroscience Medium 29339325
2020 Agrin induces chondrogenic differentiation of joint-resident progenitor cells through simultaneous activation of CREB and suppression of canonical WNT/beta-catenin signaling, inducing GDF5 expression; a single intraarticular injection induces long-lasting osteochondral regeneration in mice. Intraarticular agrin injection in mouse osteochondral defect model, signaling assay (CREB phosphorylation, beta-catenin inhibition), gene expression (GDF5), sheep cartilage regeneration model Science translational medicine Medium 32878982
2006 Agrin is required for motor axon outgrowth and branching in zebrafish; agrin morphants show reduced AChR clusters in dorsal/ventral myotome regions, truncated motor axon outgrowth, and increased motor axon branching, as well as defects in posterior/CNS development. Morpholino knockdown in zebrafish, immunostaining for AChR clusters and axon markers, confocal microscopy Glycobiology Medium 17110391
2011 A point mutation in the SEA domain of AGRIN (F1061S) causes a partial loss-of-function by altering protein processing: decreased glycosylation, altered sensitivity to neurotrypsin and other proteases, and less efficient externalization and secretion, resulting in progressive NMJ degradation postnatally. ENU chemical mutagenesis, mouse genetic model, glycosylation analysis, protease sensitivity assay, protein externalization/secretion assay, NMJ electron microscopy Human molecular genetics Medium 21890498
1988 Motor neurons synthesize agrin-like molecules, concentrate them in the Golgi apparatus, and release them to induce AChR and AChE aggregates on cultured myotubes, consistent with agrin being synthesized by motor neurons and transported to nerve terminals for incorporation into synaptic basal lamina. Anti-agrin monoclonal antibody staining of motor neuron cell bodies (Golgi localization), AChR/AChE aggregation bioassay of motor neuron extracts The Journal of cell biology Medium 2846587
2015 Anti-MuSK autoantibodies (MuSK-IgG) block MuSK-LRP4 interaction in the presence of agrin; MuSK-IgG suppresses agrin/LRP4/MuSK signaling to a greater extent than ColQ; ColQ (acetylcholinesterase anchor) also binds MuSK Ig1 and Ig4 domains and competitively suppresses agrin/LRP4/MuSK signaling. In vitro plate-binding assay for MuSK-LRP4 interaction, passive transfer of MuSK-IgG to Colq-knockout mice, quantitative signaling assays, domain mapping Scientific reports Medium 26355076

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Defective neuromuscular synaptogenesis in agrin-deficient mutant mice. Cell 783 8653788
2008 Lrp4 is a receptor for Agrin and forms a complex with MuSK. Cell 541 18848351
2017 The extracellular matrix protein agrin promotes heart regeneration in mice. Nature 529 28581497
2008 LRP4 serves as a coreceptor of agrin. Neuron 445 18957220
1991 Structure and expression of a rat agrin. Neuron 277 1851019
1994 Dystroglycan binds nerve and muscle agrin. Neuron 242 8043271
1992 The agrin gene codes for a family of basal lamina proteins that differ in function and distribution. Neuron 236 1314621
1995 Agrin is a heparan sulfate proteoglycan. The Journal of biological chemistry 226 7852425
1995 Acetylcholine receptor-aggregating activity of agrin isoforms and mapping of the active site. The Journal of cell biology 216 7860635
2017 Agrin as a Mechanotransduction Signal Regulating YAP through the Hippo Pathway. Cell reports 193 28273460
1992 cDNA that encodes active agrin. Neuron 193 1314620
1998 Agrin orchestrates synaptic differentiation at the vertebrate neuromuscular junction. Trends in neurosciences 167 9464682
2001 Physiological regulation of the immunological synapse by agrin. Science (New York, N.Y.) 149 11349136
2012 Structural basis of agrin-LRP4-MuSK signaling. Genes & development 146 22302937
2000 Agrin and microvascular damage in Alzheimer's disease. Neurobiology of aging 142 10867220
2000 Agrin isoforms with distinct amino termini: differential expression, localization, and function. The Journal of cell biology 139 11018052
