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Zyxin is involved in thrombin signaling via interaction with PAR-1 receptor

Jingyan Han^*, Guoquan Liu^*, Jasmina Profirovic^*, Jiaxin Niu^* and Tatyana Voyno-Yasenetskaya^*,

^* Department of Pharmacology and the

Center for Lung and Vascular Biology, University of Illinois, Chicago, Illinois, USA

¹ Correspondence: Department of Pharmacology (MC 868), University of Illinois at Chicago, 909 S. Wolcott Ave., Chicago, IL 60612, USA. E-mail: tvy{at}uic.edu

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.

Key Words: endothelium • G-protein-coupled receptors • actin cytoskeleton • heterotrimeric G proteins