Affinage

MUSK

Muscle, skeletal receptor tyrosine-protein kinase · UniProt O15146

Length
869 aa
Mass
97.1 kDa
Annotated
2026-06-10
100 papers in source corpus 42 papers cited in narrative 42 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

MuSK is a muscle-specific receptor tyrosine kinase that serves as the master organizer of the neuromuscular junction, where it is essential for postsynaptic membrane organization, synapse-specific transcription, and presynaptic differentiation (PMID:8653786, PMID:18084289). At the synapse MuSK is activated by neural agrin acting not directly but through the co-receptor Lrp4, which binds agrin and physically recruits MuSK; cryo-EM of the ternary complex shows arc-shaped Lrp4 simultaneously engaging agrin and MuSK in its central cavity to drive a direct agrin–MuSK contact, with a neuronal-agrin-specific z8 loop promoting the higher-order tetrameric assembly required for AChR clustering (PMID:18848351, PMID:22302937, PMID:37252960). Receptor activation proceeds through the intracellular adaptor Dok-7, which binds the MuSK juxtamembrane NPXY phosphotyrosine (Y553) and dimerizes to drive trans-autophosphorylation of activation-loop tyrosines (PMID:19244212, PMID:20603078, PMID:10619845); MuSK kinase activity alone is the initiating and instructive signal sufficient to cluster AChRs and induce synapse-specific transcription, and the basal kinase is autoinhibited by an occluding activation loop until autophosphorylation produces a large catalytic activation (PMID:11748247, PMID:12220490, PMID:10781064). Once active, MuSK forms the primary postsynaptic scaffold, anchoring rapsyn, the AChE-tethering ColQ, and the extracellular matrix protein biglycan to stabilize the receptor apparatus, while CK2-mediated serine phosphorylation of the MuSK kinase insert supports AChR clustering (PMID:9136771, PMID:15159418, PMID:22396407, PMID:16818610). Signaling is restrained by N-linked glycosylation and by the Shp2 phosphatase, and MuSK expression is itself controlled at the promoter through Wnt, agrin/Rac, and CREB/MyoD inputs that establish a feedback loop maintaining synaptic localization (PMID:12399462, PMID:15737732, PMID:12885777, PMID:15964791, PMID:12756238). Beyond its kinase function, MuSK acts as a kinase-independent BMP co-receptor that associates with the type I receptors ALK3/ALK6 and binds BMP4 to promote SMAD signaling in muscle (PMID:27601729). Human MuSK mutations cause congenital myasthenic syndrome by impairing receptor stability or signaling (PMID:15496425, PMID:23326516), and IgG4 autoantibodies against the Ig1 domain cause MuSK myasthenia gravis by blocking the MuSK–Lrp4 interaction, with Fab-arm-exchange-derived functional monovalency converting otherwise agonistic antibodies into potent pathogenic antagonists (PMID:24297891, PMID:30882021, PMID:33753489).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1996 High

    Established that MuSK is indispensable for neuromuscular synapse formation, defining it as a non-redundant organizer rather than a modulator.

    Evidence Targeted MuSK knockout mice with histology and electrophysiology, plus agrin receptor-complex biochemistry in MuSK-null myotubes

    PMID:8653786 PMID:8653787

    Open questions at the time
    • Did not identify the agrin-binding accessory component
    • Did not resolve which downstream effectors mediate clustering
  2. 1997 High

    Resolved that MuSK forms the primary structural scaffold and does not phosphorylate AChR directly, acting through other kinases and recruiting rapsyn-dependent components.

    Evidence Rapsyn-knockout mouse analysis, reciprocal immunoprecipitation from C2 myotubes, and kinase-inhibitor dissection

    PMID:8630253 PMID:9136771 PMID:9305637

    Open questions at the time
    • Identity of the AChR-phosphorylating kinase downstream of MuSK unresolved
    • Mechanism of rapsyn–MuSK ectodomain coupling not structurally defined
  3. 2000 High

    Mapped the functional phosphotyrosine code of MuSK, showing the juxtamembrane NPXY (Y553) and activation-loop tyrosines are essential and that the juxtamembrane region is a sufficient effector-recruitment site.

    Evidence Site-directed mutagenesis, MuSK-TrkA chimeras in MuSK-null myotubes, and dual mass-spectrometry phosphomapping of recombinant and endogenous Torpedo MuSK

    PMID:10619845 PMID:10781064

    Open questions at the time
    • PTB-domain effector binding Y553 not yet identified in this work
    • Functional weight of individual non-activation-loop tyrosines unclear
  4. 2001 High

    Demonstrated that MuSK kinase activity alone is the initiating instructive signal, separable from ligand and ectodomain, for AChR clustering and synapse-specific transcription.

    Evidence In vivo single-fiber gene transfer with kinase-dead controls and conditional kinase-domain deletion in MuSK-loxP mice

    PMID:11748247

    Open questions at the time
    • Did not explain how kinase activity is normally triggered in the absence of forced expression
    • Downstream transcriptional machinery not defined
  5. 2002 High

    Provided the structural and kinetic basis for MuSK autoinhibition and activation, and revealed glycosylation as a brake on ligand-independent signaling.

    Evidence Crystal structure of the unphosphorylated cytoplasmic domain with steady-state kinetics; N-glycosylation site mutagenesis with functional readouts in null myotubes

    PMID:12220490 PMID:12399462

    Open questions at the time
    • Structure did not capture the activated/phosphorylated state with bound effectors
    • Mechanism linking glycosylation to autoinhibition not defined
  6. 2003 Medium

    Identified transcriptional control loops that maintain synaptic MuSK expression via Wnt and agrin-driven pathways.

