p21 activated kinase signaling coordinates glycoprotein receptor VI-mediated platelet aggregation, lamellipodia formation, and aggregate stability under shear.
p21 activated kinase signaling coordinates glycoprotein receptor VI-mediated platelet aggregation, lamellipodia formation, and aggregate stability under shear.
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DOI：
10.1161/atvbaha.112.301165
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发表时间：
2013-07
期刊：
影响因子：
--
通讯作者：
McCarty OJ
中科院分区：
文献类型：
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作者：
Aslan JE;Itakura A;Haley KM;Tormoen GW;Loren CP;Baker SM;Pang J;Chernoff J;McCarty OJ
Rho GT3蛋白在调节血小板肌动蛋白细胞骨架的动力学中起核心作用。然而，关于Rho GTdR活化如何协调血小板活化和功能知之甚少。在这项研究中，我们的目的是表征作用的Rho GTdR效应p21激活激酶（PAK）在血小板活化，板状伪足形成和聚集体的形成下剪切。用GPVI激动剂胶原相关肽（CRP）刺激血小板，在PAK底物LIMK1和MEK磷酸化之前的时间过程中迅速激活PAK，随后激活MAPK和Akt。PAK的药理学抑制剂阻断了PAK下游的信号传导事件，并阻止了血小板分泌以及血小板对CRP的反应性聚集。PAK抑制剂还防止PAK活化和血小板在胶原表面上的扩散。PAK也需要血小板聚集体的形成，并在生理剪切流条件下保持聚集体的稳定性。这些结果表明，PAK充当血小板胶原蛋白受体GPVI下游激活后血小板功能反应的协调者。
Rho GTPase proteins play a central role in regulating the dynamics of the platelet actin cytoskeleton. Yet, little is known regarding how Rho GTPase activation coordinates platelet activation and function. In this study, we aimed to characterize the role of the Rho GTPase effector p21 activated kinase (PAK) in platelet activation, lamellipodia formation and aggregate formation under shear. Stimulation of platelets with the GPVI agonist, collagen-related peptide (CRP), rapidly activated PAK in a time course preceding phosphorylation of PAK substrates LIMK1 and MEK and the subsequent activation of MAPKs and Akt. Pharmacological inhibitors of PAK blocked signaling events downstream of PAK and prevented platelet secretion as well as platelet aggregation in response to CRP. PAK inhibitors also prevented PAK activation and platelet spreading on collagen surfaces. PAK was also required for the formation of platelet aggregates and to maintain aggregate stability under physiological shear flow conditions. These results suggest that PAK serves an orchestrator of platelet functional responses following activation downstream of the platelet collagen receptor, GPVI.