Platelet procoagulant phenotype is modulated by a p38-MK2 axis that regulates RTN4/Nogo proximal to the endoplasmic reticulum: utility of pathway analysis
Platelet procoagulant phenotype is modulated by a p38-MK2 axis that regulates RTN4/Nogo proximal to the endoplasmic reticulum: utility of pathway analysis
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DOI：
10.1152/ajpcell.00177.2017
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发表时间：
2018-05-01
影响因子：
5.5
通讯作者：
Aslan, Joseph E.
中科院分区：
文献类型：
--
作者：
Babur, Ozgun;Ngo, Anh T. P.;Aslan, Joseph E.
当遇到与内皮受损或炎症相关的生理信号时，血小板会在细胞内做出反应，最终支持止血栓的形成和血管修复。为了深入了解潜在的血小板功能的分子事件，我们使用交互作用组、通路分析和其他系统生物学工具的组合来分析可逆磷酸化修饰的蛋白质与血小板激活之间的关联。相互作用分析揭示了细胞内介质在血小板信号转导中的相对组织结构，而通路分析揭示了与血小板细胞骨架动力学、炎症反应和止血功能相关的蛋白激酶C(PKC)亚型和丝裂原活化蛋白激酶(MAPK)之间的定向信号关系。途径和因果关系分析进一步表明，血小板激活一个特定的p38-MK2轴来磷酸化RTN4(网状蛋白-4，也称为Nogo)，RTN4是一种Bclxl隔离蛋白，也是内质网(ER)生理的关键调节因子。在体外，我们发现，血小板驱动p38-MK2-RTN4-Bclxl通路，与调节ER和血小板磷脂酰丝氨酸暴露有关。总之，我们的结果支持在组学数据集分析中使用途径工具，作为一种手段来帮助为血小板研究产生新的、机械的和可检验的假说，同时揭示RTN4作为一种假定的血小板细胞生理反应调节因子。
Upon encountering physiological cues associated with damaged or inflamed endothelium, blood platelets set forth intracellular responses to ultimately support hemostatic plug formation and vascular repair. To gain insights into the molecular events underlying platelet function, we used a combination of interactome, pathway analysis, and other systems biology tools to analyze associations among proteins functionally modified by reversible phosphorylation upon platelet activation. While an interaction analysis mapped out a relative organization of intracellular mediators in platelet signaling, pathway analysis revealed directional signaling relations around protein kinase C (PKC) isoforms and mitogen-activated protein kinases (MAPKs) associated with platelet cytoskeletal dynamics, inflammatory responses, and hemostatic function. Pathway and causality analysis further suggested that platelets activate a specific p38-MK2 axis to phosphorylate RTN4 (reticulon-4, also known as Nogo), a Bcl-xl sequestration protein and critical regulator of endoplasmic reticulum (ER) physiology. In vitro, we find that platelets drive a p38-MK2-RTN4-Bcl-xl pathway associated with the regulation of the ER and platelet phosphatidylserine exposure. Together, our results support the use of pathway tools in the analysis of omics data sets as a means to help generate novel, mechanistic, and testable hypotheses for platelet studies while uncovering RTN4 as a putative regulator of platelet cell physiological responses.