    Evidence MuSK promoter-reporter assays in vivo and in myotubes with Wnt, NRG/ErbB, and Rac signaling components

    PMID:12756238 PMID:12885777

    Open questions at the time
    • Direct transcription factors at the promoter elements not all defined
    • Relative in vivo contribution of each pathway unquantified
  7. 2004 High

    Established MuSK as a direct scaffold for ColQ-anchored AChE and linked MuSK mutations to congenital myasthenic syndrome pathology.

    Evidence Cross-linking/co-IP from Torpedo membranes and transfection reconstitution; in vitro kinase assays plus in vivo electroporation of patient mutations

    PMID:15159418 PMID:15496425

    Open questions at the time
    • ColQ-binding interface on MuSK not structurally resolved here
    • Genotype–phenotype range of MuSK CMS mutations incomplete
  8. 2005 Medium

    Identified negative regulators (Shp2) and additional transcriptional repression (CREB/MyoD) that constrain MuSK signaling output.

    Evidence Shp2 RNAi and pervanadate assays in C2 myotubes; promoter-reporter, EMSA, co-IP, and siRNA for CREB

    PMID:15737732 PMID:15964791

    Open questions at the time
    • Whether Shp2 dephosphorylates MuSK directly not established
    • Physiological trigger of CREB-mediated repression unclear
  9. 2006 High

    Defined CK2 as a serine kinase acting on the MuSK kinase insert required for AChR clustering, adding a serine-phosphorylation layer to MuSK signaling.

    Evidence Co-IP, in vitro kinase assays, phosphosite mutagenesis, siRNA, and muscle-specific CK2β knockout mice

    PMID:16818610

    Open questions at the time
    • How kinase-insert serine phosphorylation alters MuSK conformation or partner binding unresolved
  10. 2007 High

    Showed postsynaptic MuSK is prepatterned and instructive, capable of directing synapse formation and rescuing agrin-null lethality.

    Evidence Transgenic ectopic MuSK expression and Agrn-null;MuSK-transgene genetic crosses with NMJ histology

    PMID:18084289

    Open questions at the time
    • Mechanism of agrin-independent MuSK prepatterning activation not defined
  11. 2008 High

    Identified Lrp4 as the agrin receptor that couples agrin to MuSK, resolving the long-missing accessory component.

    Evidence Affinity binding, co-IP, AChR clustering, and genetic studies

    PMID:18848351

    Open questions at the time
    • Stoichiometry and structural arrangement of agrin–Lrp4–MuSK not yet defined
  12. 2010 High

    Established Dok-7 as the intracellular activator of MuSK and provided the structural mechanism by which dimeric Dok-7 drives trans-autophosphorylation.

    Evidence Co-IP and MuSK phosphorylation assays with in vivo overexpression; crystal structure of Dok-7 PH-PTB bound to the MuSK NPXY phosphopeptide

    PMID:19244212 PMID:20603078

    Open questions at the time
    • How agrin/Lrp4 engagement licenses Dok-7 recruitment not mechanistically linked
  13. 2012 High

    Resolved the extracellular assembly logic, showing neuronal-agrin-specific tetrameric agrin–Lrp4 complexes drive clustering, and identified biglycan as a MuSK-stabilizing matrix partner.

    Evidence Crystal structure of agrin-LRP4 with tetramer-disrupting mutants; biglycan binding, biglycan-null mice, and rescue with purified protein

    PMID:22302937 PMID:22396407

    Open questions at the time
    • Position of MuSK within the higher-order complex not captured
    • Biglycan's signaling contribution beyond stabilization unclear
  14. 2012 Medium

    Revealed conserved non-NMJ roles for MuSK in Wnt/PCP-driven neural crest migration and receptor trafficking to recycling endosomes.

    Evidence Zebrafish morpholino knockdown and MuSK knockout mice with F-actin and trafficking live imaging

    PMID:21750038 PMID:22318632

    Open questions at the time
    • Whether endosomal trafficking role generalizes to mammalian NMJ untested
    • Wnt11r as a direct MuSK ligand not biochemically proven
  15. 2015 High

    Demonstrated the MuSK Frizzled-like cysteine-rich domain mediates Wnt-dependent prepatterning, with GSK-3 inhibition rescuing CRD-deletion defects.

    Evidence MuSK-ΔCRD knock-in mice with morphological/electrophysiological NMJ analysis and lithium chloride rescue

    PMID:25810523

    Open questions at the time
    • Direct Wnt ligand engaging the CRD at the mammalian NMJ not identified
  16. 2016 High

    Established a kinase-independent function of MuSK as a BMP co-receptor shaping SMAD/Id1 transcriptional output in muscle.

    Evidence BMP4 binding affinity, co-IP with ALK3/ALK6, SMAD phosphorylation, expression profiling, and kinase-dead MuSK analysis

    PMID:27601729

    Open questions at the time
    • In vivo physiological consequence of MuSK BMP co-receptor activity not established
    • Relationship between BMP and kinase functions of MuSK unresolved
  17. 2023 High

    Defined the complete activation assembly mechanism, showing Lrp4 simultaneously recruits agrin and MuSK to enable a direct agrin–MuSK contact.

