The protein-tyrosine phosphatase PTPMEG interacts with glutamate receptor δ2 and ε subunits

Abstract

Glutamate receptor (GluR) δ2 is selectively expressed in cerebellar Purkinje cells and plays a crucial role in cerebellum-dependent motor learning. Although GluRδ2 belongs to an ionotropic GluR family, little is known about its pharmacological features and downstream signaling cascade. To study molecular mechanisms underlying GluRδ2-dependent motor learning, we employed yeast two-hybrid screening to isolate GluRδ2-interacting molecules and identified protein-tyrosine phosphatase PTPMEG. PTPMEG is a family member of band 4.1 domain-containing protein-tyrosine phosphatases and is expressed prominently in brain. Here, we showed by in situ hybridization analysis that the PTPMEG mRNA was enriched in mouse thalamus and Purkinje cells. We also showed that PTPMEG interacted with GluRδ2 as well as with N-methyl-D- aspartate receptor GluRε1 in cultured cells and in brain. PTPMEG bound to the putative C-terminal PDZ target sequence of GluRδ2 and GluRε1 via its PDZ domain. Examination of the effect of PTPMEG on tyrosine phosphorylation of GluRε1 unexpectedly revealed that PTPMEG enhanced Fyn-mediated tyrosine phosphorylation of GluRε1 in its PTPase activity-dependent manner. Thus, we conclude that PTPMEG associates directly with GluRδ2 and GluRε1. Moreover, our data suggest that PTPMEG plays a role in signaling downstream of the GluRs and/or in regulation of their activities through tyrosine dephosphorylation.