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首页> 外文期刊>Platelets >GPIbalpha-selective activation of platelets induces platelet signaling events comparable to GPVI activation events.
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GPIbalpha-selective activation of platelets induces platelet signaling events comparable to GPVI activation events.

机译：血小板的GPIbalpha选择性激活诱导了与GPVI激活事件相当的血小板信号事件。

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摘要

Platelet glycoprotein (GP)Ib-IX-V, which binds von Willebrand factor (VWF), and GPVI, which binds collagen, form an adhesion-signaling complex on platelets and mediate platelet adhesion in flowing blood. Platelet activation following engagement of GPIb-IX-V/GPVI by VWF/collagen is critical for initiation and development of a protective thrombus across a site of damaged or exposed endothelium. We examined platelet aggregation and signaling following selective engagement of platelet GPIbalpha (the major ligand-binding subunit of GPIb-IX-V) by a multivalent surface-expressed GPIbalpha-binding VWF-A1 domain on COS-7 cells. COS-7 cells expressing the VWF-A1 domain containing an R543W mutation (a gain-of-function mutation found in Type 2B von Willebrand's Disease) were used as a selective agonist for GPIb-IX-V. When incubated in a cell-to-platelet ratio of up to 1 : 1200, VWF-A1/R543W cells caused rapid, spontaneous aggregation of washed platelets that was GPIbalpha- and alpha(IIb)beta(3)-dependent (blocked by inhibitory anti-VWF-A1, anti-GPIbalpha and anti-alpha(IIb)beta(3) antibodies). Platelet aggregation was also sensitive to inhibitors of Src, phosphoinositide 3-kinase (PI3-kinase) or Syk, confirming a role for these proteins in GPIbalpha-mediated signal transduction. Platelet tyrosine phosphorylation patterns and specific tyrosine phosphorylation of Syk after GPIbalpha engagement by VWF-A1/R543W was comparable to that induced by engagement of GPVI by collagen or collagen-related peptide (CRP). These data indicate signaling events triggered by specific ligation of GPIbalpha can lead to robust platelet activation and help define GPIb-IX-V as both an adhesion and signaling receptor on platelets.
机译：结合冯维勒布兰德因子（VWF）的血小板糖蛋白（GP）Ib-IX-V和结合胶原蛋白的GPVI在血小板上形成粘附信号复合物并介导流动血液中的血小板粘附。 VWF /胶原蛋白与GPIb-IX-V / GPVI结合后的血小板活化对于在受损或暴露的内皮细胞部位启动和发展保护性血栓至关重要。我们在COS-7细胞上通过多价表面表达GPIbalpha结合VWF-A1域选择性参与血小板GPIbalpha（GPIb-IX-V的主要配体结合亚基）选择性参与后，检查了血小板聚集和信号传导。表达含有R543W突变（在2B型von Willebrand病中发现的功能获得性突变）的VWF-A1结构域的COS-7细胞用作GPIb-IX-V的选择性激动剂。当以高达1：1200的细胞与血小板比例孵育时，VWF-A1 / R543W细胞会导致冲洗血小板快速，自发聚集，这是GPIbalpha-和alpha（IIb）beta（3）依赖性的（被抑制性阻断）抗VWF-A1，抗GPIbalpha和抗alpha（IIb）beta（3）抗体）。血小板聚集对Src，磷酸肌醇3激酶（PI3激酶）或Syk的抑制剂也很敏感，证实了这些蛋白在GPIbalpha介导的信号转导中的作用。 VWF-A1 / R543W参与GPIbalpha后，血小板酪氨酸磷酸化模式和Syk的特定酪氨酸磷酸化与胶原蛋白或胶原相关肽（CRP）参与GPVI诱导的血小板酪氨酸磷酸化模式和特异性酪氨酸磷酸化相当。这些数据表明由GPIbalpha的特异性连接触发的信号传导事件可导致强大的血小板活化，并有助于将GPIb-IX-V定义为对血小板的粘附和信号传导受体。

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