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

Glutamate receptor (GluR) delta 2 is selectively expressed in cerebellar Purkinje cells and plays a crucial role in cerebellum-dependent motor learning. Although GluR delta 2 belongs to an ionotropic GluR family, little is known about its pharmacological features and downstream signaling cascade. To study molecular mechanisms underlying GluR delta 2-dependent motor learning, we employed yeast two-hybrid screening to isolate GluR delta 2-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 GluR delta 2 as well as with N-methyl-D-aspartate receptor GluR epsilon 1 in cultured cells and in brain. PTPMEG bound to the putative C-terminal PDZ target sequence of GluR delta 2 and GluR epsilon 1 via its PDZ domain. Examination of the effect of PTPMEG on tyrosine phosphorylation of GluR epsilon 1 unexpectedly revealed that PTPMEG enhanced Fyn-mediated tyrosine phosphorylation of GluR epsilon 1 in its PTPase activity-dependent manner. Thus, we conclude that PTPMEG associates directly with GluR delta 2 and GluR epsilon 1. 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.