| Summary: | Summary: Hyperactivating mutations in the non-receptor tyrosine phosphatase SHP2 cause Noonan syndrome (NS). NS is associated with cognitive deficits, but how hyperactivation of SHP2 in NS changes neuron function is not well understood. We find that mice bearing an NS-associated SHP2 allele (NS mice) have selectively impaired Schaffer collateral-CA1 NMDA (N-methyl-D-aspartate) receptor (NMDAR)-mediated neurotransmission and that residual NMDAR-mediated currents decay faster in NS mice because of reduced contribution of GluN1:GluN2B diheteromers. Consistent with altered GluN2B function, we identify GluN2B Y1252 as an NS-associated SHP2 substrate both in vitro and in vivo. Mutation of Y1252 does not alter recombinant GluN1:GluN2B receptor kinetics. Instead, phospho-Y1252 binds the actin-regulatory adaptor protein Nck2, and this interaction is required for proper NMDAR function. These results establish SHP2 and Nck2 as NMDAR regulatory proteins and strongly suggest that NMDAR dysfunction contributes to NS cognitive deficits. : Noonan syndrome (NS) is caused by hyperactive SHP2 and is associated with cognitive deficits. Levy et al. find that NMDA receptor (NMDAR)-mediated currents are disrupted in NS and identify GluN2B Y1252 as a neural substrate of SHP2. Y1252 in turn binds the actin regulator Nck2 to control spine actin and regulate NMDAR currents. Keywords: Noonan syndrome, SHP2, NMDA receptor, GluN2B, tyrosine phosphorylation
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