Pentabromopseudilin: a myosin V inhibitor suppresses TGF-β activity by recruiting the type II TGF-β receptor to lysosomal degradation

Journal of Enzyme Inhibition and Medicinal Chemistry

Wang Shih-Wei¹  Yu-Chen Kao¹  Chung Chih-Ling¹  Chun-Lin Chen²  Hans-Joachim Knölker³  René Martin³  Meng-Shin Shiao⁴ 

[1] Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC;Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC;Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung, Taiwan, RO;Department of Chemistry, TU Dresden, Dresden, Germany;Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand;

关键词: Myosin V;    pentabromopseudilin;    subcellular trafficking;    lipid-raft;    β;   

DOI  :  10.1080/14756366.2018.1465416

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY