C3G contributes to platelet activation and aggregation by regulating major signaling pathways.,Signal Transduction and Targeted Therapy

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C3G contributes to platelet activation and aggregation by regulating major signaling pathways.
Signal Transduction and Targeted Therapy ( IF 40.8 ) Pub Date : 2020-04-01 , DOI: 10.1038/s41392-020-0119-9
Sara Gutiérrez-Herrero ₁ , Cristina Fernández-Infante _{1,

2} , Luis Hernández-Cano _{1,

2} , Sara Ortiz-Rivero ₁ , Carlos Guijas _{3,

4} , Víctor Martín-Granado ₁ , José Ramón González-Porras _{2,

5} , Jesús Balsinde _{3,

4} , Almudena Porras ₆ , Carmen Guerrero _{1,

2,

7}

Affiliation

C3G is a GEF (guanine nucleotide exchange factor) for Rap GTPases, among which the isoform Rap1b is an essential protein in platelet biology. Using transgenic mouse models with platelet-specific overexpression of C3G or mutant C3GΔCat, we have unveiled a new function of C3G in regulating the hemostatic function of platelets through its participation in the thrombin-PKC-Rap1b pathway. C3G also plays important roles in angiogenesis, tumor growth, and metastasis through its regulation of the platelet secretome. In addition, C3G contributes to megakaryopoiesis and thrombopoiesis. Here, we used a platelet-specific C3G-KO mouse model to further support the role of C3G in hemostasis. C3G-KO platelets showed a significant delay in platelet activation and aggregation as a consequence of the defective activation of Rap1, which resulted in decreased thrombus formation in vivo. Additionally, we explored the contribution of C3G-Rap1b to platelet signaling pathways triggered by thrombin, PMA or ADP, in the referenced transgenic mouse model, through the use of a battery of specific inhibitors. We found that platelet C3G is phosphorylated at Tyr504 by a mechanism involving PKC-Src. This phosphorylation was shown to be positively regulated by ERKs through their inhibition of the tyrosine phosphatase Shp2. Moreover, C3G participates in the ADP-P2Y12-PI3K-Rap1b pathway and is a mediator of thrombin-TXA2 activities. However, it inhibits the synthesis of TXA2 through cPLA2 regulation. Taken together, our data reveal the critical role of C3G in the main pathways leading to platelet activation and aggregation through the regulation of Rap1b.

中文翻译：

C3G 通过调节主要信号通路促进血小板活化和聚集。

C3G 是 Rap GTPases 的 GEF（鸟嘌呤核苷酸交换因子），其中同工型 Rap1b 是血小板生物学中的必需蛋白质。使用血小板特异性过表达 C3G 或突变体 C3GΔCat 的转基因小鼠模型，我们揭示了 C3G 通过参与凝血酶-PKC-Rap1b 途径来调节血小板止血功能的新功能。 C3G 还通过调节血小板分泌组在血管生成、肿瘤生长和转移中发挥重要作用。此外，C3G 有助于巨核细胞生成和血小板生成。在这里，我们使用血小板特异性 C3G-KO 小鼠模型来进一步支持 C3G 在止血中的作用。由于 Rap1 激活缺陷，C3G-KO 血小板显示血小板激活和聚集显着延迟，从而导致体内血栓形成减少。此外，我们通过使用一系列特定抑制剂，在参考的转基因小鼠模型中探索了 C3G-Rap1b 对凝血酶、PMA 或 ADP 触发的血小板信号传导途径的贡献。我们发现血小板 C3G 通过涉及 PKC-Src 的机制在 Tyr504 处被磷酸化。 ERK 通过抑制酪氨酸磷酸酶 Shp2 来积极调节这种磷酸化。此外，C3G 参与 ADP-P2Y12-PI3K-Rap1b 通路，并且是凝血酶-TXA2 活性的介质。然而，它通过 cPLA2 调节抑制 TXA2 的合成。综上所述，我们的数据揭示了 C3G 在通过 Rap1b 的调节导致血小板活化和聚集的主要途径中的关键作用。

更新日期：2020-04-01

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