caa a22 4500 606236082 CHVBK 20210128101246.0 cr unu---uuuuu 210128e20150801xx s 000 0 eng 10.1007/s11010-015-2443-x doi (NATIONALLICENCE)springer-10.1007/s11010-015-2443-x MAPK inhibitors modulate Smad2/3/4 complex cyto-nuclear translocation in myofibroblasts via Imp7/8 mediation [Elektronische Daten] [Yufeng Jiang, Chao Wu, Alex Boye, Jiajun Wu, Jiyu Wang, Xiaochuan Yang, Yan Yang] Mitogen-activated protein kinase (MAPK) pathway-dependent linker phosphorylation of Smad2/3 and subsequent formation of Smad2/3/4 complex and its nuclear translocation are crucial for dysregulated transforming growth factor beta (TGF)-β/Smad signaling in liver fibrosis. Abrogation of this critical step of TGF-β/Smad signaling leading to liver fibrosis could provide new insights for future therapy, but the mechanisms remain incompletely understood. In pursuit, we investigated the subcellular expression and nuclear trafficking of the rate limiting Smad2/3/4 complex in exogenous TGF-β1-stimulated myofibroblasts (MFBs) using three MAPK-specific inhibitors. Our results showed that exogenous TGF-β1 stimulation of MFBs produced both increased protein expression and nuclear translocation of phosphorylated (p)-Smad2C/L, oncogenic pSmad3L, Smad4, importin7/8 (Imp7/8), and plasminogen activator inhibitor (PAI)-1 (Protein and mRNA), while decreased Smad7 protein expression. However, the MAPK-specific inhibitors differentially reversed these observations; for instance, ERK-specific inhibitor blocked the expression and nuclear translocation of pSmad2C/L, while both JNK and p38-specific inhibitors blocked the expression and nuclear translocation of pSmad2C/L and oncogenic pSmad3L. The MAPK-specific inhibitors had no significant effect on the total protein expression of Smad4, but rather significantly blocked its nuclear translocation. All the MAPK-specific inhibitors restored Smad7 expression and also decreased Imp7/8 and PAI-1 (Protein and mRNA) expression. Evidently, the MAPK-specific inhibitors blocked Smad2/3/4 complex formation via restoration of inhibitory Smad7 expression and blockade of Smad3L phosphorylation, while they blocked nuclear translocation of Smad2/3/4 complex through inhibition of Imp7/8 leading to decreased PAI-1 (Protein and mRNA) expression. Springer Science+Business Media New York, 2015 Myofibroblasts nationallicence Imp7/8 nationallicence MAPK inhibitors nationallicence PAI-1 nationallicence Smads nationallicence TGF-β1 nationallicence Jiang Yufeng Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, 230032, Hefei, China aut Wu Chao Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, 230032, Hefei, China aut Boye Alex Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, 230032, Hefei, China aut Wu Jiajun Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, 230032, Hefei, China aut Wang Jiyu Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, 230032, Hefei, China aut Yang Xiaochuan Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, 230032, Hefei, China aut Yang Yan Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, 230032, Hefei, China aut Molecular and Cellular Biochemistry Springer US; http://www.springer-ny.com 406/1-2(2015-08-01), 255-262 0300-8177 406:1-2<255 2015 406 11010 https://doi.org/10.1007/s11010-015-2443-x text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s11010-015-2443-x text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Jiang Yufeng Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, 230032, Hefei, China aut NATIONALLICENCE 700 1- Wu Chao Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, 230032, Hefei, China aut NATIONALLICENCE 700 1- Boye Alex Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, 230032, Hefei, China aut NATIONALLICENCE 700 1- Wu Jiajun Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, 230032, Hefei, China aut NATIONALLICENCE 700 1- Wang Jiyu Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, 230032, Hefei, China aut NATIONALLICENCE 700 1- Yang Xiaochuan Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, 230032, Hefei, China aut NATIONALLICENCE 700 1- Yang Yan Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, 230032, Hefei, China aut NATIONALLICENCE 773 0- Molecular and Cellular Biochemistry Springer US; http://www.springer-ny.com 406/1-2(2015-08-01), 255-262 0300-8177 406:1-2<255 2015 406 11010