1996 Agrin-induced acetylcholine receptor clustering in mammalian muscle requires tyrosine phosphorylation. The Journal of cell biology 138 8603924
2015 An oncogenic role of Agrin in regulating focal adhesion integrity in hepatocellular carcinoma. Nature communications 131 25630468
2000 Agrin-induced acetylcholine receptor clustering is mediated by the small guanosine triphosphatases Rac and Cdc42. The Journal of cell biology 128 10893268
1988 Motor neurons contain agrin-like molecules. The Journal of cell biology 128 2846587
2014 Anti-agrin autoantibodies in myasthenia gravis. Neurology 117 24793185
1988 Regulation of agrin-induced acetylcholine receptor aggregation by Ca++ and phorbol ester. The Journal of cell biology 115 2839519
2014 Autoantibodies to agrin in myasthenia gravis patients. PloS one 113 24632822
1993 Functions of agrin and agrin-related proteins. Trends in neurosciences 113 7680504
1992 Structure and chromosomal localization of the mammalian agrin gene. The Journal of neuroscience : the official journal of the Society for Neuroscience 105 1326608
1989 Agrin-related molecules are concentrated at acetylcholine receptor clusters in normal and aneural developing muscle. The Journal of cell biology 102 2538482
1997 Neural agrin induces ectopic postsynaptic specializations in innervated muscle fibers. The Journal of neuroscience : the official journal of the Society for Neuroscience 101 9254666
2001 Agrin-induced phosphorylation of the acetylcholine receptor regulates cytoskeletal anchoring and clustering. The Journal of cell biology 98 11285269
1994 Building synapses: agrin and dystroglycan stick together. Trends in neurosciences 98 7531888
2006 Alpha3Na+/K+-ATPase is a neuronal receptor for agrin. Cell 96 16630822
2000 Expression of agrin, dystroglycan, and utrophin in normal renal tissue and in experimental glomerulopathies. The American journal of pathology 89 10793086
2018 Oncogenic Properties of NEAT1 in Prostate Cancer Cells Depend on the CDC5L-AGRN Transcriptional Regulation Circuit. Cancer research 82 29871935
1999 Agrin in Alzheimer's disease: altered solubility and abnormal distribution within microvasculature and brain parenchyma. Proceedings of the National Academy of Sciences of the United States of America 82 10339611
2020 Agrin Promotes Coordinated Therapeutic Processes Leading to Improved Cardiac Repair in Pigs. Circulation 81 32508131
1998 Muscle and neural isoforms of agrin increase utrophin expression in cultured myotubes via a transcriptional regulatory mechanism. The Journal of biological chemistry 81 9422725
1996 Substrate-bound agrin induces expression of acetylcholine receptor epsilon-subunit gene in cultured mammalian muscle cells. Proceedings of the National Academy of Sciences of the United States of America 76 8650206
1999 Neurotrophins regulate agrin-induced postsynaptic differentiation. Proceedings of the National Academy of Sciences of the United States of America 74 9927702
2000 Laminin and alpha7beta1 integrin regulate agrin-induced clustering of acetylcholine receptors. Journal of cell science 73 10910772
1999 Formation of the neuromuscular junction. Agrin and its unusual receptors. European journal of biochemistry 69 10491152
2020 Clinical features of LRP4/agrin-antibody-positive myasthenia gravis: A multicenter study. Muscle & nerve 68 32483837
1997 Sequential roles of agrin, MuSK and rapsyn during neuromuscular junction formation. Current opinion in neurobiology 68 9232805
2012 Structural mechanisms of the agrin-LRP4-MuSK signaling pathway in neuromuscular junction differentiation. Cellular and molecular life sciences : CMLS 67 23178848
1997 Expression of agrin in the developing and adult rat brain. Neuroscience 66 9015340
1998 Primary structure and high expression of human agrin in basement membranes of adult lung and kidney. European journal of biochemistry 65 9652404
