Fetal hemorrhage and platelet dysfunction in SLP-76-deficient mice
Fetal hemorrhage and platelet dysfunction in SLP-76-deficient mice
复制标题
DOI：
10.1172/jci5317
复制
发表时间：
1999-01-01
影响因子：
15.9
通讯作者：
Koretzky, GA
中科院分区：
文献类型：
--
作者：
Clements, JL;Lee, JR;Koretzky, GA
适配蛋白SLP-76在T淋巴细胞和髓系造血细胞中表达，被认为是T细胞抗原受体连接后被激活的蛋白酪氨酸激酶的底物。SLP-76在T细胞系中的瞬时过表达增强了T细胞受体连接后的转录激活，而SLP-76表达的缺失则取消了几条T细胞受体依赖的信号通路。缺乏SLP-76的突变小鼠在胸腺细胞发育的早期阶段表现出严重的阻碍，暗示SLP-76参与了促进胸腺细胞成熟的信号事件。虽然SLP-76在T淋巴细胞的发育和激活中发挥着关键作用，但对于它在其他类型的造血细胞中受体连接后启动的信号转导中的作用，人们了解得相对较少。在这份报告中，我们描述了SLP-76缺陷小鼠的胎儿出血和围产期死亡率。尽管在缺乏SLP-76的情况下巨核细胞和血小板发育正常，但胶原诱导的血小板聚集和颗粒释放明显受损。此外，胶原处理SLP-76缺陷的血小板不能诱导磷脂酶C-伽马2(PLC-伽马2)的酪氨酸磷酸化，提示SLP-76在PLC-伽马2激活的上游发挥作用。这些数据为SLP-76缺陷小鼠中观察到的胎儿出血提供了一种潜在的机制，并揭示了SLP-76的表达是血小板和T淋巴细胞中受体介导的最佳信号转导所必需的。
The adapter protein SLP-76 is expressed in T lymphocytes and hematopoietic cells of the myeloid lineage, and is known to be a substrate of the protein tyrosine kinases that are activated after ligation of the T-cell antigen receptor. Transient overexpression of SLP-76 in a T-cell line potentiates transcriptional activation after T-cell receptor ligation, while loss of SLP-76 expression abrogates several T-cell receptor-dependent signaling pathways. Mutant mice that lack SLP-76 manifest a severe block at an early stage of thymocyte development, implicating SLP-76 in signaling events that promote thymocyte maturation. While it is clear that SLP-76 plays a key role in development and activation of T lymphocytes, relatively little is understood regarding its role in transducing signals initiated after receptor ligation in other hematopoietic cell types. In this report, we describe fetal hemorrhage and perinatal mortality in SLP-76-deficient mice. Although megakaryocyte and platelet development proceeds normally in the absence of SLP-76, collagen-induced platelet aggregation and granule release is markedly impaired Furthermore, treatment of SLP-76-deficient platelets with collagen fails to elicit tyrosine phosphorylation of phospholipase C-gamma 2 (PLC-gamma 2), suggesting that SLP-76 functions upstream of PLC-gamma 2 activation. These data provide one potential mechanism for the fetal hemorrhage observed in SLP-76-deficient mice and reveal that SLP-76 expression is required for optimal receptor-mediated signal transduction in platelets as well as T lymphocytes.