The role of Rac1 in glycoprotein Ib-IX-mediated signal transduction and integrin activation.
The role of Rac1 in glycoprotein Ib-IX-mediated signal transduction and integrin activation.
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DOI：
10.1161/atvbaha.112.254920
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发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Du X
中科院分区：
文献类型：
--
作者：
Delaney MK;Liu J;Zheng Y;Berndt MC;Du X
血管性血友病因子（vonWillebrand factor，VWF）的血小板受体，即糖蛋白Ib-IX（GPIb-IX）复合物，介导血管损伤部位的血小板粘附并传递导致血小板活化的信号。VWF/GPIb-IX相互作用依次激活Src家族激酶（SFK）林恩、磷酸肌醇3-激酶（PI 3 K）和Akt，导致整合素αIIbβ3活化，以及整合素依赖性稳定血小板粘附和聚集。目前尚不清楚配体与GPIb-IX结合后，林恩如何激活PI 3 K/Akt途径。使用血小板特异性Rac 1 −/−小鼠和Rac 1抑制剂NSC 23766，我们研究了Rac 1在GPIb-IX依赖性血小板活化中的作用。Rac 1 −/−小鼠血小板和NSC 23766处理的人血小板在剪切应力下GPIb依赖性与VWF的稳定粘附、整合素活化、血栓烷A2（TXA 2）合成和血小板聚集方面存在缺陷。有趣的是，GPIb诱导的Rac 1和Rac 1的鸟嘌呤核苷酸交换因子（GEF）Vav的激活在林恩−/−和PP 2处理的血小板中均被消除，但不受PI 3 K抑制剂LY-294002的影响，表明林恩介导Vav和Rac 1的激活独立于PI 3 K。此外，GPIb诱导的Akt活化在Rac 1缺陷的血小板中被消除，表明Rac 1是PI 3 K/Akt通路的上游。林恩/Vav/Rac 1/PI 3 K/Akt通路介导VWF诱导的整合素αIIbβ3活化，促进GPIb IX依赖性血小板活化。
The platelet receptor for von Willebrand factor (VWF), the glycoprotein Ib-IX (GPIb-IX) complex, mediates platelet adhesion at sites of vascular injury and transmits signals leading to platelet activation. VWF/GPIb-IX interaction sequentially activates the Src Family Kinase (SFK) Lyn, phosphoinositide 3-kinase (PI3K) and Akt, leading to activation of integrin αIIbβ3, and integrin-dependent stable platelet adhesion and aggregation. It remains unclear how Lyn activates the PI3K/Akt pathway following ligand binding to GPIb-IX. Using platelet-specific Rac1−/− mice and the Rac1 inhibitor NSC23766, we examined the role of Rac1 in GPIb-IX-dependent platelet activation. Rac1−/− mouse platelets and NSC23766-treated human platelets were defective in GPIb-dependent stable adhesion to VWF under shear stress, integrin activation, thromboxane A2 (TXA2) synthesis and platelet aggregation. Interestingly, GPIb-induced activation of Rac1 and the guanine nucleotide exchange factor (GEF) for Rac1,Vav, was abolished in both Lyn−/− and PP2-treated platelets but was unaffected by the PI3K inhibitor LY-294002, indicating that Lyn mediates activation of Vav and Rac1 independently of PI3K. Furthermore, GPIb-induced activation of Akt was abolished in Rac1-deficient platelets, suggesting that Rac1 is upstream of the PI3K/Akt pathway. A Lyn/Vav/Rac1/PI3K/Akt pathway mediates VWF-induced activation of integrin αIIbβ3 to promote GPIb-IX-dependent platelet activation.