Protein kinase C mediates platelet secretion and thrombus formation through protein kinase D2.
Protein kinase C mediates platelet secretion and thrombus formation through protein kinase D2.
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DOI：
10.1182/blood-2010-10-312199
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发表时间：
2011-07-14
期刊：
影响因子：
20.3
通讯作者：
Poole AW
中科院分区：
文献类型：
--
作者：
Konopatskaya O;Matthews SA;Harper MT;Gilio K;Cosemans JM;Williams CM;Navarro MN;Carter DA;Heemskerk JW;Leitges M;Cantrell D;Poole AW
血小板是高度专门化的血细胞，与止血和血栓形成密切相关。蛋白激酶C(PKC)家族成员在调节血小板功能和血栓形成中的作用已经确立，但其分子机制尚不清楚。特别是，传统的蛋白激酶C亚型α是血小板颗粒分泌的主要调节因子，但从蛋白激酶Cα到分泌的分子途径尚不清楚。蛋白激酶D(PKD)是由PKC激活的一个由3个激酶组成的家族，可能代表着PKC信号通路中分泌的一步。在目前的研究中，我们证明了PKD2是在血小板中PKC下游调节的唯一的PKD成员，而传统的但不是新的PKC亚型提供了上游信号。来自PKD2两个关键磷酸化位点突变的基因敲入小鼠(Ser707Ala/Ser711Ala)的血小板显示，激动剂诱导的致密颗粒分泌显著减少，但对α颗粒分泌无明显影响。这种致密颗粒释放的不足是导致血小板聚集减少和血栓形成显著减少的原因。我们的结果表明，在分泌的分子途径中，PKD2是PKC通过选择性调节致密颗粒分泌而介导的血小板活化和血栓形成途径的关键组成部分。
Platelets are highly specialized blood cells critically involved in hemostasis and thrombosis. Members of the protein kinase C (PKC) family have established roles in regulating platelet function and thrombosis, but the molecular mechanisms are not clearly understood. In particular, the conventional PKC isoform, PKCα, is a major regulator of platelet granule secretion, but the molecular pathway from PKCα to secretion is not defined. Protein kinase D (PKD) is a family of 3 kinases activated by PKC, which may represent a step in the PKC signaling pathway to secretion. In the present study, we show that PKD2 is the sole PKD member regulated downstream of PKC in platelets, and that the conventional, but not novel, PKC isoforms provide the upstream signal. Platelets from a gene knock-in mouse in which 2 key phosphorylation sites in PKD2 have been mutated (Ser707Ala/Ser711Ala) show a significant reduction in agonist-induced dense granule secretion, but not in α-granule secretion. This deficiency in dense granule release was responsible for a reduced platelet aggregation and a marked reduction in thrombus formation. Our results show that in the molecular pathway to secretion, PKD2 is a key component of the PKC-mediated pathway to platelet activation and thrombus formation through its selective regulation of dense granule secretion.