Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA 92122, USA.
Thromb Haemost. 2009 Jun;101(6):1020-4.
Integrins are heterodimeric adhesion receptors essential for metazoan life. In addition to mediating cell-extracellular matrix and cell-cell interactions, integrins are bona fide signalling receptors in that they transmit information in both directions across the plasma membrane. The affinity of integrins for extracellular ligands is regulated through a process termed integrin activation or "inside-out signalling". On the other hand, ligand binding to integrins can induce the recruitment and activation of a number of enzymes and adaptors such as pp125(FAK) and Src family kinases, to initiate "outside-in signalling". Intensive investigation into the mechanisms of integrin signalling has revealed many of the key players; amongst these, one of the most important is talin. Our understanding of how many of these molecules interact is now understood at the atomic level thanks to detailed structural studies. Indeed structural information and model cell systems have provided unique opportunities to dissect the molecular mechanisms of many aspects of integrin signalling. Recent studies have begun testing the biological significance of these mechanisms using in-vivo models, particular genetically modified mice. The generation and characterisation of in-vivo models to study integrin signalling has provided valuable information into the functional significance of integrin signalling in fundamental physiological processes as well as within the context of human disease. Here, I will review recent insights that have been gained into integrin signalling through the use of genetically modified mice focusing on integrin alphaIIbbeta3 (GPIIb-IIIa) and the regulation of its function in haemostasis and thrombosis.
整合素是多细胞生物生命所必需的异二聚体粘附受体。除了介导细胞-细胞外基质和细胞-细胞相互作用外，整合素还是真正的信号受体，因为它们可以在质膜两侧双向传递信息。整合素与细胞外配体的亲和力通过称为整合素激活或“内-外信号”的过程来调节。另一方面，配体与整合素的结合可以诱导许多酶和衔接子的募集和激活，如 pp125(FAK)和 Src 家族激酶，从而启动“外-内信号”。对整合素信号转导机制的深入研究揭示了许多关键分子；其中，最重要的分子之一是桩蛋白。由于详细的结构研究，我们现在已经在原子水平上了解了这些分子相互作用的许多方面。事实上，结构信息和模型细胞系统为剖析整合素信号转导的许多方面的分子机制提供了独特的机会。最近的研究已经开始使用体内模型，特别是基因修饰小鼠，来测试这些机制的生物学意义。为研究整合素信号转导而生成和表征的体内模型为整合素信号转导在基本生理过程以及人类疾病中的功能意义提供了有价值的信息。在这里，我将回顾通过使用基因修饰小鼠获得的关于整合素信号转导的最新见解，重点介绍整合素 alphaIIbbeta3 (GPIIb-IIIa)及其在止血和血栓形成中功能调节。
