The role of Akt in the signaling pathway of the glycoprotein Ib-IX induced platelet activation.
The role of Akt in the signaling pathway of the glycoprotein Ib-IX induced platelet activation.
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DOI：
10.1182/blood-2007-04-085514
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发表时间：
2008-01
期刊：
影响因子：
20.3
通讯作者：
H. Yin;Aleksandra Stojanovic;N. Hay;Xiaoping Du
中科院分区：
文献类型：
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作者：
H. Yin;Aleksandra Stojanovic;N. Hay;Xiaoping Du
血小板血管性血友病因子（vWF）受体，糖蛋白Ib-IX（GPIb-IX），介导血小板粘附和诱导信号传导，导致整合素活化。磷酸肌醇3-激酶（PI 3 K）在GPIb-IX介导的信号传导中是重要的。然而，PI 3 K依赖的信号传导机制尚不清楚。我们发现，GPIb-IX诱导的血小板聚集和稳定的粘附在流动中受损的小鼠血小板缺乏PI 3 K效应，Akt 1和Akt 2，并在人类血小板与Akt抑制剂，SH-6处理。Akt 1和Akt 2在早期GPIb-IX信号传导中发挥重要作用，不依赖于Syk、二磷酸腺苷（ADP）或血栓烷A2（TXA 2），除了它们在ADP和TXA 2依赖性二级扩增途径中的公认作用外。敲除Akt 1或Akt 2可减少血小板在vWF上的铺展，但对固定的纤维蛋白原无影响。因此，Akt 1和Akt 2仅在GPIb-IX介导的整联蛋白活化（由内而外信号传导）中是必需的。相反，PI 3 K抑制剂消除血小板在vWF和纤维蛋白原上的铺展，表明PI 3 K在整合素由外向内信号传导中的作用不同于GPIb-IX介导的由内向外信号传导。此外，Akt 1或Akt 2缺陷减少vWF诱导的cGMP升高，其对GPIb-IX依赖性血小板粘附的抑制作用被外源性cGMP逆转。因此，Akt 1和Akt 2通过cGMP依赖性信号传导途径介导GPIb-IX信号传导。
The platelet von Willebrand factor (vWF) receptor, glycoprotein Ib-IX (GPIb-IX), mediates platelet adhesion and induces signaling leading to integrin activation. Phosphoinositol 3-kinase (PI3K) is important in GPIb-IX-mediated signaling. PI3K-dependent signaling mechanisms, however, are unclear. We show that GPIb-IX-induced platelet aggregation and stable adhesion under flow were impaired in mouse platelets deficient in PI3K effectors, Akt1 and Akt2, and in human platelets treated with an Akt inhibitor, SH-6. Akt1 and Akt2 play important roles in early GPIb-IX signaling independent of Syk, adenosine diphosphate (ADP), or thromboxane A2 (TXA2), in addition to their recognized roles in ADP- and TXA2-dependent secondary amplification pathways. Knockout of Akt1 or Akt2 diminished platelet spreading on vWF but not on immobilized fibrinogen. Thus, Akt1 and Akt2 are both required only in the GPIb-IX-mediated integrin activation (inside-out signaling). In contrast, PI3K inhibitors abolished platelet spreading on both vWF and fibrinogen, indicating a role for PI3K in integrin outside-in signaling distinct from that in GPIb-IX-mediated inside-out signaling. Furthermore, Akt1- or Akt2-deficiency diminished vWF-induced cGMP elevation, and their inhibitory effects on GPIb-IX-dependent platelet adhesion were reversed by exogenous cGMP. Thus, Akt1 and Akt2 mediate GPIb-IX signaling via the cGMP-dependent signaling pathway.