RASA3 is a critical inhibitor of RAP1-dependent platelet activation
RASA3 is a critical inhibitor of RAP1-dependent platelet activation
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DOI：
10.1172/jci77993
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发表时间：
2015-04-01
影响因子：
15.9
通讯作者：
Bergmeier, Wolfgang
中科院分区：
文献类型：
--
作者：
Stefanini, Lucia;Paul, David S.;Bergmeier, Wolfgang
小的GTAPRAP 1对血小板活化和血栓形成至关重要。血小板中的RAP 1活性由GEF CalDAG-GEFI和一种未知的调节剂控制，该调节剂在二磷酸腺苷（ADP）受体P2 Y12（抗血栓治疗的靶点）下游起作用。在这里，我们提供的证据表明差距，RASA 3，抑制血小板活化，并提供了P2 Y12和RAP 1信号通路的激活之间的联系。在小鼠中，RASA 3的表达减少导致血小板过早活化，并显着降低循环血小板的寿命。增加的血小板周转率和由此产生的血小板减少症被逆转伴随删除的基因编码的CalDAG-GEFI。Rasa 3突变体血小板在体外和体内均对激动剂刺激反应过度。此外，Rasa 3突变体血小板的激活独立于ADP反馈信号发生，并且对P2 Y12或PI 3激酶的抑制剂不敏感。总之，我们的研究结果表明，RASA 3通过抑制CalDAG-GEFI/RAP 1信号传导确保循环血小板保持静止，并表明P2 Y12信号传导是抑制RASA 3和在血管损伤部位实现持续RAP 1依赖性血小板活化和血栓形成所必需的。这些发现提供了深入了解P2 Y12抑制剂的抗血栓形成作用，并可能导致改善血小板相关疾病的诊断和治疗。
The small GTPase RAP1 is critical for platelet activation and thrombus formation. RAP1 activity in platelets is controlled by the GEF CalDAG-GEFI and an unknown regulator that operates downstream of the adenosine diphosphate (ADP) receptor, P2Y12, a target of antithrombotic therapy. Here, we provide evidence that the GAP, RASA3, inhibits platelet activation and provides a link between P2Y12 and activation of the RAP1 signaling pathway. In mice, reduced expression of RASA3 led to premature platelet activation and markedly reduced the life span of circulating platelets. The increased platelet turnover and the resulting thrombocytopenia were reversed by concomitant deletion of the gene encoding CalDAG-GEFI. Rasa3 mutant platelets were hyperresponsive to agonist stimulation, both in vitro and in vivo. Moreover, activation of Rasa3 mutant platelets occurred independently of ADP feedback signaling and was insensitive to inhibitors of P2Y12 or PI3 kinase. Together, our results indicate that RASA3 ensures that circulating platelets remain quiescent by restraining CalDAG-GEFI/RAP1 signaling and suggest that P2Y12 signaling is required to inhibit RASA3 and enable sustained RAP1-dependent platelet activation and thrombus formation at sites of vascular injury. These findings provide insight into the antithrombotic effect of P2Y12 inhibitors and may lead to improved diagnosis and treatment of platelet-related disorders.