BMP-7/TGF-尾1 signalling in myoblasts: Components involved in signalling and BMP-7-dependent blockage of TGF-尾-mediated CTGF expression
- 作者：Steffen K. Meurer ; smeurer@ukaachen.de ; Marcel Esser ; Lidia Tihaa ; Ralf Weiskirchen ; rweiskirchen@ukaachen.de
- 关键词：ALK ; Activin-like kinase(s) ; BMP-7 ; Bone morphogenetic protein-7 ; CTGF ; connective tissue growth factor ; DM ; Dorsomorphin ; EMT ; epithelial-to-mesenchymal transition ; HSC ; hepatic stellate cell(s) ; Id ; Inhibitor of differentiation ; MAPK ; Mitogen-activated
- 刊名：European Journal of Cell Biology
- 出版年：2012
- 期刊代码：15_01719335
- 类别：bio
- 出版时间：June-July, 2012
- 卷：91
- 期：6-7
- 页码：450-463
- 文件大小：1664 K
摘要
We and others have recently described the antagonistic role of Bone morphogenetic protein-7 (BMP-7) in TGF-尾 signalling and myogenic differentiation. To specify the underlying mechanism(s), we here analysed the expression and function of the individual components mediating TGF-尾1 and BMP-7 responses. We found that BMP-7 at a concentration of 25 ng/ml induces signalling exclusively via ALK2 and ALK3 leading to the activation of Smad1 and Smad5 and subsequent expression of Id proteins. In contrast, low doses of TGF-尾1 (0.1 ng/ml) lead to an exclusive activation of ALK5 and phosphorylation of Smad2 and Smad3 that regulate specific target genes including connective tissue growth factor (CTGF). CTGF is rapidly induced by TGF-尾1 already 1 h after stimulation and reduced by BMP-7 application. Smad1/Smad5 or Id1/2 overexpression reduced the TGF-尾1-mediated expression of CTGF. However, although siRNA-mediated knock down of Alk2/3 or Smad1/5 counteracts the BMP-7 effect on basal CTGF expression there was no consistent reversion of the observed BMP-7 effect on TGF-尾1-mediated CTGF expression. Moreover, ALK5 inhibition using the SB431542 inhibitor significantly affected CTGF expression only at later time points whereas ERK1/2 inhibition completely abrogated CTGF expression. These findings point towards a regulatory role of BMP-7 that relies on modulation of Mitogen-activated protein kinases rather than mechanisms that are exclusively driven by differential Smad activation.