Differential roles for the adapters Gads and LAT in platelet activation by GPVI and CLEC-2.
Differential roles for the adapters Gads and LAT in platelet activation by GPVI and CLEC-2.
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DOI：
10.1111/j.1538-7836.2008.03166.x
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发表时间：
2008-12
期刊：
影响因子：
--
通讯作者：
Watson SP
中科院分区：
文献类型：
--
作者：
Hughes CE;Auger JM;McGlade J;Eble JA;Pearce AC;Watson SP
背景：衔接蛋白SLP-76和LAT在血小板GPVI/FcRγ和C型凝集素受体CLEC-2下游的PLCγ2活化中发挥关键作用。SLP-76与血小板中的衔接子Gads组成性相关，衔接子Gads也与酪氨酸磷酸化LAT结合，从而提供了调节SLP-76的潜在途径。目的：在本研究中，我们比较了Gads的作用，以及LAT的激活后的主要血小板糖蛋白受体使用的两个衔接蛋白缺陷的小鼠。结果：Gads被发现是响应于GPVI和CLEC-2的次最大刺激的聚集和分泌的有效开始所必需的，但是在两种受体的更强刺激之后被抑制激活。Gads也被认为是通过整合素αIIbβ3或GPIb-IX-V复合物诱导的扩散。此外，Gads在小动脉剪切速率下在胶原蛋白上的聚集体形成中起可忽略的作用。与此形成鲜明对比的是，衔接LAT中缺乏的血小板在GPVI和CLEC-2活化后表现出聚集和分泌的显著减少，并且在小动脉剪切下不能在胶原蛋白上形成稳定的聚集体。结论：结果表明，Gads在连接接头LAT到SLP-76中起关键作用，以响应GPVI和CLEC-2的弱激活，而LAT是在更广泛的激动剂浓度范围内完全激活所必需的。这些结果揭示了LAT下游血小板活化的Gads非依赖性途径的存在。
Background:The adapter proteins SLP-76 and LAT have been shown to play critical roles in the activation of PLCγ2 in platelets downstream of GPVI/FcRγ and the C-type lectin receptor CLEC-2. SLP-76 is constitutively associated with the adapter Gads in platelets, which also binds to tyrosine phosphorylated LAT, thereby providing a potential pathway of regulation of SLP-76. Objective:In the present study, we have compared the role of Gads alongside that of LAT following activation of the major platelet glycoprotein receptors using mice deficient in the two adapter proteins. Results:Gads was found to be required for the efficient onset of aggregation and secretion in response to submaximal stimulation of GPVI and CLEC-2, but to be dispensable for activation following stronger stimulation of the two receptors. Gads was also dispensable for spreading induced through integrin αIIbβ3 or the GPIb–IX–V complex. Further, Gads plays a negligible role in aggregate formation on collagen at an arteriolar rate of shear. In stark contrast, platelets deficient in the adapter LAT exhibit a marked decrease in aggregation and secretion following activation of GPVI and CLEC-2, and are unable to form stable aggregates on collagen at arteriolar shear. Conclusions:The results demonstrate that Gads plays a key role in linking the adapter LAT to SLP-76 in response to weak activation of GPVI and CLEC-2 whereas LAT is required for full activation over a wider range of agonist concentrations. These results reveal the presence of a Gads-independent pathway of platelet activation downstream of LAT.
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