From phosphorylation to phenotype – Recent key findings on kinase regulation, downstream signaling and disease surrounding the receptor tyrosine kinase MuSK

Prömer, Jakob; Barresi, Cinzia; Herbst, Ruth

doi:10.1016/j.cellsig.2022.110584

Cited by 5 publications

(4 citation statements)

References 141 publications

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“…MuSK-Abs seemed to impair the transition from unclustered AChRs to microclusters and then to fully matured clusters, but this could be due to a mechanism acting independently of the canonical clustering pathway. 6 , 7 There are some parallels between the results reported here and those found with a mutation in the tyrosine kinase domain of MuSK, A617V. 18 In cells constitutively expressing MuSK A617V, MuSK phosphorylation was increased, whereas AChR clusters were reduced, but in this case, microclusters were increased over the numbers in medium alone.…”

Section: Discussionsupporting

confidence: 69%

“…RNA for Rho GTPase was upregulated by MuSK-IgG1-3, but the enzyme activity was not different between agrin, IgG1-3, and IgG4 antibody-treated myotubes (data not shown). Three main pathways are now known to be involved in the formation and maintenance of the neuromuscular junction (reviewed in references 7 , 21 ). Wnt signaling 22 - 25 and BMP4 modulate the transcription of genes involved in AChR clustering 26 including MUSK, DOK7, and Wnt11, but none of these were changed in MuSK or NCS-87877-treated cells.…”

Section: Discussionmentioning

confidence: 99%

“… 3 , 4 Agrin binds to low-density lipoprotein receptor-related protein 4 (LRP4) which then interacts with MuSK on the postsynaptic membrane. 5 This triggers MuSK phosphorylation and recruitment of Downstream of Kinase 7 (DOK7) leading to a phosphorylation cascade that eventually reaches rapsyn and the AChR which cocluster (reviewed in references 6 , 7 ).…”

Section: Introductionmentioning

confidence: 99%

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IgG1-3 MuSK Antibodies Inhibit AChR Cluster Formation, Restored by SHP2 Inhibitor, Despite Normal MuSK, DOK7, or AChR Subunit Phosphorylation

Cao,

Liu,

Maxwell

et al. 2023

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesUp to 50% of patients with myasthenia gravis (MG) without acetylcholine receptor antibodies (AChR-Abs) have antibodies to muscle-specific kinase (MuSK). Most MuSK antibodies (MuSK-Abs) are IgG4 and inhibit agrin-induced MuSK phosphorylation, leading to impaired clustering of AChRs at the developing or mature neuromuscular junction. However, IgG1-3 MuSK-Abs also exist in MuSK-MG patients, and their potential mechanisms have not been explored fully.MethodsC2C12 myotubes were exposed to MuSK-MG plasma IgG1-3 or IgG4, with or without purified agrin. MuSK, Downstream of Kinase 7 (DOK7), and βAChR were immunoprecipitated and their phosphorylation levels identified by immunoblotting. Agrin and agrin-independent AChR clusters were measured by immunofluorescence and AChR numbers by binding of125I-α-bungarotoxin. Transcriptomic analysis was performed on treated myotubes.ResultsIgG1-3 MuSK-Abs impaired AChR clustering without inhibiting agrin-induced MuSK phosphorylation. Moreover, the well-established pathway initiated by MuSK through DOK7, resulting in βAChR phosphorylation, was not impaired by MuSK-IgG1-3 and was agrin-independent. Nevertheless, the AChR clusters did not form, and both the number of AChR microclusters that precede full cluster formation and the myotube surface AChRs were reduced. Transcriptomic analysis did not throw light on the pathways involved. However, the SHP2 inhibitor, NSC-87877, increased the number of microclusters and led to fully formed AChR clusters.DiscussionMuSK-IgG1-3 is pathogenic but seems to act through a noncanonical pathway. Further studies should throw light on the mechanisms involved at the neuromuscular junction.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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IgG1-3 MuSK Antibodies Inhibit AChR Cluster Formation, Restored by SHP2 Inhibitor, Despite Normal MuSK, DOK7, or AChR Subunit Phosphorylation