    Evidence Cryo-EM structure of the agrin/LRP4/MuSK ternary complex at 1:1:1 stoichiometry

    PMID:37252960

    Open questions at the time
    • How extracellular assembly is transmitted to intracellular trans-autophosphorylation not structurally captured
    • Full-length, membrane-embedded complex not resolved
  18. 2021 High

    Defined the molecular basis of MuSK myasthenia gravis, showing Ig1-targeting IgG4 blocks MuSK–Lrp4 and that Fab-arm-exchange-derived monovalency converts antibodies from agonists into pathogenic antagonists.

    Evidence Epitope mapping, MuSK-Lrp4 and phosphorylation assays, recombinant patient-derived monovalent vs. bivalent antibodies, and passive transfer in mice

    PMID:24297891 PMID:30882021 PMID:33753489

    Open questions at the time
    • In vivo prevalence and dynamics of Fab-arm exchange in patients not quantified here
    • Therapeutic exploitation of valency not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the extracellular agrin/Lrp4/MuSK assembly is mechanically coupled to intracellular Dok-7-driven trans-autophosphorylation, and how the kinase versus BMP co-receptor functions of MuSK are coordinated in vivo, remains unresolved.
  • No structure of the full-length transmembrane complex in an activated state
  • In vivo role of the BMP co-receptor function uncharacterized
  • Transmembrane signal transmission mechanism unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0005198 structural molecule activity 3 GO:0016740 transferase activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3 R-HSA-112316 Neuronal System 2
Partners
BGNCOLQCSNK2BDOK7ERBINLRP4PTPN11RAPSN
Complex memberships
MuSK–ALK3/ALK6 BMP co-receptor complexMuSK–Erbin–ErbB2 complexagrin–LRP4–MuSK ternary complex

