Deficiency of Src homology 2 domain-containing inositol 5-phosphatase 1 affects platelet responses and thrombus growth
Deficiency of Src homology 2 domain-containing inositol 5-phosphatase 1 affects platelet responses and thrombus growth
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DOI：
10.1172/jci29967
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发表时间：
2007-04-01
影响因子：
15.9
通讯作者：
Payrastre, Bernard
中科院分区：
文献类型：
--
作者：
Severin, Sonia;Gratacap, Marie-Pierre;Payrastre, Bernard
血小板对于正常止血至关重要。它们的失调会导致出血或动脉血栓形成，这是心脏病发作和缺血性中风的主要原因。含Src同源2结构域的肌醇5-磷酸酶1（SHIP 1）是能够将磷脂酰肌醇3，4，5-三磷酸第二信使脱磷酸化为磷脂酰肌醇3，4-二磷酸的5-磷酸酶。SHIP 1在调节血小板中这两种脂质的水平中起关键作用。使用SHIP 1缺陷小鼠，我们发现它的损失影响血小板聚集反应的几种激动剂与纤维蛋白原结合和β 3整合素酪氨酸磷酸化的影响较小。因此，SHIP 1基因敲除小鼠在局部激光诱导损伤后动脉血栓形成方面表现出缺陷。此外，这些小鼠具有延长的尾部出血时间。刺激后，SHIP 1缺陷型血小板表现出大的膜延伸，开放的小管系统异常，密切的细胞-细胞接触急剧减少。有趣的是，SHIP 1似乎是血小板收缩性、血栓机化和纤维蛋白凝块收缩所必需的。这些数据表明，SHIP 1是血小板信号传导机制的重要组成部分，以支持正常止血。据我们所知，这是首次报道阐明SHIP 1在造血细胞活化中的重要功能，与其在淋巴细胞负调节中的充分记录的作用相反。
Platelets are critical for normal hemostasis. Their deregulation can lead to bleeding or to arterial thrombosis, a primary cause of heart attack and ischemic stroke. Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIPl) is a 5-phosphatase capable of dephosphorylating the phosphatidylinositol 3,4,5-trisphosphate second messenger into phosphatidylinositol 3,4-bisphosphate. SHIP1 plays a critical role in regulating the level of these 2 lipids in platelets. Using SHIP1-deficient mice, we found that its loss affects platelet aggregation in response to several agonists with minor effects on fibrinogen binding and (33 integrin tyrosine phosphorylation. Accordingly, SHIP1-null mice showed defects in arterial thrombus formation in response to a localized laser-induced injury. Moreover, these mice had a prolonged tail bleeding time. Upon stimulation, SHIP1-deficient platelets showed large membrane extensions, abnormalities in the open canalicular system, and a dramatic decrease in close cell-cell contacts. Interestingly, SHIP1 appeared to be required for platelet contractility, thrombus organization, and fibrin clot retraction. These data indicate that SHIP1 is an important element of the platelet signaling machinery to support normal hemostasis. To our knowledge, this is the first report unraveling an important function of SHIPl in the activation of hematopoietic cells, in contrast to its well-documented role in the negative regulation of lymphocytes.