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基因靶向表明 Cdc42 GTP 酶参与了 GPVI 和非-GPVI 介导的血小板丝状伪足形成、分泌和聚集。

Gene targeting implicates Cdc42 GTPase in GPVI and non-GPVI mediated platelet filopodia formation, secretion and aggregation.

机构信息

Department of Biomedical Sciences, College of Osteopathic Medicine, Ohio University, Athens, Ohio, United States of America.

出版信息

PLoS One. 2011;6(7):e22117. doi: 10.1371/journal.pone.0022117. Epub 2011 Jul 18.

DOI:10.1371/journal.pone.0022117
PMID:21789221
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3138762/
Abstract

BACKGROUND

Cdc42 and Rac1, members of the Rho family of small GTPases, play critical roles in actin cytoskeleton regulation. We have shown previously that Rac1 is involved in regulation of platelet secretion and aggregation. However, the role of Cdc42 in platelet activation remains controversial. This study was undertaken to better understand the role of Cdc42 in platelet activation.

METHODOLOGY/PRINCIPAL FINDINGS: We utilized the Mx-cre;Cdc42(lox/lox) inducible mice with transient Cdc42 deletion to investigate the involvement of Cdc42 in platelet function. The Cdc42-deficient mice exhibited a significantly reduced platelet count than the matching Cdc42(+/+) mice. Platelets isolated from Cdc42(-/-), as compared to Cdc42(+/+), mice exhibited (a) diminished phosphorylation of PAK1/2, an effector molecule of Cdc42, (b) inhibition of filopodia formation on immobilized CRP or fibrinogen, (c) inhibition of CRP- or thrombin-induced secretion of ATP and release of P-selectin, (d) inhibition of CRP, collagen or thrombin induced platelet aggregation, and (e) minimal phosphorylation of Akt upon stimulation with CRP or thrombin. The bleeding times were significantly prolonged in Cdc42(-/-) mice compared with Cdc42(+/+) mice.

CONCLUSION/SIGNIFICANCE: Our data demonstrate that Cdc42 is required for platelet filopodia formation, secretion and aggregation and therefore plays a critical role in platelet mediated hemostasis and thrombosis.

摘要

背景

Rho 家族的小 GTP 酶成员 Cdc42 和 Rac1 在肌动蛋白细胞骨架调节中发挥关键作用。我们之前已经表明 Rac1 参与了血小板分泌和聚集的调节。然而，Cdc42 在血小板激活中的作用仍存在争议。本研究旨在更好地了解 Cdc42 在血小板激活中的作用。

方法/主要发现：我们利用 Mx-cre;Cdc42(lox/lox)诱导型小鼠进行瞬时 Cdc42 缺失，以研究 Cdc42 在血小板功能中的参与。Cdc42 缺陷型小鼠的血小板计数明显低于匹配的 Cdc42(+/+)小鼠。与 Cdc42(+/+)小鼠相比，从 Cdc42(-/-)小鼠分离的血小板表现出 (a) PAK1/2 的磷酸化减少，PAK1/2 是 Cdc42 的效应分子，(b) 固定化 CRP 或纤维蛋白原上的丝状伪足形成受到抑制，(c) CRP 或凝血酶诱导的 ATP 分泌和 P-选择素释放受到抑制，(d) CRP、胶原或凝血酶诱导的血小板聚集受到抑制，以及 (e) CRP 或凝血酶刺激时 Akt 的磷酸化最小。与 Cdc42(+/+)小鼠相比，Cdc42(-/-)小鼠的出血时间明显延长。

结论/意义：我们的数据表明，Cdc42 是血小板丝状伪足形成、分泌和聚集所必需的，因此在血小板介导的止血和血栓形成中发挥关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b2db/3138762/b30cac670205/pone.0022117.g008.jpg
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