1. Pentabromopseudilin: a myosin V inhibitor suppresses TGF-β activity by recruiting the type II TGF-β receptor to lysosomal degradation.
- Author
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Shih-Wei W, Chih-Ling C, Kao YC, Martin R, Knölker HJ, Shiao MS, and Chen CL
- Subjects
- Alteromonas chemistry, Animals, Cell Line, Dose-Response Relationship, Drug, HEK293 Cells, Hep G2 Cells, Humans, Mink, Molecular Structure, Myosin Type V metabolism, Protein Serine-Threonine Kinases biosynthesis, Pseudomonas chemistry, Pyrroles chemistry, Pyrroles isolation & purification, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta biosynthesis, Structure-Activity Relationship, Transforming Growth Factor beta metabolism, Lysosomes drug effects, Lysosomes metabolism, Myosin Type V antagonists & inhibitors, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyrroles pharmacology, Receptors, Transforming Growth Factor beta antagonists & inhibitors, Transforming Growth Factor beta antagonists & inhibitors
- Abstract
Pentabromopseudilin (PBrP) is a marine antibiotic isolated from the marine bacteria Pseudomonas bromoutilis and Alteromonas luteoviolaceus. PBrP exhibits antimicrobial, anti-tumour, and phytotoxic activities. In mammalian cells, PBrP is known to act as a reversible and allosteric inhibitor of myosin Va (MyoVa). In this study, we report that PBrP is a potent inhibitor of transforming growth factor-β (TGF-β) activity. PBrP inhibits TGF-β-stimulated Smad2/3 phosphorylation, plasminogen activator inhibitor-1 (PAI-1) protein production and blocks TGF-β-induced epithelial-mesenchymal transition in epithelial cells. PBrP inhibits TGF-β signalling by reducing the cell-surface expression of type II TGF-β receptor (TβRII) and promotes receptor degradation. Gene silencing approaches suggest that MyoVa plays a crucial role in PBrP-induced TβRII turnover and the subsequent reduction of TGF-β signalling. Because, TGF-β signalling is crucial in the regulation of diverse pathophysiological processes such as tissue fibrosis and cancer development, PBrP should be further explored for its therapeutic role in treating fibrotic diseases and cancer.
- Published
- 2018
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