Signaling-mediated cooperativity between glycoprotein Ib-IX and protease-activated receptors in thrombin-induced platelet activation
Signaling-mediated cooperativity between glycoprotein Ib-IX and protease-activated receptors in thrombin-induced platelet activation
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DOI：
10.1182/blood-2015-04-638387
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发表时间：
2016-02-04
期刊：
影响因子：
20.3
通讯作者：
Du, Xiaoping
中科院分区：
文献类型：
--
作者：
Estevez, Brian;Kim, Kyungho;Du, Xiaoping
凝血酶诱导的血小板细胞反应不仅需要蛋白酶激活受体（PAR），而且还涉及另一种凝血酶受体，糖蛋白Ib-IX复合物（GPIb-IX）。凝血酶与GPIb-IX结合如何刺激血小板反应仍有争议。有人提出GPIb-IX作为一个码头，促进凝血酶切割蛋白酶激活的受体，但也有报告表明，凝血酶结合GPIb-IX诱导血小板活化的PAR无关。在这里，我们表明，GPIb既不是一个被动的凝血酶码头，也不是PAR独立的信号受体。我们证明了一种新的信号介导的PAR和GPIb-IX之间的协同性。低剂量凝血酶诱导的PAR依赖性细胞应答需要GPIb-IX信号传导的协同性，相反，凝血酶诱导的GPIb-IX信号传导需要PAR的协同性。这种相互依赖的协同性需要GPIb-IX特异性14-3-3-Rac 1-LIMK 1信号传导途径，并且该途径的激活也需要PAR信号传导。因此，GPIb-IX信号传导和PAR信号传导之间的协同性在低浓度凝血酶下驱动血小板活化，这对于体内血栓形成是重要的。
Thrombin-induced cellular response in platelets not only requires protease-activated receptors (PARs), but also involves another thrombin receptor, the glycoprotein Ib-IX complex (GPIb-IX). It remains controversial how thrombin binding to GPIb-IX stimulates platelet responses. It was proposed that GPIb-IX serves as a dock that facilitates thrombin cleavage of protease-activated receptors, but there are also reports suggesting that thrombin binding to GPIb-IX induces platelet activation independent of PARs. Here we show that GPIb is neither a passive thrombin dock nor a PAR-independent signaling receptor. We demonstrate a novel signaling-mediated cooperativity between PARs and GPIb-IX. Low-dose thrombin-induced PAR-dependent cell responses require the cooperativity of GPIb-IX signaling, and conversely, thrombin-induced GPIb-IX signaling requires cooperativity of PARs. This mutually dependent cooperativity requires a GPIb-IX-specific 14-3-3-Rac1-LIMK1 signaling pathway, and activation of this pathway also requires PAR signaling. The cooperativity between GPIb-IX signaling and PAR signaling thus drives platelet activation at low concentrations of thrombin, which are important for in vivo thrombosis.