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The tyrosine phosphatase Shp‐2 interacts with the dopamine D 1 receptor and triggers D 1 ‐mediated Erk signaling in striatal neurons
Author(s) -
Fiorentini Chiara,
Mattanza Cinzia,
Collo Ginetta,
Savoia Paola,
Spano PierFranco,
Missale Cristina
Publication year - 2011
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07196.x
Subject(s) - protein tyrosine phosphatase , phosphatase , dopamine , chemistry , mapk/erk pathway , microbiology and biotechnology , neuroscience , signal transduction , dopamine receptor , dusp6 , phosphorylation , protein phosphatase 2 , biology , biochemistry
J. Neurochem. (2011) 117 , 253–263. Abstract We report a novel mechanism for dopamine D 1 receptor (D 1 R)‐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 D 1 R interacts with Shp‐2, that D 1 R stimulation results in Shp‐2 tyrosine phosphorylation and activation in primary striatal neuronal cultures and that D 1 R/Shp‐2 interaction is required for transmitting D 1 R‐dependent signaling to Erk1/2 activation. D 1 R‐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 D 1 R‐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 D 1 R signaling to the Erk pathway and suggest that Shp‐2 or the D 1 R/Shp‐2 interface could represent a potential drug target for disorders of dopamine transmission involving malfunctioning of D 1 R signaling.