SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody

Neurol Neuroimmunol Neuroinflamm. 2019 Dec 12;7(1):e645. doi: 10.1212/NXI.0000000000000645. Print 2020 Jan.


Objective: To determine whether an SRC homology 2 domain-containing phosphotyrosine phosphatase 2 (SHP2) inhibitor would increase muscle-specific kinase (MuSK) phosphorylation and override the inhibitory effect of MuSK-antibodies (Abs).

Methods: The effect of the SHP2 inhibitor NSC-87877 on MuSK phosphorylation and AChR clustering was tested in C2C12 myotubes with 31 MuSK-myasthenia gravis (MG) sera and purified MuSK-MG IgG4 preparations.

Results: In the absence of MuSK-MG Abs, NSC-87877 increased MuSK phosphorylation and the number of AChR clusters in C2C12 myotubes in vitro and in DOK7-overexpressing C2C12 myotubes that form spontaneous AChR clusters. In the presence of MuSK-MG sera, the AChR clusters were reduced, as expected, but NSC-87877 was able to protect or restore the clusters. Two purified MuSK-MG IgG4 preparations inhibited both MuSK phosphorylation and AChR cluster formation, and in both, clusters were restored with NSC-87877.

Conclusions: Stimulating the agrin-LRP4-MuSK-DOK7 AChR clustering pathway with NSC-87877, or other drugs, could represent a novel therapeutic approach for MuSK-MG and could potentially improve other NMJ disorders with reduced AChR numbers or disrupted NMJs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Inhibitors / pharmacology*
  • Humans
  • In Vitro Techniques
  • Muscle Fibers, Skeletal
  • Myasthenia Gravis / immunology*
  • Phosphorylation / drug effects*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors*
  • Quinolines / pharmacology*
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptors, Cholinergic / drug effects*
  • Receptors, Cholinergic / metabolism


  • Enzyme Inhibitors
  • NSC-87877
  • Quinolines
  • Receptors, Cholinergic
  • MUSK protein, human
  • Receptor Protein-Tyrosine Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11