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首页> 外文期刊>Cellular Signalling >Isoform-specific roles of the GTPase activating protein Nadrin in cytoskeletal reorganization of platelets
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Isoform-specific roles of the GTPase activating protein Nadrin in cytoskeletal reorganization of platelets

机译：GTPase活化蛋白Nadrin在血小板细胞骨架重组中的同工型特异性作用

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Cytoskeletal reorganization of activated platelets plays a crucial role in hemostasis and thrombosis and implies activation of Rho GTPases. Rho GTPases are important regulators of cytoskeletal dynamics and function as molecular switches that cycle between an inactive and an active state. They are regulated by GTPase activating proteins (GAPs) that stimulate GTP hydrolysis to terminate Rho signaling. The regulation of Rho GTPases in platelets is not explored. A detailed characterization of Rho regulation is necessary to understand activation and inactivation of Rho GTPases critical for platelet activation and aggregation. Nadrin is a RhoGAP regulating cytoplasmic protein explored in the central nervous system. Five Nadrin isoforms are known that share a unique GAP domain, a serine/threonine/proline-rich domain, a SH3-binding motif and an N-terminal BAR domain but differ in their C-terminus. Here we identified Nadrin in platelets where it co-localizes to actin-rich regions and Rho GTPases. Different Nadrin isoforms selectively regulate Rho GTPases (RhoA, Cdc42 and Rac1) and cytoskeletal reorganization suggesting that - beside the GAP domain - the C-terminus of Nadrin determines Rho specificity and influences cell physiology. Furthermore, Nadrin controls RhoA-mediated stress fibre and focal adhesion formation. Spreading experiments on fibrinogen revealed strongly reduced cell adhesion upon Nadrin overexpression. Unexpectedly, the Nadrin BAR domain controls Nadrin-GAP activity and acts as a guidance domain to direct this GAP to its substrate at the plasma membrane. Our results suggest a critical role for Nadrin in the regulation of RhoA, Cdc42 and Rac1 in platelets and thus for platelet adhesion and aggregation.
机译：活化血小板的细胞骨架重组在止血和血栓形成中起关键作用，并暗示Rho GTPases的活化。 Rho GTPases是细胞骨架动力学的重要调节剂，并充当在非活性状态和活性状态之间循环的分子开关。它们由刺激GTP水解以终止Rho信号传导的GTPase活化蛋白（GAP）调节。没有探索Rho GTPases在血小板中的调控。 Rho调节的详细表征对于了解对血小板激活和聚集至关重要的Rho GTPases的激活和失活是必要的。 Nadrin是一种在中枢神经系统中探索的RhoGAP调节细胞质蛋白。已知五种Nadrin亚型，它们共有一个独特的GAP域，一个富含丝氨酸/苏氨酸/脯氨酸的域，一个SH3结合基序和一个N端BAR域，但它们的C末端不同。在这里，我们在血小板中鉴定了Nadrin，并将其共定位于富含肌动蛋白的区域和Rho GTPases。不同的Nadrin同工型选择性调节Rho GTPases（RhoA，Cdc42和Rac1）和细胞骨架重组，这表明，除了GAP结构域以外，Nadrin的C端决定Rho特异性并影响细胞生理。此外，Nadrin控制RhoA介导的应力纤维和粘着斑的形成。在纤维蛋白原上的铺展实验表明，Nadrin过表达后细胞粘附力大大降低。出乎意料的是，Nadrin BAR域控制Nadrin-GAP活性，并充当引导域，以将该GAP引导至质膜的底物。我们的结果表明，Nadrin在调节RhoA，Cdc42和Rac1在血小板中，从而在血小板粘附和聚集中起着至关重要的作用。

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