Zyxin is involved in thrombin signaling via interaction with PAR-1 receptor
Zyxin is involved in thrombin signaling via interaction with PAR-1 receptor
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DOI：
10.1096/fj.09-131862
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发表时间：
2009-12-01
期刊：
影响因子：
4.8
通讯作者：
Voyno-Yasenetskaya, Tatyana
中科院分区：
文献类型：
--
作者：
Han, Jingyan;Liu, Guoquan;Voyno-Yasenetskaya, Tatyana
蛋白酶激活受体1（PAR-1）介导人内皮细胞中的凝血酶信号传导。作为G蛋白偶联受体，PAR-1通过激活异源三聚体G蛋白Gi、Gq和G12/13传递凝血酶信号。在这项研究中，我们证明了zyxin，一个含LIM结构域的蛋白质，参与凝血酶介导的肌动蛋白细胞骨架重塑和血清反应元件（SRE）依赖的基因转录。我们确定zyxin结合到PAR-1的C-末端结构域，提供了zyxin作为PAR-1信号传导中的信号转导子参与的可能机制。数据显示，PAR-1-zyxin相互作用的中断抑制凝血酶诱导的应力纤维的形成和SRE激活支持这一假设。同样，zyxin使用siRNA耗竭抑制凝血酶诱导的肌动蛋白应力纤维的形成和SRE依赖的基因转录。此外，zyxin的耗尽导致延迟凝血酶治疗后的内皮屏障恢复。值得注意的是，zyxin的下调并不影响凝血酶诱导的RhoA或Gi、Gq和G12/13异源三聚体G蛋白的活化，这暗示了一种新的由PAR-1调节的信号通路，而不是由G蛋白介导的。观察到zyxin靶向VASP，zyxin的合作伙伴在调节肌动蛋白组装和动力学，以局灶性粘连和沿着应力纤维凝血酶刺激表明，zyxin可能参与凝血酶诱导的细胞骨架重塑通过募集VASP。总之，这项研究确立了zyxin在内皮细胞凝血酶信号传导中的关键作用，并为zyxin介导的新型PAR-1信号传导途径提供了证据。Han，J.，Liu，G.，Profirovic，J.，Niu，J.，沃伊诺-亚谢涅茨卡娅Zyxin通过与PAR-1受体相互作用参与凝血酶信号传导。FASEB J.23，4193-4206（2009）. www.fasebj.org
Protease-activated receptor 1 (PAR-1) mediates thrombin signaling in human endothelial cells. As a G-protein-coupled receptor, PAR-1 transmits thrombin signal through activation of the heterotrimeric G proteins, Gi, Gq, and G12/13. In this study, we demonstrated that zyxin, a LIM-domain-containing protein, is involved in thrombin-mediated actin cytoskeleton remodeling and serum response element (SRE)dependent gene transcription. We determined that zyxin binds to the C-terminal domain of PAR-1, providing a possible mechanism of involvement of zyxin as a signal transducer in PAR-1 signaling. Data showing that disruption of PAR-1-zyxin interaction inhibited thrombin-induced stress fiber formation and SRE activation supports this hypothesis. Similarly, depletion of zyxin using siRNA inhibited thrombin-induced actin stress fiber formation and SRE-dependent gene transcription. In addition, depletion of zyxin resulted in delay of endothelial barrier restoration after thrombin treatment. Notably, down-regulation of zyxin did not affect thrombin-induced activation of RhoA or Gi, Gq, and G12/13 heterotrimeric G proteins, implicating a novel signaling pathway regulated by PAR-1 that is not mediated by G-proteins. The observation that zyxin targets VASP, a partner of zyxin in regulation of actin assembly and dynamics, to focal adhesions and along stress fibers on thrombin stimulation suggests that zyxin may participate in thrombin-induced cytoskeletal remodeling through recruitment of VASP. In summary, this study establishes a crucial role of zyxin in thrombin signaling in endothelial cells and provides evidence for a novel PAR-1 signaling pathway mediated by zyxin.-Han, J., Liu, G., Profirovic, J., Niu, J., Voyno-Yasenetskaya, T. Zyxin is involved in thrombin signaling via interaction with PAR-1 receptor. FASEB J. 23, 4193-4206 (2009). www.fasebj.org