2005 Agrin binds alpha-synuclein and modulates alpha-synuclein fibrillation. Glycobiology 63 16037493
2012 Dynamics of expression patterns of AQP4, dystroglycan, agrin and matrix metalloproteinases in human glioblastoma. Cell and tissue research 57 22307776
2018 Collagen 18 and agrin are secreted by neural crest cells to remodel their microenvironment and regulate their migration during enteric nervous system development. Development (Cambridge, England) 56 29678817
2012 The role of agrin in synaptic development, plasticity and signaling in the central nervous system. Neurochemistry international 56 22414531
1995 The alpha-dystroglycan-beta-dystroglycan complex. Membrane organization and relationship to an agrin receptor. The Journal of biological chemistry 56 7592785
2015 Collagen Q and anti-MuSK autoantibody competitively suppress agrin/LRP4/MuSK signaling. Scientific reports 54 26355076
2002 The agrin/muscle-specific kinase pathway: new targets for autoimmune and genetic disorders at the neuromuscular junction. Muscle & nerve 54 11754179
1993 Developmental expression and alternative splicing of chick agrin RNA. Developmental biology 54 8393816
2020 Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis. Science translational medicine 52 32878982
2018 Linking Extracellular Matrix Agrin to the Hippo Pathway in Liver Cancer and Beyond. Cancers 51 29415512
1996 Agrin is synthesized by retinal cells and colocalizes with gephyrin [corrected]. Molecular and cellular neurosciences 49 8923451
2021 Agrin-Matrix Metalloproteinase-12 axis confers a mechanically competent microenvironment in skin wound healing. Nature communications 48 34732729
1993 Muscle agrin: neural regulation and localization at nerve-induced acetylcholine receptor clusters. The Journal of neuroscience : the official journal of the Society for Neuroscience 48 8388922
2017 Agrin-LRP4-MuSK signaling as a therapeutic target for myasthenia gravis and other neuromuscular disorders. Expert opinion on therapeutic targets 47 28825343
2014 Agrin and perlecan mediate tumorigenic processes in oral squamous cell carcinoma. PloS one 47 25506919
2019 Agrin-Lrp4-Ror2 signaling regulates adult hippocampal neurogenesis in mice. eLife 45 31268420
2012 Neuregulin-1 potentiates agrin-induced acetylcholine receptor clustering through muscle-specific kinase phosphorylation. Journal of cell science 43 22328506
2011 The critical role of agrin in the hematopoietic stem cell niche. Blood 43 21653324
2011 Apoptosis inhibitors and mini-agrin have additive benefits in congenital muscular dystrophy mice. EMBO molecular medicine 43 21674808
2006 Transmembrane agrin regulates filopodia in rat hippocampal neurons in culture. Molecular and cellular neurosciences 42 16860570
2003 Expression of mouse agrin in normal, denervated and dystrophic muscle. Neuromuscular disorders : NMD 42 12798796
1996 Agrin: an extracellular matrix heparan sulfate proteoglycan involved in cell interactions and synaptogenesis. Perspectives on developmental neurobiology 42 9117266
2017 Screening for lipoprotein receptor-related protein 4-, agrin-, and titin-antibodies and exploring the autoimmune spectrum in myasthenia gravis. Journal of neurology 41 28516329
2008 Muscle-specific receptor tyrosine kinase endocytosis in acetylcholine receptor clustering in response to agrin. The Journal of neuroscience : the official journal of the Society for Neuroscience 41 18272689
1997 Differential distribution of agrin isoforms in the developing and adult avian retina. Molecular and cellular neurosciences 40 9532577
2011 A valid mouse model of AGRIN-associated congenital myasthenic syndrome. Human molecular genetics 39 21890498
2006 Agrin is required for posterior development and motor axon outgrowth and branching in embryonic zebrafish. Glycobiology 38 17110391
2002 Agrin in the CNS: a protein in search of a function? Neuroreport 37 12218692
2020 Agrin Mediates Angiogenesis in the Tumor Microenvironment. Trends in cancer 36 32061308