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 MuSK is required for neuromuscular junction formation in vivo: mice with targeted disruption of MuSK fail to form neuromuscular synapses, demonstrating MuSK is essential for all aspects of synapse formation including postsynaptic membrane organization, synapse-specific transcription, and presynaptic differentiation. Targeted gene disruption (knockout mouse), histology, electrophysiology Cell High 8653786
1996 Agrin acts via a receptor complex that includes MuSK as well as a myotube-specific accessory component; agrin stimulates MuSK phosphorylation and downstream AChR clustering. Receptor binding assays, phosphorylation assays, genetic complementation using MuSK knockout myotubes Cell High 8653787
1996 Rapsyn clusters and activates MuSK in transfected non-muscle cells: rapsyn induces MuSK clustering, stimulates MuSK autophosphorylation, and MuSK-dependent phosphorylation of the AChR beta subunit. Transfection of QT-6 fibroblasts, co-clustering assay, phosphorylation assay Neuron Medium 8630253
1997 Rapsyn is required for an early step in MuSK signaling (AChR phosphorylation) and recruits synaptic components to a MuSK-containing scaffold; rapsyn–MuSK interactions are mediated by the MuSK ectodomain; MuSK remains concentrated at synaptic sites in rapsyn-deficient mice, indicating MuSK forms the primary structural scaffold. Rapsyn-knockout mouse analysis, non-muscle cell transfection, co-clustering assay, immunolocalization Neuron High 9136771
1997 MuSK is physically associated with the AChR in mammalian muscle, and this association is increased by agrin treatment; agrin causes a transient activation of AChR-associated MuSK; MuSK is not directly responsible for AChR phosphorylation but acts through other kinases. Immunoprecipitation from C2 myotubes, phosphorylation time-course assay, kinase inhibitor experiments The EMBO journal Medium 9305637
1997 Agonist single-chain antibodies (scFv) that induce MuSK dimerization stimulate MuSK tyrosine phosphorylation and AChR clustering in myotubes, providing direct evidence that MuSK activation is sufficient to trigger AChR clustering. Phage display scFv library screen, Ba/F3 proliferation assay, MuSK phosphorylation assay, AChR clustering assay in myotubes Nature biotechnology Medium 9255792
1998 MuSK is co-distributed with AChRs at the developing motor endplate from the earliest observable clusters; MuSK expression is regulated by innervation and muscle activity, and is extrajunctionally upregulated by denervation or paralysis. Immunohistochemistry, in situ hybridization, denervation/reinnervation experiments in adult rodent muscle Developmental biology Medium 9698449
1998 Laminin-induced AChR aggregation does not involve phosphorylation of MuSK or AChR beta subunit, demonstrating a MuSK-independent pathway for AChR clustering mediated by laminin and alpha-dystroglycan. MuSK phosphorylation assay, AChR clustering assay in C2 myotubes with laminin, anti-dystroglycan antibody blocking The Journal of neuroscience Medium 9454835
1999 A MuSK splice variant lacking the third Ig-like domain is expressed at ~10-fold lower levels; overexpression of both MuSK forms causes AChR clustering, demonstrating that the third Ig-like domain is dispensable for kinase-induced AChR clustering. RT-PCR, gene transfer into individual muscle fibers in vivo, AChR clustering assay FEBS letters Medium 9928988
2000 The juxtamembrane tyrosine of MuSK (within an NPXY motif, Y553) is phosphorylated in vivo by agrin stimulation and is essential for agrin-stimulated AChR phosphorylation and clustering; activation loop tyrosines are also essential; the NPXY-containing juxtamembrane region functions as a phosphotyrosine-binding domain recruitment site sufficient to activate MuSK signaling. Site-directed mutagenesis, MuSK-TrkA chimera expression in MuSK−/− myotubes, phosphorylation and AChR clustering assays The EMBO journal High 10619845
2000 Six intracellular tyrosines are phosphorylated in activated MuSK: juxtamembrane Y553, activation loop Y750/Y754/Y755, Y576 near the kinase domain N-lobe, and C-terminal lobe Y812; these phosphorylation sites correlate with functional signaling requirements. In vitro kinase assay with baculovirus-expressed MuSK + MALDI-MS; endogenous MuSK from Torpedo electric organ analyzed by nanoelectrospray tandem MS Proceedings of the National Academy of Sciences of the United States of America High 10781064
2001 MuSK kinase activity alone, without its ectodomain or exogenous agrin, is sufficient to induce AChR clusters and epsilon-subunit-specific transcripts in vivo; kinase-inactive MuSK fails to cluster AChRs, establishing that MuSK kinase activity is the initiating signal. In vivo gene transfer into single rat muscle fibers, conditional kinase-domain deletion with Cre recombinase in MuSK-loxP mice, AChR clustering assay The Journal of cell biology High 11748247
2002 Crystal structure of the unphosphorylated MuSK cytoplasmic domain at 2.05 Å reveals an autoinhibited kinase with the activation loop occluding ATP and substrate binding; autophosphorylation produces a 200-fold increase in kcat and 10-fold decrease in Km for ATP. X-ray crystallography, steady-state kinetic analysis Structure High 12220490
2002 N-linked glycosylation of MuSK restrains ligand-independent tyrosine phosphorylation and downstream signaling, but is not required for agrin to stimulate MuSK; glycosylation sites identified in the ectodomain. N-glycosylation site mutagenesis, MuSK expression in MuSK−/− myotubes, phosphorylation and AChR clustering assays The Journal of biological chemistry Medium 12399462
2002 The juxtamembrane region of MuSK (including a single phosphotyrosine docking site) is sufficient to restore presynaptic and postsynaptic differentiation in MuSK-null mice when expressed as a MuSK/TrkA chimeric receptor, demonstrating that this region activates multiple downstream pathways for NMJ formation. Transgenic chimeric receptor rescue of MuSK knockout mice, morphological and behavioral assessment Development High 12403715
