ArticleThe Journal of biological chemistry2020
The Noonan syndrome-associated D61G variant of the protein tyrosine phosphatase SHP2 prevents synaptic down-scaling.
Article in The Journal of biological chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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5 citing papers in PubMed, 8 citations in OpenAlex.
- Targeting Shp2 as a therapeutic strategy for neurodegenerative diseases.Translational psychiatry · 2025Review
- Rasopathy-Associated Mutation Ptpn11Cellular and molecular neurobiology · 2024Article
- SHP2 regulates GluA2 tyrosine phosphorylation required for AMPA receptor endocytosis and mGluR-LTD.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Aberrant Cortical Layer Development of Brain Organoids Derived from Noonan Syndrome-iPSCs.International journal of molecular sciences · 2022Article
- Drosophila RASopathy models identify disease subtype differences and biomarkers of drug efficacy.iScience · 2021Article
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5 authors at 3 institutions in 1 country.
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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.
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