The Noonan syndrome-associated D61G variant of the protein tyrosine phosphatase SHP2 prevents synaptic down-scaling.
J Biol Chem
; 295(29): 10023-10031, 2020 07 17.
Article
en En
| MEDLINE
| ID: mdl-32499374
ABSTRACT
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.
Palabras clave
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)
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Sinapsis
/
Mutación Missense
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Proteína Tirosina Fosfatasa no Receptora Tipo 11
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Síndrome de Noonan
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
J Biol Chem
Año:
2020
Tipo del documento:
Article
País de afiliación:
China