2003 Neuronal agrin activates MuSK to regulate musk gene expression via two pathways: (1) agrin-induced NRG-1/ErbB assembly, and (2) a direct pathway via Agrin-induced Rac activation; both converge on the same regulatory element in the musk promoter, establishing a positive feedback loop maintaining MuSK expression at the synapse. musk promoter-reporter transfection in muscle fibers in vivo and in myotubes, co-transfection of signaling components The Journal of cell biology Medium 12756238
2003 Wnt signaling increases MuSK expression in muscle cells via an E-box-like cis-element in the MuSK promoter; neuregulin does not regulate MuSK promoter activity, identifying a Wnt-dependent mechanism for MuSK synapse-specific expression. MuSK promoter-reporter assay in muscle cells, Wnt stimulation, deletion and mutation analysis of promoter elements The Journal of biological chemistry Medium 12885777
2004 ColQ (collagenic tail of AChE) directly binds MuSK; cross-linking and immunoprecipitation of Torpedo postsynaptic membranes and transfection of MuSK constructs in MuSK-deficient myotubes demonstrate a ColQ–MuSK interaction required for AChE synaptic clustering. Cross-linking/co-immunoprecipitation from Torpedo postsynaptic membranes, MuSK transfection in MuSK-deficient myotubes, COS-7 cell transfection The Journal of cell biology High 15159418
2004 A missense MuSK mutation (V790M) does not affect MuSK catalytic kinase activity but diminishes MuSK expression and stability, leading to decreased agrin-dependent AChR aggregation; a frameshift mutation abolishes MuSK expression; overexpression of the missense mutant in mouse muscle recapitulates patient NMJ pathology. In vitro kinase activity assay, AChR aggregation assay, in vivo electroporation in mouse muscle Human molecular genetics Medium 15496425
2005 CREB1 binds a CRE-like element in the MuSK promoter to attenuate MuSK expression; CREB also interacts directly with MyoD to inhibit MuSK promoter activity via a CRE-independent mechanism; siRNA knockdown of CREB increases MuSK promoter activity. Promoter-reporter assays, EMSA, CREB-MyoD co-immunoprecipitation, siRNA knockdown Molecular and cellular biology Medium 15964791
2005 Cell-surface MuSK complexes with agrin form a stop signal that selectively inhibits motor neurite (ciliary ganglion) outgrowth; an antibody to the MuSK extracellular domain completely reverses inhibition, and partial reversal by anti-agrin antibody implicates an agrin/MuSK complex. Co-culture of ciliary ganglion neurons with MuSK-expressing non-muscle cells, antibody blocking, neurite outgrowth assay Molecular and cellular neurosciences Medium 15691710
2005 Tyrosine phosphatase Shp2 negatively regulates MuSK activation; Shp2 knockdown by RNAi increases both agrin-independent and agrin-dependent AChR clustering in myotubes; MuSK activation stimulates downstream tyrosine phosphatases that feedback to suppress MuSK. Pervanadate treatment, anti-MuSK antibody-bead focal activation, Shp2 siRNA knockdown, AChR clustering assay in C2 myotubes Molecular and cellular neurosciences Medium 15737732
2006 CK2 interacts and colocalizes with MuSK at postsynaptic specializations; CK2 phosphorylates serine residues in the MuSK kinase insert; CK2 inhibition or phosphoserine-to-alanine mutations impair AChR clustering; muscle-specific CK2β knockout mice develop a myasthenic phenotype with impaired endplate structure. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, CK2 siRNA knockdown, CK2β muscle-specific knockout mice Genes & development High 16818610
2006 MuSK is expressed in hippocampal neurons and is required for memory consolidation; hippocampal MuSK knockdown after training impairs memory retention, prevents learning-dependent CREB phosphorylation and C/EBPβ expression, and blocks LTP induction and maintenance. Temporally restricted siRNA knockdown in hippocampus, behavioral memory assays, electrophysiology (LTP), Western blot for CREB/C/EBP The Journal of neuroscience Medium 16870737
2007 MuSK expression is prepatterned in muscle before innervation; ectopic MuSK expression promotes ectopic synapse formation and rescues lethality of agrin-null mice, demonstrating that postsynaptic MuSK has an instructive role in directing synapse formation independent of agrin. Transgenic ectopic Musk expression, Agrn−/−;MuSK transgene crosses, immunohistochemistry of NMJ formation Nature neuroscience High 18084289
2008 Lrp4 is a receptor for agrin, forms a complex with MuSK, and mediates MuSK activation by agrin; identified by functional and biochemical studies showing Lrp4 binds agrin and physically associates with MuSK. Affinity binding assays, co-immunoprecipitation, AChR clustering assays, genetic studies Cell High 18848351
2009 Dok-7 directly interacts with the cytoplasmic portion of MuSK and activates MuSK kinase activity; neural agrin requires Dok-7 to activate MuSK; Dok-7 overexpression in vivo increases MuSK activation and NMJ formation; Dok-7 is required for MuSK localization in the central region of muscle. Co-immunoprecipitation, MuSK phosphorylation assay in myotubes, in vivo Dok-7 overexpression, immunolocalization Science signaling High 19244212
2010 Crystal structure of Dok-7 PH-PTB domains bound to a phosphopeptide from the MuSK juxtamembrane NPXY site reveals that dimeric Dok-7 facilitates MuSK trans-autophosphorylation of the activation loop, providing the structural basis for MuSK activation by Dok-7. X-ray crystallography, biochemical dimerization and trans-autophosphorylation assays Molecular cell High 20603078
2010 Erbin directly binds MuSK and forms a trimeric complex with MuSK and ErbB2 at the NMJ; Erbin knockdown reduces density of agrin-dependent AChR aggregates; Erbin overexpression reduces AChR-epsilon-reporter expression; MuSK-Erbin-ErbB2 signaling influences TGF-β signaling. Co-immunoprecipitation, epitope mapping, siRNA knockdown, AChR clustering assay in primary myotubes and C2C12 cells The Journal of neuroscience Medium 20463225
