Thrombospondins as matricellular modulators of cell function
Thrombospondins as matricellular modulators of cell function
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DOI：
10.1172/jci12749
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发表时间：
2001-04-01
影响因子：
15.9
通讯作者：
Bornstein, P
中科院分区：
文献类型：
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作者：
Bornstein, P
凝血酶反应蛋白1最初被鉴定为凝血酶敏感蛋白(TSP)，可在凝血酶激活血小板时释放，因此得名。当TSP1从激活的血小板中释放出来时，它以一种依赖于钙离子的方式与血小板表面结合。血小板结合的TSP1与整合素αIIbβ3和αvβ3相互作用，与CD36和整合素相关蛋白相互作用，与整合素结合的纤维蛋白原和纤维连接蛋白相互作用。早期的抗体抑制实验表明，TSP1是血小板聚集的第二分泌依赖阶段所必需的。最近，TSP1被证明通过与IAP(11)结合而激活αIIbβ3。这种相互作用导致血小板在纤维连接蛋白涂层的表面铺展，并组装包含整合素、IAP、c-Src、FAK和Syk蛋白激酶的信号复合体，最终导致血小板聚集。然而，这些发现现在必须与TSP1基因缺失的小鼠没有出血缺陷并显示出正常的凝血酶诱导的血小板聚集的报告相一致。可能，这些小鼠的代偿性变化保持了正常的血小板聚集潜力。TSP1还可以在血液中发挥其他功能，因为它被结合到纤维蛋白凝块中，并与许多血浆蛋白结合，包括纤维蛋白原、纤溶酶原和富含组氨酸的糖蛋白。另一方面，血小板TSP1主要作用于损伤和出血部位，影响参与伤口愈合的巨噬细胞、成纤维细胞和内皮细胞。矛盾的是，尽管TSP1存在于血小板中，而TSP2不存在，但TSP2基因缺失的小鼠表现出出血的素质(4)。Kyriakides等人(12)最近报道巨核细胞含有丰富的TSP2，其中大部分可能由骨髓基质细胞产生，并被细胞外环境中的巨核细胞摄取。TSP2是如何在巨核细胞碎裂形成血小板的过程中丢失的，目前还不清楚。来自TSP2缺失动物的血小板在体外对ADP反应的聚集能力降低，并且在体内小鼠颈总动脉裸露的内皮下形成聚集也受到损害(12)。因此，TSP2似乎是从巨核细胞生成正常血小板所必需的，但TSP2缺失的血小板产生的生化缺陷尚不清楚。鉴于在TSP2基因缺失的小鼠中观察到的异常的胶原纤维生成，也有可能是内皮下的异常可能导致体内血小板的缺陷聚集。
Thrombospondin 1 was first identified as a thrombin-sensitive protein (TSP) that was released in response to activation of platelets by thrombin, hence its name. Upon release from activated platelets, TSP1 binds to the platelet surface in a Ca2+-dependent manner. Platelet-bound TSP1 interacts with integrins αIIbβ3 and αvβ3, with CD36 and the integrin-associated protein (IAP), and with integrin-bound fibrinogen and fibronectin. Early antibody inhibition experiments indicated that TSP1 was required for the secondary secretion-dependent phase of platelet aggregation. More recently, TSP1 was shown to activate αIIbβ3 by its binding to IAP (11). This interaction results in spreading of platelets on fibronectincoated surfaces and assembly of a signaling complex containing the integrin, IAP, c-Src, FAK, and Syk protein kinase, and culminates in platelet aggregation. However, these findings must now be reconciled with the report that TSP1-null mice are free of bleeding defects and show normal thrombin-induced platelet aggregation (5). Possibly, compensatory changes in these mice maintain a normal potential for platelet aggregation. TSP1 may also perform other functions in blood, since it is incorporated into fibrin clots and binds to a number of plasma proteins including fibrinogen, plasminogen, and histidine-rich glycoprotein. On the other hand, platelet TSP1 could function primarily at sites of injury and bleeding to influence macrophages, fibroblasts, and endothelial cells that participate in wound healing. Paradoxically, although TSP1 is present in platelets and TSP2 is not, it is TSP2-null mice that display a bleeding diathesis (4). Kyriakides et al.(12) have recently reported that megakaryocytes contain abundant TSP2, most of which is probably produced by marrow stromal cells and is taken up by megakaryocytes from the extracellular milieu. Just how TSP2 is lost from megakaryocytes as they fragment to form platelets is not understood. Platelets from TSP2-null animals show a reduced ability to aggregate in vitro in response to ADP and are also compromised in the formation of aggregates on the denuded subendothelium of the common carotid artery of mice in vivo (12). TSP2 therefore seems to be required for the generation of normal platelets from megakaryocytes, but the resulting biochemical defect in TSP2-null platelets is not known. It is also possible, in view of the abnormal collagen fibrillogenesis observed in TSP2-null mice, that abnormalities in the subendothelium could contribute to the defective aggregation of platelets in vivo.