Cao,

Liu,

Maxwell

et al. 2023

Neurol Neuroimmunol Neuroinflamm

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“…Importantly, MuSK activation and phosphorylation follows a particular pattern. 51 Successful MuSK agonism, next to not interfering with endogenous MuSK function, should induce downstream signalling similar to the natural ligand agrin. 52 It will be interesting to learn what characteristics of a MuSK antibody define a successful therapeutic agonist.…”

Section: Discussionmentioning

confidence: 99%

Patient-specific therapeutic benefit of MuSK agonist antibody ARGX-119 in MuSK myasthenia gravis passive transfer models

Lim,

Jensen,

Plomp

et al. 2024

Preprint

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Muscle-specific kinase (MuSK) orchestrates establishment and maintenance of neuromuscular synapses, which enable muscle contraction. Autoantibodies targeting MuSK cause myasthenia gravis (MG), a disease characterized by fatigable skeletal muscle weakness which requires chronic immunosuppressive treatment and ventilatory support at some point in ∼30% of patients. MuSK autoantibodies are predominantly IgG4 and are bispecific, functionally monovalent antibodies due to Fab-arm exchange. Through monovalent binding, MuSK IgG4 autoantibodies act as antagonists on the MuSK signalling pathway, impairing neuromuscular synaptic function. In contrast, bivalent MuSK antibodies act as agonists of the MuSK signalling pathway. Since symptoms in MuSK MG are largely caused by antagonistic monovalent MuSK antibodies, we hypothesized that a bivalent MuSK agonist could rescue MuSK MG, bypassing the need for generalized immunosuppression. In this study, we investigated whether an agonist antibody targeting the Frizzled-like domain of MuSK, ARGX-119, can ameliorate disease in MuSK MG models induced by passive transfer of polyclonal IgG4 from unrelated patients. For each patient material we first established the minimal dose for a progressive MG phenotype based on muscle function tests. ARGX-119 significantly improved survival and muscle weakness in a mouse model induced by one patient material, but not by three others. Mechanistically, this patient-specific efficacy could not be explained by autoantibody epitope specificity, titer or competition for ARGX-119 binding, but rather correlated to the presence of MuSK activating antibodies in some patients. We further provide evidence that anin vitroassay may predict which patients potentially benefit from ARGX-119 and that this treatment, when effective in MuSK MG mice, follows a bell-shaped dose-effect curve. These results provide first proof of concept of a MuSK agonist in a clinically relevant model for MuSK MG. We anticipate this to be a starting point for investigating the therapeutic benefit of ARGX-119 in MuSK MG and other neuromuscular diseases hallmarked by neuromuscular synaptic dysfunction.Graphical abstractHighlightsMuSK agonist ARGX-119 can rescue MuSK MG in a patient-specific mannerMuSK agonism follows a bell-shaped efficacy curve in this MuSK MG mouse modelVariation in ARGX-119 efficacy between patient models is not explained by competition for binding on MuSK, but rather appears related to an agonistic fraction of patient antibodiesAnin vitroassay is potentially predictive for treatment efficacy of the MuSK agonist

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Theranostic applications of peptide-based nanoformulations for growth factor defective cancers

Ghosh,

Maske,

Patel

et al. 2024

International Journal of Biological Macromolecules

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From phosphorylation to phenotype – Recent key findings on kinase regulation, downstream signaling and disease surrounding the receptor tyrosine kinase MuSK

Cited by 5 publications

References 141 publications

IgG1-3 MuSK Antibodies Inhibit AChR Cluster Formation, Restored by SHP2 Inhibitor, Despite Normal MuSK, DOK7, or AChR Subunit Phosphorylation

IgG1-3 MuSK Antibodies Inhibit AChR Cluster Formation, Restored by SHP2 Inhibitor, Despite Normal MuSK, DOK7, or AChR Subunit Phosphorylation

Patient-specific therapeutic benefit of MuSK agonist antibody ARGX-119 in MuSK myasthenia gravis passive transfer models

Theranostic applications of peptide-based nanoformulations for growth factor defective cancers

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