Proteomic and phospho-proteomic profile of human platelets in basal, resting state: insights into integrin signaling.
Proteomic and phospho-proteomic profile of human platelets in basal, resting state: insights into integrin signaling.
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DOI：
10.1371/journal.pone.0007627
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发表时间：
2009-10-27
期刊：
影响因子：
3.7
通讯作者：
Gupta V
中科院分区：
文献类型：
--
作者：
Qureshi AH;Chaoji V;Maiguel D;Faridi MH;Barth CJ;Salem SM;Singhal M;Stoub D;Krastins B;Ogihara M;Zaki MJ;Gupta V
在动脉粥样硬化和血管炎症过程中，静息血小板被激活，通过内向外信号传导增加整合素α ib β3的表面表达和配体亲和力。凝血酶、ADP和肾上腺素等多种信号通过各自的gpcr转导信号，激活蛋白激酶，最终导致整合素αIIbβ3胞质尾部磷酸化，增强其功能。将信号从GPCR传递到整合素的胞质结构域的信号通路尚未明确。为了更好地理解这些途径，我们结合了蛋白质组学分析和分离的人类血小板的计算分析。我们分析了10个独立的人类样本，并在血小板中鉴定了总共1507种独特的蛋白质。这是迄今为止最全面的血小板蛋白质组，包括190个膜相关蛋白和262个磷酸化蛋白，这些蛋白是通过独立的蛋白质组学和磷酸化蛋白质组学分析鉴定的。我们使用这个蛋白质组学数据集创建了血小板蛋白-蛋白相互作用（PPI）网络，并应用了关于磷酸化步骤的新上下文信息，在PPI图中引入了有限的方向性。这个新开发的上下文PPI网络计算概括了整合素信号通路。最重要的是，我们的方法不仅提供了对静息血小板中整合素αIIbβ3激活机制的见解，而且为未来分析和发现PPI动力学和信号通路提供了改进的模型。
During atherogenesis and vascular inflammation quiescent platelets are activated to increase the surface expression and ligand affinity of the integrin αIIbβ3 via inside-out signaling. Diverse signals such as thrombin, ADP and epinephrine transduce signals through their respective GPCRs to activate protein kinases that ultimately lead to the phosphorylation of the cytoplasmic tail of the integrin αIIbβ3 and augment its function. The signaling pathways that transmit signals from the GPCR to the cytosolic domain of the integrin are not well defined. In an effort to better understand these pathways, we employed a combination of proteomic profiling and computational analyses of isolated human platelets. We analyzed ten independent human samples and identified a total of 1507 unique proteins in platelets. This is the most comprehensive platelet proteome assembled to date and includes 190 membrane-associated and 262 phosphorylated proteins, which were identified via independent proteomic and phospho-proteomic profiling. We used this proteomic dataset to create a platelet protein-protein interaction (PPI) network and applied novel contextual information about the phosphorylation step to introduce limited directionality in the PPI graph. This newly developed contextual PPI network computationally recapitulated an integrin signaling pathway. Most importantly, our approach not only provided insights into the mechanism of integrin αIIbβ3 activation in resting platelets but also provides an improved model for analysis and discovery of PPI dynamics and signaling pathways in the future.
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