Regulator of G-protein signaling 18 integrates activating and inhibitory signaling in platelets
Regulator of G-protein signaling 18 integrates activating and inhibitory signaling in platelets
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DOI：
10.1182/blood-2011-11-390369
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发表时间：
2012-04-19
期刊：
影响因子：
20.3
通讯作者：
Smolenski, Albert
中科院分区：
文献类型：
--
作者：
Gegenbauer, Kristina;Elia, Giuliano;Smolenski, Albert
G蛋白信号转导调节因子18（Regulator of G-protein signaling 18，RGS 18）是一种GTP酶激活蛋白，作用于异源三聚体G蛋白的G-α-q和G-α-i亚基，关闭G蛋白偶联受体的信号转导。RGS 18在血小板中高度表达。在本研究中，我们表明，14-3-3 γ蛋白结合磷酸化的丝氨酸49和218的RGS 18。凝血酶、血栓素A2或ADP激活血小板可刺激14-3-3 γ和RGS 18的结合，可能是通过增加丝氨酸49的磷酸化。相比之下，用前列环素和一氧化氮处理血小板，触发涉及环AMP依赖性蛋白激酶A（PKA）和环GMP依赖性蛋白激酶I（PKGI）的抑制性环核苷酸信号传导，诱导RGS 18的丝氨酸216的磷酸化和14-3-3的分离。丝氨酸216磷酸化能够阻断14-3-3与RGS 18的结合，即使在凝血酶、血栓烷A2或ADP存在下。14-3-3-与14-3-3-结合的RGS 18相比，缺陷型RGS 18更有活性，导致对凝血酶诱导的钙离子从细胞内储存释放的更明显的抑制。因此，PKA和PKGI介导的14-3-3的脱离激活RGS 18以阻断Gq依赖性钙信号传导。这些发现表明在RGS 18和Gq水平上血小板活化和抑制途径之间存在串扰。（血。2012;119（16）：3799-3807）
Regulator of G-protein signaling 18 (RGS18) is a GTPase-activating protein for the G-alpha-q and G-alpha-i subunits of heterotrimeric G-proteins that turns off signaling by G-protein coupled receptors. RGS18 is highly expressed in platelets. In the present study, we show that the 14-3-3 gamma protein binds to phosphorylated serines 49 and 218 of RGS18. Platelet activation by thrombin, thromboxaneA2, or ADP stimulates the association of 14-3-3 gamma and RGS18, probably by increasing the phosphorylation of serine 49. In contrast, treatment of platelets with prostacyclin and nitric oxide, which trigger inhibitory cyclic nucleotide signaling involving cyclic AMP-dependent protein kinase A (PKA) and cyclic GMP-dependent protein kinase I (PKGI), induces the phosphorylation of serine 216 of RGS18 and the detachment of 14-3-3. Serine 216 phosphorylation is able to block 14-3-3 binding to RGS18 even in the presence of thrombin, thromboxane A2, or ADP. 14-3-3-deficient RGS18 is more active compared with 14-3-3-bound RGS18, leading to a more pronounced inhibition of thrombin-induced release of calcium ions from intracellular stores. Therefore, PKA- and PKGI-mediated detachment of 14-3-3 activates RGS18 to block Gq-dependent calcium signaling. These findings indicate cross-talk between platelet activation and inhibition pathways at the level of RGS18 and Gq. (Blood. 2012;119(16):3799-3807)