SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody.
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
Journal
Neurology(R) neuroimmunology & neuroinflammation
ISSN: 2332-7812
Titre abrégé: Neurol Neuroimmunol Neuroinflamm
Pays: United States
ID NLM: 101636388
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
15
08
2019
accepted:
08
10
2019
entrez:
14
12
2019
pubmed:
14
12
2019
medline:
16
2
2021
Statut:
epublish
Résumé
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). 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. 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. 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.
Identifiants
pubmed: 31831571
pii: 7/1/e645
doi: 10.1212/NXI.0000000000000645
pmc: PMC6935836
pii:
doi:
Substances chimiques
Enzyme Inhibitors
0
NSC-87877
0
Quinolines
0
Receptors, Cholinergic
0
MUSK protein, human
EC 2.7.10.1
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Protein Tyrosine Phosphatase, Non-Receptor Type 11
EC 3.1.3.48
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Medical Research Council
ID : MR/M006824/1
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
Références
Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):4995-5000
pubmed: 10220407
J Biol Chem. 1998 Mar 13;273(11):6467-73
pubmed: 9497380
Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):20783-8
pubmed: 24297891
Elife. 2018 Feb 20;7:
pubmed: 29460776
JCI Insight. 2019 Jun 20;4(12):null
pubmed: 31217355
Cancer Sci. 2009 Oct;100(10):1786-93
pubmed: 19622105
Dev Neurobiol. 2007 Nov;67(13):1789-801
pubmed: 17659592
Nat Commun. 2015 Nov 30;6:8859
pubmed: 26617336
PLoS One. 2013 Nov 07;8(11):e80695
pubmed: 24244707
Science. 2006 Sep 29;313(5795):1975-8
pubmed: 16917026
Nat Med. 2001 Mar;7(3):365-8
pubmed: 11231638
Cancer Res. 2017 Nov 1;77(21):5701-5705
pubmed: 28855209
Aging (Albany NY). 2011 Mar;3(3):192-222
pubmed: 21422497
Neurol Neuroimmunol Neuroinflamm. 2017 Jun 05;4(4):e357
pubmed: 28626780
Brain. 2003 Oct;126(Pt 10):2304-11
pubmed: 12821509
Mol Pharmacol. 2006 Aug;70(2):562-70
pubmed: 16717135
J Autoimmun. 2017 Feb;77:104-115
pubmed: 27965060
Neurol Neuroimmunol Neuroinflamm. 2019 Feb 21;6(3):e547
pubmed: 30882021
Development. 2010 Apr;137(7):1017-33
pubmed: 20215342
Neurosignals. 2006-2007;15(2):53-63
pubmed: 16837792
Blood. 2007 Feb 1;109(3):862-7
pubmed: 17053061
Nat Protoc. 2013 Nov;8(11):2281-2308
pubmed: 24157548
Hum Mol Genet. 2012 Sep 1;21(17):3765-75
pubmed: 22661499