| First Author | Lu W | Year | 2020 |
| Journal | J Biol Chem | Volume | 295 |
| Issue | 29 | Pages | 10023-10031 |
| PubMed ID | 32499374 | Mgi Jnum | J:297046 |
| Mgi Id | MGI:6466897 | Doi | 10.1074/jbc.RA119.010331 |
| Citation | Lu W, et al. (2020) The Noonan syndrome-associated D61G variant of the protein tyrosine phosphatase SHP2 prevents synaptic down-scaling. J Biol Chem 295(29):10023-10031 |
| abstractText | 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. |
