The tyrosine phosphatase Shp-2 interacts with the dopamine D(1) receptor and triggers D(1) -mediated Erk signaling in striatal neurons.

Autor: Fiorentini C; Division of Pharmacology, Department of Biomedical Sciences and Biotechnology and National Institute of Neuroscience, University of Brescia, Brescia, Italy. chiara.fiorentini@med.unibs.it, Mattanza C, Collo G, Savoia P, Spano P, Missale C
Jazyk: angličtina
Zdroj: Journal of neurochemistry [J Neurochem] 2011 Apr; Vol. 117 (2), pp. 253-63. Date of Electronic Publication: 2011 Feb 24.
DOI: 10.1111/j.1471-4159.2011.07196.x
Abstrakt: 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.
(© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.)
Databáze: MEDLINE
Externí odkaz: