The Noonan syndrome-associated D61G variant of the protein tyrosine phosphatase SHP2 prevents synaptic down-scaling.
SHP2
Src homology 2 domain (SH2 domain)
phosphatase
phosphorylation
phosphotyrosine signaling
postsynaptic density protein 95 (PSD95)
protein tyrosine phosphatase non-receptor type 11 (PTPN11)
synaptic scaling
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor)
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
17 07 2020
17 07 2020
Historique:
received:
23
07
2019
revised:
01
06
2020
pubmed:
6
6
2020
medline:
15
1
2021
entrez:
6
6
2020
Statut:
ppublish
Résumé
Homeostatic scaling of the synapse, such as synaptic down-scaling, has been proposed to offset deleterious effects induced by sustained synaptic strength enhancement. Proper function and subcellular distribution of Src homology 2 domain-containing nonreceptor protein tyrosine phosphatase (SHP2) are required for synaptic plasticity. However, the role of SHP2 in synaptic down-scaling remains largely unknown. Here, using biochemical assays and cell-imaging techniques, we found that synaptic SHP2 levels are temporally regulated during synaptic down-scaling in cultured hippocampal neurons. Furthermore, we observed that a Noonan syndrome-associated mutation of SHP2, resulting in a D61G substitution, prevents synaptic down-scaling. We further show that this effect is due to an inability of the SHP2-D61G variant to properly disassociate from postsynaptic density protein 95, leading to impaired SHP2 dispersion from synaptic sites after synaptic down-scaling. Our findings reveal a molecular mechanism of the Noonan syndrome-associated genetic variant SHP2-D61G that contributes to deficient synaptic down-scaling.
Identifiants
pubmed: 32499374
pii: S0021-9258(17)48941-1
doi: 10.1074/jbc.RA119.010331
pmc: PMC7380183
doi:
Substances chimiques
Disks Large Homolog 4 Protein
0
Dlg4 protein, mouse
0
Protein Tyrosine Phosphatase, Non-Receptor Type 11
EC 3.1.3.48
Ptpn11 protein, mouse
EC 3.1.3.48
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
10023-10031Informations de copyright
© 2020 Lu et al.
Déclaration de conflit d'intérêts
Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article.
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