2011 MuSK and its putative ligand Wnt11r are required for segmental neural crest cell migration in zebrafish; MuSK knockout causes neural crest cells to fail to retract non-productive leading edges via a planar cell polarity (PCP)-like pathway; this role is evolutionarily conserved as MuSK knockout mice show similar neural crest migration defects. Zebrafish morpholino knockdown, MuSK knockout mice analysis, F-actin biosensor live imaging Development Medium 21750038
2012 Wnt11r and Wnt4a induce MuSK translocation from muscle membranes to recycling endosomes in zebrafish; this endosomal translocation is required for AChR accumulation at synaptic sites; PCP pathway components colocalize to recycling endosomes in a MuSK-dependent manner. In vivo zebrafish morpholino knockdown, live imaging of MuSK trafficking, AChR localization assays Development Medium 22318632
2012 Crystal structure of an agrin-LRP4 complex reveals two agrin-LRP4 heterodimers; the z8 loop (specific to neuronal agrin) promotes formation of a tetrameric complex; the tetrameric complex is essential for neuronal agrin-induced AChR clustering, providing structural insight into agrin-LRP4-MuSK signaling. X-ray crystallography, AChR clustering functional assay with tetramer-disrupting mutants Genes & development High 22302937
2012 Biglycan is an extracellular MuSK-binding protein; in biglycan-null mice, MuSK levels are selectively reduced at synapses and AChR clusters formed by agrin are unstable; purified biglycan rescues AChR cluster stability in biglycan-null myotubes. Co-immunoprecipitation/binding assay, biglycan-null mouse analysis, rescue with purified biglycan protein The Journal of neuroscience Medium 22396407
2012 Increasing MuSK expression (3-fold transgenic overexpression) in SOD1G93A ALS mice delays onset and reduces extent of muscle denervation, improving motor function; demonstrates MuSK participates in retrograde signaling that promotes nerve terminal attachment. Transgenic MuSK overexpression crossed into SOD1G93A mice, histological and behavioral assessment Cell reports Medium 22939980
2013 Pathogenic IgG4 autoantibodies in MuSK MG bind a structural epitope in the first Ig-like domain of MuSK, prevent MuSK–Lrp4 binding, and inhibit agrin-stimulated MuSK phosphorylation; they do not directly affect MuSK dimerization or internalization. Passive transfer in mice, epitope mapping, MuSK-Lrp4 binding assay, MuSK phosphorylation assay Proceedings of the National Academy of Sciences of the United States of America High 24297891
2013 A MuSK missense mutation (Met835Val) causes constitutive MuSK activation and decreases agrin- and Dok-7-dependent MuSK phosphorylation, as well as agrin-dependent AChR aggregation, reproducing congenital myasthenic syndrome phenotypes. In vitro AChR aggregation assay, MuSK phosphorylation assay, in vivo electroporation in mouse muscle PloS one Medium 23326516
2015 The MuSK cysteine-rich domain (CRD/Frizzled-like domain) is required for muscle prepatterning and NMJ formation; MuSKΔCRD mice show deficient AChR clustering, excessive axonal growth, and adult myasthenic phenotype; lithium chloride (GSK-3 inhibitor) rescues NMJ defects in MuSKΔCRD mice, implicating Wnt-MuSK CRD signaling. CRD-deleted MuSK knock-in mice, morphological and electrophysiological NMJ analysis, lithium chloride treatment The Journal of neuroscience High 25810523
2015 ColQ and anti-MuSK IgG competitively suppress agrin/LRP4/MuSK signaling; MuSK-IgG blocks MuSK–LRP4 interaction in the presence of agrin; LRP4 and ColQ both bind to the Ig1 and Ig4 domains of MuSK; the AChE/ColQ complex itself suppresses agrin/LRP4/MuSK signaling. In vitro plate-binding assay, passive transfer of MuSK-IgG into Colq-knockout mice, epitope mapping Scientific reports Medium 26355076
2016 MuSK functions as a BMP co-receptor: MuSK binds BMP4 and related BMPs with low nanomolar affinity in vitro and associates with type I BMP receptors ALK3/ALK6 in a ligand-independent manner; MuSK promotes BMP4-dependent SMAD phosphorylation and Id1 transcription in myoblasts; this BMP co-receptor function is independent of MuSK tyrosine kinase activity. Binding assays (BMP4 affinity), co-immunoprecipitation with ALK3/ALK6, SMAD phosphorylation assay, gene expression profiling, kinase-dead MuSK mutant analysis Science signaling High 27601729
2019 Monovalent anti-MuSK IgG4 (mimicking Fab-arm exchanged serum IgG4) abolishes agrin-induced MuSK phosphorylation and AChR clustering, whereas bivalent monospecific MuSK antibodies activate MuSK phosphorylation and partially induce AChR clustering independent of agrin; valency determines agonist vs. antagonist activity. Generation of recombinant patient-derived MuSK monoclonal antibodies and Fab fragments, MuSK phosphorylation assay, AChR clustering assay in myotube cultures Neurology(R) neuroimmunology & neuroinflammation High 30882021
2021 Functional monovalency of IgG4 (via Fab-arm exchange) amplifies pathogenicity in MuSK MG: monovalent anti-MuSK IgG4 caused rapid severe myasthenic weakness in mice whereas bivalent forms were less potent or inactive; mechanistically, bivalent antibodies activate MuSK signaling while monovalent antibodies inhibit it. Passive transfer of monovalent vs. bivalent anti-MuSK IgG4 into mice, electrophysiology, MuSK signaling assays Proceedings of the National Academy of Sciences of the United States of America High 33753489
2023 Cryo-EM structure of the extracellular agrin/LRP4/MuSK ternary complex (1:1:1 stoichiometry) reveals that arc-shaped LRP4 simultaneously recruits both agrin and MuSK to its central cavity, facilitating a direct agrin–MuSK interaction, thereby uncovering the assembly mechanism for MuSK receptor activation. Cryo-EM structure determination of ternary complex Proceedings of the National Academy of Sciences of the United States of America High 37252960

