title: TGF-β-induced mesenchymal transition of MS-1 endothelial cells requires Smad-dependent cooperative activation of Rho signals and MRTF-A.
abstract: Endothelial-mesenchymal transition (EndMT) plays important roles in various physiological and pathological processes. While signals mediated by transforming growth factor (TGF)-β have been implicated in EndMT, the molecular mechanisms underlying it remain to be fully elucidated. Here, we examined the effects of TGF-β signals on the EndMT of mouse pancreatic microvascular endothelial cells (MS-1). By addition of TGF-β2, MS-1 cells underwent mesenchymal transition characterized by re-organization of actin stress fibre and increased expression of various mesenchymal markers such as α-smooth muscle actin (α-SMA) through activation of Rho signals. Whereas activation of Rho signals via TGF-β-induced non-Smad signals has been implicated in epithelial-mesenchymal transition (EMT), we found that Arhgef5, a guanine nucleotide exchange factor, is induced by Smad signals and contributes to the TGF-β2-induced α-SMA expression in MS-1 cells. We also found that TGF-β2 induces the expression of myocardin-related transcription factor-A (MRTF-A) in a Smad-dependent fashion and its nuclear accumulation in MS-1 cells and that MRTF-A is required and sufficient for TGF-β2-induced α-SMA expression. These results indicate that activation of Smad signals by TGF-β2 have dual effects on the activation of Rho signals and MRTF-A leading to the mesenchymal transition of MS-1 endothelial cells.
authors: Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors: Hajime
authors: H
authors: Mihira
authors: Hiroshi I
authors: HI
authors: Suzuki
authors: Yuichi
authors: Y
authors: Akatsu
authors: Yasuhiro
authors: Y
authors: Yoshimatsu
authors: Takashi
authors: T
authors: Igarashi
authors: Kohei
authors: K
authors: Miyazono
authors: Tetsuro
authors: T
authors: Watabe
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D051379:Mice; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C511173:Mrtfa protein, mouse; D051785:Smad Proteins; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D020741:rho GTP-Binding Proteins