Thromboxane A2 Activates YAP/TAZ Protein to Induce Vascular Smooth Muscle Cell Proliferation and Migration

J Biol Chem. 2016 Sep 2;291(36):18947-58. doi: 10.1074/jbc.M116.739722. Epub 2016 Jul 5.

Abstract

The thromboxane A2 receptor (TP) has been implicated in restenosis after vascular injury, which induces vascular smooth muscle cell (VSMC) migration and proliferation. However, the mechanism for this process is largely unknown. In this study, we report that TP signaling induces VSMC migration and proliferation through activating YAP/TAZ, two major downstream effectors of the Hippo signaling pathway. The TP-specific agonists [1S-[1α,2α(Z),3β(1E,3S*),4 α]]-7-[3-[3-hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (I-BOP) and 9,11-dideoxy-9α,11α-methanoepoxy-prosta-5Z,13E-dien-1-oic acid (U-46619) induce YAP/TAZ activation in multiple cell lines, including VSMCs. YAP/TAZ activation induced by I-BOP is blocked by knockout of the receptor TP or knockdown of the downstream G proteins Gα12/13 Moreover, Rho inhibition or actin cytoskeleton disruption prevents I-BOP-induced YAP/TAZ activation. Importantly, TP activation promotes DNA synthesis and cell migration in VSMCs in a manner dependent on YAP/TAZ. Taken together, thromboxane A2 signaling activates YAP/TAZ to promote VSMC migration and proliferation, indicating YAP/TAZ as potential therapeutic targets for cardiovascular diseases.

Keywords: G protein-coupled receptor (GPCR); Hippo pathway; TAZ; cell migration; thromboxane A2; vascular smooth muscle cells; yes-associated protein (YAP).

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cell Movement / physiology*
  • Cell Proliferation / physiology*
  • Fatty Acids, Unsaturated / pharmacology
  • GTP-Binding Protein alpha Subunits, G12-G13 / genetics
  • GTP-Binding Protein alpha Subunits, G12-G13 / metabolism
  • Gene Knockdown Techniques
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / metabolism*
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / metabolism*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Receptors, Thromboxane A2, Prostaglandin H2 / agonists
  • Receptors, Thromboxane A2, Prostaglandin H2 / genetics
  • Receptors, Thromboxane A2, Prostaglandin H2 / metabolism
  • Signal Transduction / physiology*
  • Thromboxane A2 / genetics
  • Thromboxane A2 / metabolism*
  • Transcription Factors

Substances

  • Adaptor Proteins, Signal Transducing
  • Bridged Bicyclo Compounds, Heterocyclic
  • Fatty Acids, Unsaturated
  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • Receptors, Thromboxane A2, Prostaglandin H2
  • Transcription Factors
  • WWTR1 protein, human
  • YAP1 (Yes-associated) protein, human
  • 7-(3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo(2.2.1)heptan-2-yl)-5-heptenoic acid
  • Thromboxane A2
  • GTP-Binding Protein alpha Subunits, G12-G13