SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody

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

*Autore corrispondente per questo lavoro

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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