Screening for Inhibitors of YAP Nuclear Localization Identifies Aurora Kinase A as a Modulator of Lung Fibrosis
| العنوان: | Screening for Inhibitors of YAP Nuclear Localization Identifies Aurora Kinase A as a Modulator of Lung Fibrosis |
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| المؤلفون: | Yang Yang, Daniela M. Santos, Lorena Pantano, Rachel Knipe, Elizabeth Abe, Amanda Logue, Gina Pronzati, Katharine E. Black, Jillian J. Spinney, Francesca Giacona, Michael Bieler, Cedrickx Godbout, Paul Nicklin, David Wyatt, Andrew M. Tager, Peter Seither, Franziska E. Herrmann, Benjamin D. Medoff |
| المصدر: | Am J Respir Cell Mol Biol |
| بيانات النشر: | American Thoracic Society, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Cell Nucleus, Pulmonary and Respiratory Medicine, Pulmonary Fibrosis, Clinical Biochemistry, Cell Cycle Proteins, YAP-Signaling Proteins, Cell Biology, Fibroblasts, Phosphoproteins, Idiopathic Pulmonary Fibrosis, Mice, Transforming Growth Factor beta, Animals, Humans, Molecular Biology, Original Research, Adaptor Proteins, Signal Transducing, Aurora Kinase A |
| الوصف: | Idiopathic pulmonary fibrosis is a progressive lung disease with limited therapeutic options that is characterized by pathological fibroblast activation and aberrant lung remodeling with scar formation. YAP (Yes-associated protein) is a transcriptional coactivator that mediates mechanical and biochemical signals controlling fibroblast activation. We previously identified HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) as YAP inhibitors based on a high-throughput small-molecule screen in primary human lung fibroblasts. Here we report that several Aurora kinase inhibitors were also identified from the top hits of this screen. MK-5108, a highly selective inhibitor for AURKA (Aurora kinase A), induced YAP phosphorylation and cytoplasmic retention and significantly reduced profibrotic gene expression in human lung fibroblasts. The inhibitory effect on YAP nuclear translocation and profibrotic gene expression is specific to inhibition of AURKA, but not Aurora kinase B or C, and is independent of the Hippo pathway kinases LATS1 and LATS2 (Large Tumor Suppressor 1 and 2). Further characterization of the effects of MK-5108 demonstrate that it inhibits YAP nuclear localization indirectly via effects on actin polymerization and TGFβ (Transforming Growth Factor β) signaling. In addition, MK-5108 treatment reduced lung collagen deposition in the bleomycin mouse model of pulmonary fibrosis. Our results reveal a novel role for AURKA in YAP-mediated profibrotic activity in fibroblasts and highlight the potential of small-molecule screens for YAP inhibitors for identification of novel agents with antifibrotic activity. |
| تدمد: | 1535-4989 1044-1549 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d6fada14bae95a8a79f19d9635326a85 https://doi.org/10.1165/rcmb.2021-0428oc |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....d6fada14bae95a8a79f19d9635326a85 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15354989 10441549 |
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