Genetic evidence for a predominant role of PI3Kβ catalytic activity in ITAM- and integrin-mediated signaling in platelets
Genetic evidence for a predominant role of PI3Kβ catalytic activity in ITAM- and integrin-mediated signaling in platelets
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DOI：
10.1182/blood-2009-03-208074
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发表时间：
2009-09-03
期刊：
影响因子：
20.3
通讯作者：
Torti, Mauro
中科院分区：
文献类型：
--
作者：
Canobbio, Ilaria;Stefanini, Lucia;Torti, Mauro
磷脂酰肌醇3-激酶（PI3K）异构体PI3K β和PI3K γ与血小板粘附、活化和聚集有关，但它们的相对作用尚不清楚或存在争议。在这里，我们报告了对表达PI3K β或PI3K γ催化失活形式的小鼠血小板的首次比较功能分析。我们证明，这两种同工异构体同样需要最大限度地激活小GTPase Rap1b，并在G蛋白偶联受体的5'-二磷酸腺苷（ADP）或U46619刺激下完成血小板聚集。然而，他们对这些事件的贡献在很大程度上是多余和可有可无的。然而，Akt磷酸化、Rap1激活以及携带受体糖蛋白VI （GPVI）的免疫受体酪氨酸激活基元（ITAM）下游的血小板聚集，绝对需要PI3K β酶活性，而非PI3K γ酶活性。此外，PI3K β是血小板粘附纤维蛋白原和整合素α (IIb) β(3)介导的扩散的重要调节因子。这些结果为PI3K β在GPVI和整合素α (IIb) β信号传导中的关键和选择性作用提供了遗传学证据(3)。(血。2009;114:2193 - 2196)
Phosphatidylinositol 3-kinase (PI3K) isoforms PI3K beta and PI3K gamma are implicated in platelet adhesion, activation, and aggregation, but their relative contribution is still unclear or controversial. Here, we report the first comparative functional analysis of platelets from mice expressing a catalytically inactive form of PI3K beta or PI3K gamma. We demonstrate that both isoforms were similarly required for maximal activation of the small GTPase Rap1b and for complete platelet aggregation upon stimulation of G protein-coupled receptors for adenosine 5'-diphosphate (ADP) or U46619. Their contribution to these events, however, was largely redundant and dispensable. However, PI3K beta, but not PI3K gamma, enzymatic activity was absolutely required for Akt phosphorylation, Rap1 activation, and platelet aggregation down-stream of the immunoreceptor tyrosine-based activation motif (ITAM)-bearing receptor glycoprotein VI (GPVI). Moreover, PI3K beta was a major essential regulator of platelet adhesion to fibrinogen and of integrin alpha(IIb)beta(3)-mediated spreading. These results provide genetic evidence for a crucial and selective role of PI3K beta in signaling through GPVI and integrin alpha(IIb)beta(3). (Blood. 2009;114:2193-2196)