PMID- 31831571
OWN - NLM
STAT- MEDLINE
DCOM- 20210215
LR  - 20210215
IS  - 2332-7812 (Electronic)
IS  - 2332-7812 (Linking)
VI  - 7
IP  - 1
DP  - 2020 Jan
TI  - SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody.
LID - 10.1212/NXI.0000000000000645 [doi]
LID - e645
AB  - 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.
CI  - Copyright (c) 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on 
      behalf of the American Academy of Neurology.
FAU - Huda, Saif
AU  - Huda S
AD  - From the Department of Clinical Neurosciences (S.H., M.C., M.W., P.M.R.C., J.C., 
      D.B., A.V.), Weatherall Institute of Molecular Medicine and Nuffield, University 
      of Oxford, UK; Department of Clinical and Experimental Medicine (A.D.R., M.M., 
      R.R.), Neurology Unit, Pisa; and Department of Neuroscience (A.E.), Catholic 
      University, Rome, Italy.
FAU - Cao, Michelangelo
AU  - Cao M
AD  - From the Department of Clinical Neurosciences (S.H., M.C., M.W., P.M.R.C., J.C., 
      D.B., A.V.), Weatherall Institute of Molecular Medicine and Nuffield, University 
      of Oxford, UK; Department of Clinical and Experimental Medicine (A.D.R., M.M., 
      R.R.), Neurology Unit, Pisa; and Department of Neuroscience (A.E.), Catholic 
      University, Rome, Italy.
FAU - De Rosa, Anna
AU  - De Rosa A
AD  - From the Department of Clinical Neurosciences (S.H., M.C., M.W., P.M.R.C., J.C., 
      D.B., A.V.), Weatherall Institute of Molecular Medicine and Nuffield, University 
      of Oxford, UK; Department of Clinical and Experimental Medicine (A.D.R., M.M., 
      R.R.), Neurology Unit, Pisa; and Department of Neuroscience (A.E.), Catholic 
      University, Rome, Italy.
FAU - Woodhall, Mark
AU  - Woodhall M
AD  - From the Department of Clinical Neurosciences (S.H., M.C., M.W., P.M.R.C., J.C., 
      D.B., A.V.), Weatherall Institute of Molecular Medicine and Nuffield, University 
      of Oxford, UK; Department of Clinical and Experimental Medicine (A.D.R., M.M., 
      R.R.), Neurology Unit, Pisa; and Department of Neuroscience (A.E.), Catholic 
      University, Rome, Italy.
FAU - Rodriguez Cruz, Pedro M
AU  - Rodriguez Cruz PM
AD  - From the Department of Clinical Neurosciences (S.H., M.C., M.W., P.M.R.C., J.C., 
      D.B., A.V.), Weatherall Institute of Molecular Medicine and Nuffield, University 
      of Oxford, UK; Department of Clinical and Experimental Medicine (A.D.R., M.M., 
      R.R.), Neurology Unit, Pisa; and Department of Neuroscience (A.E.), Catholic 
      University, Rome, Italy.
FAU - Cossins, Judith
AU  - Cossins J
AD  - From the Department of Clinical Neurosciences (S.H., M.C., M.W., P.M.R.C., J.C., 
      D.B., A.V.), Weatherall Institute of Molecular Medicine and Nuffield, University 
      of Oxford, UK; Department of Clinical and Experimental Medicine (A.D.R., M.M., 
      R.R.), Neurology Unit, Pisa; and Department of Neuroscience (A.E.), Catholic 
      University, Rome, Italy.
FAU - Maestri, Michelangelo
AU  - Maestri M
AD  - From the Department of Clinical Neurosciences (S.H., M.C., M.W., P.M.R.C., J.C., 
      D.B., A.V.), Weatherall Institute of Molecular Medicine and Nuffield, University 
      of Oxford, UK; Department of Clinical and Experimental Medicine (A.D.R., M.M., 
      R.R.), Neurology Unit, Pisa; and Department of Neuroscience (A.E.), Catholic 
      University, Rome, Italy.
