Korean J Physiol Pharmacol.  2020 Mar;24(2):129-135. 10.4196/kjpp.2020.24.2.129.

Connecting the dots between SHP2 and glutamate receptors

• Ryu HH
• Kim SY
• Lee YS

• KMID: 2471034
• DOI: http://doi.org/10.4196/kjpp.2020.24.2.129

Abstract

SHP2 is an unusual protein phosphatase that functions as an activator for several signaling pathways, including the RAS pathway, while most other phosphatases suppress their downstream signaling cascades. The physiological and pathophysiological roles of SHP2 have been extensively studied in the field of cancer research. Mutations in the PTPN11 gene which encodes SHP2 are also highly associated with developmental disorders, such as Noonan syndrome (NS), and cognitive deficits including learning disabilities are common among NS patients. However, the molecular and cellular mechanism by which SHP2 is involved in cognitive functions is not well understood. Recent studies using SHP2 mutant mice or pharmacological inhibitors have shown that SHP2 plays critical role in learning and memory and synaptic plasticity. Here, we review the recent studies demonstrating that SHP2 is involved in synaptic plasticity, and learning and memory, by the regulation of the expression and/or function of glutamate receptors. We suggest that each cell type may have distinct paths connecting the dots between SHP2 and glutamate receptors, and these paths may also change with aging.

Keyword

AMPA receptor; Learning and memory; NMDA receptor; Rasopathy; Synaptic plasticity

MeSH Terms

Aging
Animals
Cognition
Cognition Disorders
Glutamic Acid*
Humans
Learning
Learning Disorders
Memory
Mice
Neuronal Plasticity
Noonan Syndrome
Phosphoric Monoester Hydrolases
Receptors, AMPA
Receptors, Glutamate*
Glutamic Acid
Phosphoric Monoester Hydrolases
Receptors, AMPA
Receptors, Glutamate

Figure

• 

  Fig. 1 Graphical summary of the roles of Shp2 in regulating glutamate receptor function in the nervous system. Shp2 is involved in regulating the phosphorylation of GluN2A at Y1325 and GluN2B at Y1252 and Y1472. Src positively regulates the phosphorylation of GluN2A at Y1325 and GluN2B at Y1472. In the forebrain, the activation of Src is negatively regulated by Shp2 [39]. Therefore, Shp2 has a negative effect on N-methyl-D-aspartate receptor (NMDAR) activation through suppressing Src activity in the forebrain. However, in the dorsal horn, Shp2 was shown to positively regulate the phosphorylation of GluN2B at Y1472 and interaction between GluN2B and PSD95 [48]. In contrast, the phosphorylation of GluN2B at Y1252 and binding to Nck2 are decreased in juvenile Shp2D61G/+ knock-in mice, suggesting that Shp2 negatively regulates the phosphorylation of GluN2B at 1252 [32]. In adult mice, Shp2 promotes the surface expression of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) [31]. The red and green circles represent negative and positive regulation between NMDAR and its interaction partners (Nck2 and PSD95), respectively. The dashed lines indicate controversial results [3964].

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