SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody

Amelia Evoli Stampanoni-B, Saif Huda, Michelangelo Cao, Anna De Rosa, Mark Woodhall, Pedro M. Rodriguez Cruz, Judith Cossins, Michelangelo Maestri, Roberta Ricciardi, David Beeson, Angela Vincent

Risultato della ricerca: Contributo in rivistaArticolo in rivista

5 Citazioni (Scopus)


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.
Lingua originaleEnglish
pagine (da-a)1-11
Numero di pagine11
Stato di pubblicazionePubblicato - 2020


  • myasthenia gravis


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