Sequential activation of p38 and ERK pathways by cGMP-dependent protein kinase leading to activation of the platelet integrin αIIbβ3
Sequential activation of p38 and ERK pathways by cGMP-dependent protein kinase leading to activation of the platelet integrin αIIbβ3
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DOI：
10.1182/blood-2005-03-1308
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发表时间：
2006-02-01
期刊：
影响因子：
20.3
通讯作者：
Du, XP
中科院分区：
文献类型：
--
作者：
Li, ZY;Zhang, GY;Du, XP
血小板中的整合素活化（由内向外信号传导）可由激动剂如血管性血友病因子（VWF）和凝血酶引发。在此，我们发现丝裂原活化蛋白激酶（MAPK）p38在VWF和凝血酶诱导的整合素α（IIb）β（3）活化中起重要作用。p38的显性失活突变体p38 AF抑制VWF与其受体血小板糖蛋白Ib-IX（GPIb-IX）结合诱导的α（IIb）β（3）活化，p38抑制剂减少VWF或低剂量凝血酶诱导的血小板聚集。p38抑制剂的抑制作用不太可能是由先前提出的对环氧合酶的作用引起的，因为在存在高浓度环氧合酶抑制剂阿司匹林的情况下也观察到抑制作用。VWF或凝血酶诱导p38活化，其在cGMP依赖性蛋白激酶（PKG）敲除的小鼠血小板和PKG受体处理的人血小板中被抑制，表明p38的活化在信号通路中PKG的下游。p38 AF或p38抑制剂减少PKG诱导的细胞外刺激应答激酶（ERK）的磷酸化，这在整合素活化中也是重要的。因此，p38在介导PKG依赖性ERK激活中起重要作用。这些数据描绘了一种新的信号通路，其中血小板激动剂依次激活PKG，p38和ERK通路，导致整合素激活。
Integrin activation (inside-out signaling) in platelets can be initiated by agonists such as von Willebrand factor (VWF) and thrombin. Here we show that a mitogen-activated protein kinase (MAPK), p38, plays an important role in the activation of integrin alpha(IIb)beta(3) induced by VWF and thrombin. A dominant-negative mutant of p38, p38AF, inhibits alpha(IIb)beta(3) activation induced by VWF binding to its receptor, the platelet glycoprotein Ib-IX (GPIb-IX), and p38 inhibitors diminish platelet aggregation induced by VWF or low-dose thrombin. The inhibitory effect of p38 inhibitor is unlikely to be caused by the previous suggested effect on cyclo-oxygenase, as inhibition also was observed in the presence of high concentrations of cyclooxygenase inhibitor, aspirin. VWF or thrombin induces p38 activation, which is inhibited in cGMP-dependent protein kinase (PKG)-knockout mouse platelets and PKG inhibitor-treated human platelets, indicating that activation of p38 is downstream from PKG in the signaling pathway. p38AF or p38 inhibitors diminish PKG-induced phosphorylation of extracellular stimuli-responsive kinase (ERK), which also is important in integrin activation. Thus, p38 plays an important role in mediating PKG-dependent activation of ERK. These data delineate a novel signaling pathway in which platelet agonists sequentially activate PKG, p38, and ERK pathways leading to integrin activation.