The tyrosine phosphatase Shp-2 interacts with the dopamine D1 receptor and triggers D1-mediated Erk signaling in striatal neurons

Abstract

We report a novel mechanism for dopamine D1 receptor (D 1R)-mediated extracellular signal-regulated kinases (Erk) activation in rat striatum. Erk signaling depends on phosphorylation and dephosphorylation events mediated by specific kinases and phosphatases. The tyrosine phosphatase Shp-2, that is required for Erk activation by tyrosine kinase receptors, has been recently shown to regulate signaling downstream of few G protein-coupled receptors. We show that the D1R interacts with Shp-2, that D 1R stimulation results in Shp-2 tyrosine phosphorylation and activation in primary striatal neuronal cultures and that D1R/Shp-2 interaction is required for transmitting D1R-dependent signaling to Erk1/2 activation. D1R-mediated Erk1/2 phosphorylation in cultured striatal neurons is in fact abolished by over-expression of the inactive Shp-2(C/S) mutant and by small interfering RNA-induced Shp-2 silencing. Moreover, by using selective inhibitors we show that both D1R-induced Shp-2 activation and Erk1/2 phosphorylation are dependent on the cyclic AMP/protein kinase A pathway and require Src. These results, which were substantiated also in transfected human embryonic kidney 293 cells, provide a novel mechanism by which to converge D1R signaling to the Erk pathway and suggest that Shp-2 or the D1R/Shp-2 interface could represent a potential drug target for disorders of dopamine transmission involving malfunctioning of D1R signaling. © 2011 The Authors Journal of Neurochemistry © 2011 International Society for Neurochemistry.