2001 Decreased glomerular expression of agrin in diabetic nephropathy and podocytes, cultured in high glucose medium. Experimental nephrology 36 11340306
2012 Agrin is required for survival and function of monocytic cells. Blood 35 22517892
2008 Agrin expression during synaptogenesis induced by traumatic brain injury. Journal of neurotrauma 35 18627255
2006 Agrin is involved in lymphocytes activation that is mediated by alpha-dystroglycan. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 34 16394267
2018 Agrin has a pathological role in the progression of oral cancer. British journal of cancer 33 29872149
1999 Expression, distribution and ultrastructural localization of the synapse-organizing molecule agrin in the mature avian retina. The European journal of neuroscience 32 10594644
2021 The extracellular matrix protein agrin is essential for epicardial epithelial-to-mesenchymal transition during heart development. Development (Cambridge, England) 30 33969874
2003 Expression of Trisk 51, agrin and nicotinic-acetycholine receptor epsilon-subunit during muscle development in a novel three-dimensional muscle-neuronal co-culture system. Cell and tissue research 29 12955494
2018 Induction of Anti-agrin Antibodies Causes Myasthenia Gravis in Mice. Neuroscience 28 29339325
2018 Agrin and LRP4 antibodies as new biomarkers of myasthenia gravis. Annals of the New York Academy of Sciences 28 29377176
2020 Agrin Promotes Limbal Stem Cell Proliferation and Corneal Wound Healing Through Hippo-Yap Signaling Pathway. Investigative ophthalmology & visual science 27 32392315
2017 A Novel Missense Variant in the AGRN Gene; Congenital Myasthenic Syndrome Presenting With Head Drop. Journal of clinical neuromuscular disease 27 28221305
2006 Neural agrin: a synaptic stabiliser. The international journal of biochemistry & cell biology 27 17126587
2021 Characterization of LRP4/Agrin Antibodies From a Patient With Myasthenia Gravis. Neurology 26 34233932
2009 Transmembrane form agrin-induced process formation requires lipid rafts and the activation of Fyn and MAPK. The Journal of biological chemistry 26 19139104
2007 Agrin and laminin induce acetylcholine receptor clustering by convergent, Rho GTPase-dependent signaling pathways. Journal of cell science 26 17298982
2002 Dual role for calcium in agrin signaling and acetylcholine receptor clustering. Journal of neurobiology 26 11748634
2002 Modulation of agrin binding and activity by the CT and related carbohydrate antigens. Molecular and cellular neurosciences 26 11988021
1997 Sequence and functional relationships between androgen-binding protein/sex hormone-binding globulin and its homologs protein S, Gas6, laminin, and agrin. Steroids 26 9292933
2023 AGRN promotes lung adenocarcinoma progression by activating Notch signaling pathway and acts as a therapeutic target. Pharmacological research 25 37321467
2015 Combination of agrin and laminin increase acetylcholine receptor clustering and enhance functional neuromuscular junction formation In vitro. Developmental neurobiology 25 26251299
2006 Agrin is highly expressed by chondrocytes and is required for normal growth. Histochemistry and cell biology 25 17186266
2005 The effect of agrin and laminin on acetylcholine receptor dynamics in vitro. Developmental biology 25 16256100
2023 Structural insights into the assembly of the agrin/LRP4/MuSK signaling complex. Proceedings of the National Academy of Sciences of the United States of America 24 37252960
2016 Identification of a novel agrin-dependent pathway in cell signaling and adhesion within the erythroid niche. Cell death and differentiation 24 26990660
2010 Agrin binds BMP2, BMP4 and TGFbeta1. PloS one 24 20505824
2020 Agrin promotes the proliferation, invasion and migration of rectal cancer cells via the WNT signaling pathway to contribute to rectal cancer progression. Journal of receptor and signal transduction research 23 32862766

Missed literature

Know a paper Affinage missed for AGRN? Flag it for the maintainers and the community.

No submissions yet.