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SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody

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 pho...

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Autores principales: Huda, Saif, Cao, Michelangelo, De Rosa, Anna, Woodhall, Mark, Rodriguez Cruz, Pedro M., Cossins, Judith, Maestri, Michelangelo, Ricciardi, Roberta, Evoli, Amelia, Beeson, David, Vincent, Angela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935836/
https://www.ncbi.nlm.nih.gov/pubmed/31831571
http://dx.doi.org/10.1212/NXI.0000000000000645
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author Huda, Saif
Cao, Michelangelo
De Rosa, Anna
Woodhall, Mark
Rodriguez Cruz, Pedro M.
Cossins, Judith
Maestri, Michelangelo
Ricciardi, Roberta
Evoli, Amelia
Beeson, David
Vincent, Angela
author_facet Huda, Saif
Cao, Michelangelo
De Rosa, Anna
Woodhall, Mark
Rodriguez Cruz, Pedro M.
Cossins, Judith
Maestri, Michelangelo
Ricciardi, Roberta
Evoli, Amelia
Beeson, David
Vincent, Angela
author_sort Huda, Saif
collection PubMed
description 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.
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spelling pubmed-69358362020-02-10 SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody Huda, Saif Cao, Michelangelo De Rosa, Anna Woodhall, Mark Rodriguez Cruz, Pedro M. Cossins, Judith Maestri, Michelangelo Ricciardi, Roberta Evoli, Amelia Beeson, David Vincent, Angela Neurol Neuroimmunol Neuroinflamm Article 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. Lippincott Williams & Wilkins 2019-12-12 /pmc/articles/PMC6935836/ /pubmed/31831571 http://dx.doi.org/10.1212/NXI.0000000000000645 Text en Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Article
Huda, Saif
Cao, Michelangelo
De Rosa, Anna
Woodhall, Mark
Rodriguez Cruz, Pedro M.
Cossins, Judith
Maestri, Michelangelo
Ricciardi, Roberta
Evoli, Amelia
Beeson, David
Vincent, Angela
SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody
title SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody
title_full SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody
title_fullStr SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody
title_full_unstemmed SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody
title_short SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody
title_sort shp2 inhibitor protects achrs from effects of myasthenia gravis musk antibody
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935836/
https://www.ncbi.nlm.nih.gov/pubmed/31831571
http://dx.doi.org/10.1212/NXI.0000000000000645
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