title: Thromboxane A2 Activates YAP/TAZ Protein to Induce Vascular Smooth Muscle Cell Proliferation and Migration.
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.
authors.affiliation: From the Key Laboratory of Molecular Medicine of the Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Feng
authors.affiliation: From the Key Laboratory of Molecular Medicine of the Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: From the Key Laboratory of Molecular Medicine of the Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: From the Key Laboratory of Molecular Medicine of the Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Meng-Tian
authors.initials: MT
authors.lastname: Li
authors.affiliation: From the Key Laboratory of Molecular Medicine of the Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Fu-Long
authors.initials: FL
authors.lastname: Li
authors.affiliation: From the Key Laboratory of Molecular Medicine of the Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: the Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92130.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Meng
authors.affiliation: From the Key Laboratory of Molecular Medicine of the Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Sun
authors.affiliation: the Key Laboratory of Food Safety Research, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.affiliation: From the Key Laboratory of Molecular Medicine of the Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China, the Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599 yxiong@email.unc.edu.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: From the Key Laboratory of Molecular Medicine of the Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China, yuanhaixin@fudan.edu.cn.
authors.forename: Hai-Xin
authors.initials: HX
authors.lastname: Yuan
authors.affiliation: From the Key Laboratory of Molecular Medicine of the Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China, the Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92130, kuguan@ucsd.edu.
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013928:Thromboxane A2 / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C061750:7-(3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo(2.2.1)heptan-2-yl)-5-heptenoic acid; D013928:Thromboxane A2; D044365:GTP-Binding Protein alpha Subunits, G12-G13
keywords: G protein-coupled receptor (GPCR); Hippo pathway; TAZ; cell migration; thromboxane A2; vascular smooth muscle cells; yes-associated protein (YAP)