Pdlim7 Regulates Arf6-Dependent Actin Dynamics and Is Required for Platelet-Mediated Thrombosis in Mice.
Pdlim7 Regulates Arf6-Dependent Actin Dynamics and Is Required for Platelet-Mediated Thrombosis in Mice.
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DOI：
10.1371/journal.pone.0164042
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Simon HG
中科院分区：
文献类型：
--
作者：
Urban AE;Quick EO;Miller KP;Krcmery J;Simon HG
在血管损伤时，血小板被激活并迅速重组其肌动蛋白细胞骨架，以粘附在内皮损伤部位，引发富含纤维蛋白的塞的形成，以防止进一步的失血。Pdlim7的失活提供了新的视角，即血小板中肌动蛋白细胞骨架变化的调节依赖于编码的PDZ-LIM蛋白。Pdlim7的功能丧失会引发高凝血病，并导致小鼠明显的围产期死亡率。我们的体内和体外研究表明，Pdlim7沿着肌动蛋白纤维动态分布，缺乏Pdlim7导致肌动蛋白细胞骨架明显无法重排。具体来说，Pdlim7的缺失会阻止血小板将肌动蛋白纤维捆绑成一个同心环，从而定义活化血小板的圆形扩散形状。同样，在小鼠胚胎成纤维细胞中，Pdlim7的缺失会消除形成典型的细长成纤维细胞形状所需的应激纤维。除了揭示在肌动蛋白细胞骨架组织中的基本细胞生物学作用外，我们还证明了Pdlim7在调节Arf6的GTP/ gdp结合状态之间的循环中的功能。小GTPase Arf6是肌动蛋白动力学、细胞骨架重排和血小板活化所必需的重要因子。与我们的研究结果一致，初始f -肌动蛋白比率显著升高，随后出现形态畸变，Pdlim7的缺失导致静息血小板中Arf6-GTP水平升高。这些发现确定了一个新的Pdlim7- arf6轴控制肌动蛋白动力学，并暗示Pdlim7是血小板依赖性止血的主要内源性调节因子。
Upon vessel injury, platelets become activated and rapidly reorganize their actin cytoskeleton to adhere to the site of endothelial damage, triggering the formation of a fibrin-rich plug to prevent further blood loss. Inactivation of Pdlim7 provides the new perspective that regulation of actin cytoskeletal changes in platelets is dependent on the encoded PDZ-LIM protein. Loss-of-function of Pdlim7 triggers hypercoagulopathy and causes significant perinatal lethality in mice. Our in vivo and in vitro studies reveal that Pdlim7 is dynamically distributed along actin fibers, and lack of Pdlim7 leads to a marked inability to rearrange the actin cytoskeleton. Specifically, the absence of Pdlim7 prevents platelets from bundling actin fibers into a concentric ring that defines the round spread shape of activated platelets. Similarly, in mouse embryonic fibroblasts, loss of Pdlim7 abolishes the formation of stress fibers needed to adopt the typical elongated fibroblast shape. In addition to revealing a fundamental cell biological role in actin cytoskeletal organization, we also demonstrate a function of Pdlim7 in regulating the cycling between the GTP/GDP-bound states of Arf6. The small GTPase Arf6 is an essential factor required for actin dynamics, cytoskeletal rearrangements, and platelet activation. Consistent with our findings of significantly elevated initial F-actin ratios and subsequent morphological aberrations, loss of Pdlim7 causes a shift in balance towards an increased Arf6-GTP level in resting platelets. These findings identify a new Pdlim7-Arf6 axis controlling actin dynamics and implicate Pdlim7 as a primary endogenous regulator of platelet-dependent hemostasis.
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影响因子：
--
作者：
Camarata T;Snyder D;Schwend T;Klosowiak J;Holtrup B;Simon HG
通讯作者：
Simon HG
影响因子：
4
作者：
Krcmery, Jennifer;Camarata, Troy;Kulisz, Andre;Simon, Hans-Georg
通讯作者：
Simon, Hans-Georg
DOI：
10.1111/j.1538-7836.2007.02377.x
发表时间：
2007-03
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
--
作者：
Calaminus SD;McCarty OJ;Auger JM;Pearce AC;Insall RH;Watson SP;Machesky LM
通讯作者：
Machesky LM
影响因子：
2.7
作者：
Krause, A;Zacharias, W;Simon, HG
通讯作者：
Simon, HG
影响因子：
2.7
作者：
Bimber, Benjamin;Dettman, Robert W.;Simon, Hans-Georg
通讯作者：
Simon, Hans-Georg