The tyrosine phosphatase Shp-2 interacts with the dopamine D1 receptor and triggers D1-mediated Erk signaling in striatal neurons
The tyrosine phosphatase Shp-2 interacts with the dopamine D1 receptor and triggers D1-mediated Erk signaling in striatal neurons
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DOI：
10.1111/j.1471-4159.2011.07196.x
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发表时间：
2011-04-01
影响因子：
4.7
通讯作者：
Missale, Cristina
中科院分区：
文献类型：
--
作者：
Fiorentini, Chiara;Mattanza, Cinzia;Missale, Cristina
P>我们报告了大鼠纹状体中多巴胺 D-1 受体 (D1R) 介导的细胞外信号调节激酶 (Erk) 激活的新机制。 Erk 信号传导依赖于特定激酶和磷酸酶介导的磷酸化和去磷酸化事件。酪氨酸磷酸酶 Shp-2 是酪氨酸激酶受体激活 Erk 所必需的，最近已被证明可以调节少数 G 蛋白偶联受体下游的信号传导。我们发现D1R与Shp-2相互作用，D1R刺激导致原代纹状体神经元培养物中Shp-2酪氨酸磷酸化和激活，并且D1R/Shp-2相互作用是将D1R依赖性信号传导至Erk1/2激活所必需的。事实上，培养的纹状体神经元中 D1R 介导的 Erk1/2 磷酸化被无活性的 Shp-2(C/S) 突变体的过度表达和小干扰 RNA 诱导的 Shp-2 沉默所消除。此外，通过使用选择性抑制剂，我们表明 D1R 诱导的 Shp-2 激活和 Erk1/2 磷酸化都依赖于环 AMP/蛋白激酶 A 途径，并且需要 Src。这些结果也在转染的人胚胎肾293细胞中得到证实，提供了一种将D1R信号汇聚到Erk通路的新机制，并表明Shp-2或D1R/Shp-2界面可能代表涉及D1R信号故障的多巴胺传递障碍的潜在药物靶点。
P>We report a novel mechanism for dopamine D-1 receptor (D1R)-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 D1R 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.