PAK Membrane Translocation and Phosphorylation Regulate Platelet Aggregation Downstream of Gi and G12/13 Pathways
PAK Membrane Translocation and Phosphorylation Regulate Platelet Aggregation Downstream of Gi and G12/13 Pathways
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PAK 膜易位和磷酸化调节 Gi 和 G12/13 通路下游的血小板聚集
DOI：
10.1055/s-0040-1714745
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发表时间：
2020-08
影响因子：
6.7
通讯作者：
Zhongren Ding
中科院分区：
文献类型：
--
作者：
Jianjun Zhang;Yan Zhang;Shuang Zheng;Yangyang Liu;Lin Chang;Guanxing Pan;Liang Hu;Si Zhang;Junling Liu;Soochong Kim;Jianzeng Dong;Zhongren Ding
摘要血小板活化在生理性止血和病理性血栓形成中起着关键作用。先前的研究得出结论，Gi和G12/13信号通路的同时激活足以引起血小板聚集。然而，使用Gq敲除小鼠和Gq特异性抑制剂，我们在这里证明了Gi和G12/13共激活下游的血小板聚集取决于激动剂浓度; Gi和G12/13途径的共激活仅在较高的激动剂浓度下诱导血小板聚集。我们通过显示在低和高激动剂浓度下刺激的血小板中cAMP（环磷酸腺苷）减少和RhoA活化来证实Gi和G12/13途径活化。有趣的是，我们发现，虽然Akt和PAK（p21激活的激酶）易位到血小板膜上的低和高激动剂刺激，膜易位的Akt和PAK仅在高激动剂浓度磷酸化，以及与伴随Gi和G12/13途径激活的血小板聚集下游相关。PAK抑制剂消除Akt磷酸化，抑制体外血小板聚集和体内动脉血栓形成。我们认为PAK-PI 3 K/Akt通路介导了Gi和G12/13下游的血小板聚集，PAK可能是一个潜在的抗血小板和抗血栓的靶点。
Abstract Platelet activation plays a pivotal role in physiological hemostasis and pathological thrombosis causing heart attack and stroke. Previous studies conclude that simultaneous activation of Gi and G12/13 signaling pathways is sufficient to cause platelet aggregation. However, using Gq knockout mice and Gq-specific inhibitors, we here demonstrated that platelet aggregation downstream of coactivation of Gi and G12/13 depends on agonist concentrations; coactivation of Gi and G12/13 pathways only induces platelet aggregation under higher agonist concentrations. We confirmed Gi and G12/13 pathway activation by showing cAMP (cyclic adenosine monophosphate) decrease and RhoA activation in platelets stimulated at both low and high agonist concentrations. Interestingly, we found that though Akt and PAK (p21-activated kinase) translocate to the platelet membrane upon both low and high agonist stimulation, membrane-translocated Akt and PAK only phosphorylate at high agonist concentrations, correlating well with platelet aggregation downstream of concomitant Gi and G12/13 pathway activation. PAK inhibitor abolishes Akt phosphorylation, inhibits platelet aggregation in vitro and arterial thrombus formation in vivo. We propose that the PAK-PI3K/Akt pathway mediates platelet aggregation downstream of Gi and G12/13, and PAK may represent a potential antiplatelet and antithrombotic target.
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影响因子：
6.7
作者：
Dangelmaier C;Manne BK;Liverani E;Jin J;Bray P;Kunapuli SP
通讯作者：
Kunapuli SP
影响因子：
5.5
作者：
Aslan, Joseph E.;Baker, Sandra M.;McCarty, Owen J. T.
通讯作者：
McCarty, Owen J. T.
影响因子：
64.5
作者：
Manning BD;Toker A
通讯作者：
Toker A
影响因子：
20.3
作者：
H. Yin;Aleksandra Stojanovic;N. Hay;Xiaoping Du
通讯作者：
H. Yin;Aleksandra Stojanovic;N. Hay;Xiaoping Du
影响因子：
3.5
作者：
Savi, P;Beauverger, P;Herbert, JM
通讯作者：
Herbert, JM