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo. Cell 777 8653786
1996 Agrin acts via a MuSK receptor complex. Cell 570 8653787
2008 Lrp4 is a receptor for Agrin and forms a complex with MuSK. Cell 541 18848351
2004 Detection and characterization of MuSK antibodies in seronegative myasthenia gravis. Annals of neurology 322 15048899
2011 Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis. Journal of neurology 242 21814823
2013 MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4. Proceedings of the National Academy of Sciences of the United States of America 213 24297891
1997 Rapsyn is required for MuSK signaling and recruits synaptic components to a MuSK-containing scaffold. Neuron 210 9136771
2007 MuSK controls where motor axons grow and form synapses. Nature neuroscience 161 18084289
2004 MUSK, a new target for mutations causing congenital myasthenic syndrome. Human molecular genetics 148 15496425
2012 Structural basis of agrin-LRP4-MuSK signaling. Genes & development 146 22302937
2000 The juxtamembrane region of MuSK has a critical role in agrin-mediated signaling. The EMBO journal 144 10619845
2013 The role of MuSK in synapse formation and neuromuscular disease. Cold Spring Harbor perspectives in biology 135 23637281
2004 MuSK is required for anchoring acetylcholinesterase at the neuromuscular junction. The Journal of cell biology 132 15159418
2002 Crystal structure of the MuSK tyrosine kinase: insights into receptor autoregulation. Structure (London, England : 1993) 115 12220490
1998 Laminin and alpha-dystroglycan mediate acetylcholine receptor aggregation via a MuSK-independent pathway. The Journal of neuroscience : the official journal of the Society for Neuroscience 111 9454835
2010 The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization. Molecular cell 108 20603078
2017 Myasthenia gravis with antibodies to MuSK: an update. Annals of the New York Academy of Sciences 107 29266255
2012 Passive and active immunization models of MuSK-Ab positive myasthenia: electrophysiological evidence for pre and postsynaptic defects. Experimental neurology 102 22326541
1997 Association of muscle-specific kinase MuSK with the acetylcholine receptor in mammalian muscle. The EMBO journal 98 9305637
2011 Anti-MuSK autoantibodies block binding of collagen Q to MuSK. Neurology 95 22013178
1996 Rapsyn clusters and activates the synapse-specific receptor tyrosine kinase MuSK. Neuron 95 8630253
2004 Clinical comparison of muscle-specific tyrosine kinase (MuSK) antibody-positive and -negative myasthenic patients. Muscle & nerve 92 15221879
2004 Are MuSK antibodies the primary cause of myasthenic symptoms? Neurology 91 15184594
2009 Dok-7 activates the muscle receptor kinase MuSK and shapes synapse formation. Science signaling 85 19244212
2000 The in vitro and in vivo phosphotyrosine map of activated MuSK. Proceedings of the National Academy of Sciences of the United States of America 81 10781064
2020 MuSK-Associated Myasthenia Gravis: Clinical Features and Management. Frontiers in neurology 78 32793097
2012 Increasing MuSK activity delays denervation and improves motor function in ALS mice. Cell reports 76 22939980
1998 Localization and regulation of MuSK at the neuromuscular junction. Developmental biology 74 9698449
2013 Olfactory receptor and neural pathway responsible for highly selective sensing of musk odors. Neuron 73 24361078
2006 MuSK expressed in the brain mediates cholinergic responses, synaptic plasticity, and memory formation. The Journal of neuroscience : the official journal of the Society for Neuroscience 73 16870737
2019 MuSK myasthenia gravis monoclonal antibodies: Valency dictates pathogenicity. Neurology(R) neuroimmunology & neuroinflammation 71 30882021
2003 A novel pathway for MuSK to induce key genes in neuromuscular synapse formation. The Journal of cell biology 68 12756238
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
2007 Clinical and experimental features of MuSK antibody positive MG in Japan. European journal of neurology 67 17718696
2015 MuSK frizzled-like domain is critical for mammalian neuromuscular junction formation and maintenance. The Journal of neuroscience : the official journal of the Society for Neuroscience 60 25810523
2017 IgG-specific cell-based assay detects potentially pathogenic MuSK-Abs in seronegative MG. Neurology(R) neuroimmunology & neuroinflammation 59 28626780
2011 A novel role for MuSK and non-canonical Wnt signaling during segmental neural crest cell migration. Development (Cambridge, England) 57 21750038
2016 The musk chemical composition and microbiota of Chinese forest musk deer males. Scientific reports 56 26744067
2015 MuSK autoantibodies in myasthenia gravis detected by cell based assay--A multinational study. Journal of neuroimmunology 55 26025053
2012 Biglycan is an extracellular MuSK binding protein important for synapse stability. The Journal of neuroscience : the official journal of the Society for Neuroscience 55 22396407
2015 Collagen Q and anti-MuSK autoantibody competitively suppress agrin/LRP4/MuSK signaling. Scientific reports 54 26355076
2005 The synaptic muscle-specific kinase (MuSK) complex: new partners, new functions. BioEssays : news and reviews in molecular, cellular and developmental biology 54 16237673
2002 Restoration of synapse formation in Musk mutant mice expressing a Musk/Trk chimeric receptor. Development (Cambridge, England) 54 12403715
2006 Casein kinase 2-dependent serine phosphorylation of MuSK regulates acetylcholine receptor aggregation at the neuromuscular junction. Genes & development 53 16818610
1997 Direct demonstration of MuSK involvement in acetylcholine receptor clustering through identification of agonist ScFv. Nature biotechnology 53 9255792
1999 Musk xylene and musk ketone amino metabolites in the aquatic environment. Toxicology letters 51 10630699
2012 Initiation of synapse formation by Wnt-induced MuSK endocytosis. Development (Cambridge, England) 49 22318632
2011 MuSK levels differ between adult skeletal muscles and influence postsynaptic plasticity. The European journal of neuroscience 49 21255125
2016 Ligand Specificity and Evolution of Mammalian Musk Odor Receptors: Effect of Single Receptor Deletion on Odor Detection. The Journal of neuroscience : the official journal of the Society for Neuroscience 46 27098692
2018 Mechanisms underlying B cell immune dysregulation and autoantibody production in MuSK myasthenia gravis. Annals of the New York Academy of Sciences 41 29381221
