The β isoform of the catalytic subunit of protein phosphatase 2B restrains platelet function by suppressing outside-in αII b β3 integrin signaling.
The β isoform of the catalytic subunit of protein phosphatase 2B restrains platelet function by suppressing outside-in αII b β3 integrin signaling.
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DOI：
10.1111/jth.12761
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发表时间：
2014-12
期刊：
影响因子：
--
通讯作者：
Vijayan KV
中科院分区：
文献类型：
--
作者：
Khatlani T;Pradhan S;Da Q;Gushiken FC;Bergeron AL;Langlois KW;Molkentin JD;Rumbaut RE;Vijayan KV
钙依赖性信号传导机制在血小板活化中发挥关键作用。与钙激活蛋白酶和激酶不同，钙激活蛋白丝氨酸/苏氨酸磷酸酶在血小板激活中的作用尚不清楚。评估蛋白磷酸酶 2B (PP2B) 或钙调磷酸酶催化亚基在血小板功能中的作用。在这里，我们发现 PP2B 活性的增加与激动剂诱导的人和小鼠血小板的激活有关。蛋白磷酸酶 2B (PP2B-A) 催化亚基的药理学抑制剂，例如环孢菌素 A (CsA) 或他克莫司 (FK506)，可增强人血小板的聚集。缺乏 PP2B-A β 亚型 (PP2B-Aβ−/−) 的小鼠血小板在低剂量激动剂浓度下表现出聚集增加。 PP2B-Aβ的缺失并不影响激动剂诱导的整合素αIIbβ3内向外信号传导，但增加了基础Src激活和p38丝裂原激活蛋白激酶（MAPK）的外向内αIIbβ3信号传导，同时增强了血小板在固定纤维蛋白原上的扩散和更大的纤维蛋白凝块收缩。 Src 抑制剂可阻断 PP2B-Aβ−/− 血小板中纤维蛋白原诱导的 p38 活化增加。 PP2B-Aβ−/− 血小板和 PP2B-Aβ 耗尽的人胚胎肾 293 αIIbβ3 细胞均表现出对固定纤维蛋白原的粘附增加。细丝蛋白 A 是一种肌动蛋白交联磷蛋白，已知与 β3 相关，在纤维蛋白原粘附的野生型中 Ser2152 上被去磷酸化，但在 PP2B-Aβ−/− 血小板中却没有去磷酸化。在 FeCl3 损伤血栓形成模型中，PP2B-Aβ−/− 小鼠表现出颈动脉闭塞时间缩短。这些观察结果表明，PP2B-Aβ 通过抑制由外向内的 αIIbβ3 整合素信号传导来限制血小板对血管损伤的反应。
Calcium dependent signaling mechanisms play a critical role in platelet activation. Unlike calcium-activated protease and kinase, the contribution of calcium-activated protein serine/threonine phosphatase in platelet activation is poorly understood. To assess the role of catalytic subunit of protein phosphatase 2B (PP2B) or calcineurin in platelet function. Here, we showed that an increase in PP2B activity was associated with agonist-induced activation of human and murine platelets. Pharmacological inhibitors of the catalytic subunit of protein phosphatase 2B (PP2B-A) such as cyclosporine A (CsA) or tacrolimus (FK506) potentiated aggregation of human platelets. Murine platelets lacking the β isoform of PP2B-A (PP2B-Aβ−/−) displayed increased aggregation with low doses of agonist concentrations. Loss of PP2B-Aβ did not affect agonist-induced integrin αIIbβ3 inside-out signaling, but increased basal Src activation and outside-in αIIbβ3 signaling to p38 mitogen activated protein kinase (MAPK), with a concomitant enhancement in platelet spreading on immobilized fibrinogen and greater fibrin clot retraction. Fibrinogen induced increased p38 activation in PP2B-Aβ−/− platelets were blocked by Src inhibitor. Both PP2B-Aβ−/− platelets and PP2B-Aβ depleted human embryonal kidney 293 αIIbβ3 cells displayed increased adhesion to immobilized fibrinogen. Filamin A, an actin crosslinking phosphoprotein that is known to associate with β3 was dephosphorylated on Ser2152 in fibrinogen adhered wild type but not in PP2B-Aβ−/− platelets. In a FeCl3 injury thrombosis model, PP2B-Aβ−/− mice showed decreased time to occlusion in the carotid artery. These observations suggest that PP2B-Aβ by suppressing outside-in αIIbβ3 integrin signaling limits platelet response to vascular injury.
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影响因子：
64.5
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