FAU - Ricciardi, Roberta
AU  - Ricciardi R
AD  - From the Department of Clinical Neurosciences (S.H., M.C., M.W., P.M.R.C., J.C., 
      D.B., A.V.), Weatherall Institute of Molecular Medicine and Nuffield, University 
      of Oxford, UK; Department of Clinical and Experimental Medicine (A.D.R., M.M., 
      R.R.), Neurology Unit, Pisa; and Department of Neuroscience (A.E.), Catholic 
      University, Rome, Italy.
FAU - Evoli, Amelia
AU  - Evoli A
AD  - From the Department of Clinical Neurosciences (S.H., M.C., M.W., P.M.R.C., J.C., 
      D.B., A.V.), Weatherall Institute of Molecular Medicine and Nuffield, University 
      of Oxford, UK; Department of Clinical and Experimental Medicine (A.D.R., M.M., 
      R.R.), Neurology Unit, Pisa; and Department of Neuroscience (A.E.), Catholic 
      University, Rome, Italy.
FAU - Beeson, David
AU  - Beeson D
AD  - From the Department of Clinical Neurosciences (S.H., M.C., M.W., P.M.R.C., J.C., 
      D.B., A.V.), Weatherall Institute of Molecular Medicine and Nuffield, University 
      of Oxford, UK; Department of Clinical and Experimental Medicine (A.D.R., M.M., 
      R.R.), Neurology Unit, Pisa; and Department of Neuroscience (A.E.), Catholic 
      University, Rome, Italy.
FAU - Vincent, Angela
AU  - Vincent A
AD  - From the Department of Clinical Neurosciences (S.H., M.C., M.W., P.M.R.C., J.C., 
      D.B., A.V.), Weatherall Institute of Molecular Medicine and Nuffield, University 
      of Oxford, UK; Department of Clinical and Experimental Medicine (A.D.R., M.M., 
      R.R.), Neurology Unit, Pisa; and Department of Neuroscience (A.E.), Catholic 
      University, Rome, Italy. angela.vincent@ndcn.ox.ac.uk.
LA  - eng
GR  - MR/M006824/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191212
PL  - United States
TA  - Neurol Neuroimmunol Neuroinflamm
JT  - Neurology(R) neuroimmunology & neuroinflammation
JID - 101636388
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (NSC-87877)
RN  - 0 (Quinolines)
RN  - 0 (Receptors, Cholinergic)
RN  - EC 2.7.10.1 (MUSK protein, human)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
SB  - IM
CIN - Neurol Neuroimmunol Neuroinflamm. 2019 Dec 12;7(1):. PMID: 31831572
MH  - Enzyme Inhibitors/*pharmacology
MH  - Humans
MH  - In Vitro Techniques
MH  - Muscle Fibers, Skeletal
MH  - Myasthenia Gravis/*immunology
MH  - Phosphorylation/*drug effects
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 11/*antagonists & inhibitors
MH  - Quinolines/*pharmacology
MH  - Receptor Protein-Tyrosine Kinases/*metabolism
MH  - Receptors, Cholinergic/*drug effects/metabolism
PMC - PMC6935836
EDAT- 2019/12/14 06:00
MHDA- 2021/02/16 06:00
PMCR- 2019/12/12
CRDT- 2019/12/14 06:00
PHST- 2019/08/15 00:00 [received]
PHST- 2019/10/08 00:00 [accepted]
PHST- 2019/12/14 06:00 [entrez]
PHST- 2019/12/14 06:00 [pubmed]
PHST- 2021/02/16 06:00 [medline]
PHST- 2019/12/12 00:00 [pmc-release]
AID - 7/1/e645 [pii]
AID - NEURIMMINFL2019023077 [pii]
AID - 10.1212/NXI.0000000000000645 [doi]
PST - epublish
SO  - Neurol Neuroimmunol Neuroinflamm. 2019 Dec 12;7(1):e645. doi: 
      10.1212/NXI.0000000000000645. Print 2020 Jan.