Petrich Brian G, Marchese Patrizia, Ruggeri Zaverio M, Spiess Saskia, Weichert Rachel A M, Ye Feng, Tiedt Ralph, Skoda Radek C, Monkley Susan J, Critchley David R, Ginsberg Mark H
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
J Exp Med. 2007 Dec 24;204(13):3103-11. doi: 10.1084/jem.20071800. Epub 2007 Dec 17.
Integrins are critical for hemostasis and thrombosis because they mediate both platelet adhesion and aggregation. Talin is an integrin-binding cytoplasmic adaptor that is a central organizer of focal adhesions, and loss of talin phenocopies integrin deletion in Drosophila. Here, we have examined the role of talin in mammalian integrin function in vivo by selectively disrupting the talin1 gene in mouse platelet precursor megakaryocytes. Talin null megakaryocytes produced circulating platelets that exhibited normal morphology yet manifested profoundly impaired hemostatic function. Specifically, platelet-specific deletion of talin1 led to spontaneous hemorrhage and pathological bleeding. Ex vivo and in vitro studies revealed that loss of talin1 resulted in dramatically impaired integrin alphaIIbbeta3-mediated platelet aggregation and beta1 integrin-mediated platelet adhesion. Furthermore, loss of talin1 strongly inhibited the activation of platelet beta1 and beta3 integrins in response to platelet agonists. These data establish that platelet talin plays a crucial role in hemostasis and provide the first proof that talin is required for the activation and function of mammalian alpha2beta1 and alphaIIbbeta3 integrins in vivo.
整合素对于止血和血栓形成至关重要，因为它们介导血小板的黏附和聚集。踝蛋白是一种与整合素结合的胞质衔接蛋白，是黏着斑的核心组织者，在果蝇中，踝蛋白缺失会模拟整合素缺失的表型。在此，我们通过选择性破坏小鼠血小板前体巨核细胞中的踝蛋白1基因，研究了踝蛋白在哺乳动物整合素体内功能中的作用。踝蛋白缺失的巨核细胞产生的循环血小板形态正常，但止血功能严重受损。具体而言，血小板特异性缺失踝蛋白1会导致自发性出血和病理性出血。体外和体内研究表明，踝蛋白1缺失会导致整合素αIIbβ3介导的血小板聚集和β1整合素介导的血小板黏附显著受损。此外，踝蛋白1缺失强烈抑制血小板β1和β3整合素对血小板激动剂的反应激活。这些数据表明血小板踝蛋白在止血中起关键作用，并首次证明踝蛋白是哺乳动物α2β1和αIIbβ3整合素在体内激活和功能所必需的。
