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

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

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)4193-4206
Number of pages14
JournalFASEB Journal
Volume23
Issue number12
DOIs
StatePublished - Dec 1 2009

Keywords

  • Actin cytoskeleton
  • Endothelium
  • G-protein-coupled receptors
  • Heterotrimeric G proteins

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    Han, J., Liu, G., Profirovic, J., Niu, J., & Voyno-Yasenetskaya, T. (2009). Zyxin is involved in thrombin signaling via interaction with PAR-1 receptor. FASEB Journal, 23(12), 4193-4206. https://doi.org/10.1096/fj.09-131862