Noonan Syndrome-Associated SHP2 Dephosphorylates GluN2B to Regulate NMDA Receptor Function

• Published in: Cell reports (Cambridge) Vol. 24; no. 6; pp. 1523 - 1535
• Main Authors: Levy, Aaron D., Xiao, Xiao, Shaw, Juliana E., Sudarsana Devi, Suma Priya, Katrancha, Sara Marie, Bennett, Anton M., Greer, Charles A., Howe, James R., Machida, Kazuya, Koleske, Anthony J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07-08-2018; Elsevier
• Subjects: Animals; Disease Models, Animal; GluN2B; Humans; Mice; NMDA receptor; Noonan syndrome; Noonan Syndrome - genetics; Noonan Syndrome - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; SHP2; Signal Transduction; tyrosine phosphorylation; SHP2; tyrosine phosphorylation; NMDA receptor; Noonan syndrome; GluN2B
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.07.006

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.
[Display omitted]
•NMDA receptor-mediated transmission is disrupted in Noonan syndrome (NS) model mice•NS-associated hyperactive SHP2 selectively dephosphorylates GluN2B Y1252•The actin regulatory protein Nck2 binds to phosphorylated GluN2B Y1252•Disrupting Nck2-pY interactions alters NMDAR currents similar to NS mice
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.