2013 Structure and activation of MuSK, a receptor tyrosine kinase central to neuromuscular junction formation. Biochimica et biophysica acta 41 23467009
2023 Immunotherapies in MuSK-positive Myasthenia Gravis; an IgG4 antibody-mediated disease. Frontiers in immunology 40 37564637
2021 Zoology, chemical composition, pharmacology, quality control and future perspective of Musk (Moschus): a review. Chinese medicine 40 34147113
2016 Compromised fidelity of B-cell tolerance checkpoints in AChR and MuSK myasthenia gravis. Annals of clinical and translational neurology 40 27547772
2001 MuSK induces in vivo acetylcholine receptor clusters in a ligand-independent manner. The Journal of cell biology 40 11748247
2022 Comparison of Fixed and Live Cell-Based Assay for the Detection of AChR and MuSK Antibodies in Myasthenia Gravis. Neurology(R) neuroimmunology & neuroinflammation 39 36270951
2021 Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis. Proceedings of the National Academy of Sciences of the United States of America 38 33753489
2013 A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia. PloS one 37 23326516
2015 MuSK: a new target for lethal fetal akinesia deformation sequence (FADS). Journal of medical genetics 36 25612909
2014 Preferential production of IgG1, IL-4 and IL-10 in MuSK-immunized mice. Clinical immunology (Orlando, Fla.) 36 24589747
2013 The role of muscle-specific tyrosine kinase (MuSK) and mystery of MuSK myasthenia gravis. Journal of anatomy 36 23458718
2019 MuSk function during health and disease. Neuroscience letters 35 31811897
2022 Comparative analysis of gut microbial composition and potential functions in captive forest and alpine musk deer. Applied microbiology and biotechnology 34 35037997
2016 MuSK is a BMP co-receptor that shapes BMP responses and calcium signaling in muscle cells. Science signaling 34 27601729
2005 Tyrosine phosphatase regulation of MuSK-dependent acetylcholine receptor clustering. Molecular and cellular neurosciences 34 15737732
2014 Treatment of MuSK-Associated Myasthenia Gravis. Current treatment options in neurology 33 24504626
2014 Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence. European journal of human genetics : EJHG 33 25537362
2012 Pathogenic IgG4 subclass autoantibodies in MuSK myasthenia gravis. Annals of the New York Academy of Sciences 33 23278586
2018 The draft genome sequence of forest musk deer (Moschus berezovskii). GigaScience 31 29635287
2021 Chemical compositions and pharmacological activities of natural musk (Moschus) and artificial musk: A review. Journal of ethnopharmacology 28 34748869
2014 Muscle-specific kinase (MuSK) autoantibodies suppress the MuSK pathway and ACh receptor retention at the mouse neuromuscular junction. The Journal of physiology 28 24860174
2014 T cell repertoire in DQ5-positive MuSK-positive myasthenia gravis patients. Journal of autoimmunity 27 24397960
2021 MuSK-antibodies are associated with worse outcome in myasthenic crisis requiring mechanical ventilation. Journal of neurology 26 33970337
2020 Multiple MuSK signaling pathways and the aging neuromuscular junction. Neuroscience letters 26 32353380
2002 MuSK glycosylation restrains MuSK activation and acetylcholine receptor clustering. The Journal of biological chemistry 25 12399462
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
2014 Guidelines for pre-clinical animal and cellular models of MuSK-myasthenia gravis. Experimental neurology 24 25542979
2020 Viral metagenomics revealed diverse CRESS-DNA virus genomes in faeces of forest musk deer. Virology journal 23 32334626
2016 The antidepressant effect of musk in an animal model of depression: a histopathological study. Cell and tissue research 23 27481508
2015 Dental follicle mesenchymal stem cell administration ameliorates muscle weakness in MuSK-immunized mice. Journal of neuroinflammation 23 26646841
2003 Regulation of MuSK expression by a novel signaling pathway. The Journal of biological chemistry 23 12885777
2008 Dok-7/MuSK signaling and a congenital myasthenic syndrome. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology 22 19108574
2005 Motor neurite outgrowth is selectively inhibited by cell surface MuSK and agrin. Molecular and cellular neurosciences 21 15691710
2019 Comparative Genomics Reveals the Genetic Mechanisms of Musk Secretion and Adaptive Immunity in Chinese Forest Musk Deer. Genome biology and evolution 20 30903183
2017 Musk gland seasonal development and musk secretion are regulated by the testis in muskrat (Ondatra zibethicus). Biological research 20 28259185
2008 Dual constraints on synapse formation and regression in schizophrenia: neuregulin, neuroligin, dysbindin, DISC1, MuSK and agrin. The Australian and New Zealand journal of psychiatry 20 18622774
2022 From musk to body odor: Decoding olfaction through genetic variation. PLoS genetics 19 35113854
2021 Activation of Muscle-Specific Kinase (MuSK) Reduces Neuromuscular Defects in the Delta7 Mouse Model of Spinal Muscular Atrophy (SMA). International journal of molecular sciences 19 34360794
2018 The role of agrin, Lrp4 and MuSK during dendritic arborization and synaptogenesis in cultured embryonic CNS neurons. Developmental biology 19 30385274
2012 Developmental consequences of the ColQ/MuSK interactions. Chemico-biological interactions 19 23089045
2010 Identification of Erbin interlinking MuSK and ErbB2 and its impact on acetylcholine receptor aggregation at the neuromuscular junction. The Journal of neuroscience : the official journal of the Society for Neuroscience 19 20463225
2005 Inhibition of MuSK expression by CREB interacting with a CRE-like element and MyoD. Molecular and cellular biology 19 15964791
2025 Multiomics analysis provides insights into musk secretion in muskrat and musk deer. GigaScience 18 40036429
2017 MuSK myasthenia gravis and pregnancy. Neuromuscular disorders : NMD 18 29305138
1999 Identification and characterization of a novel splice variant of MuSK. FEBS letters 18 9928988
2022 An odorant receptor that senses four classes of musk compounds. Current biology : CB 16 36370695
2022 Clinical pitfalls and serological diagnostics of MuSK myasthenia gravis. Journal of neurology 16 36396811
2018 Microbiota Changes in the Musk Gland of Male Forest Musk Deer During Musk Maturation. Frontiers in microbiology 16 30619139
2016 Limb-girdle congenital myasthenic syndrome in a Chinese family with novel mutations in MUSK gene and literature review. Clinical neurology and neurosurgery 16 27588369

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