Diabetes and Cell Biology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia.
Cell Mol Life Sci. 2010 Jun;67(12):2077-90. doi: 10.1007/s00018-010-0315-9. Epub 2010 Mar 7.
Transforming growth factor (TGF)-beta treatment of human vascular smooth-muscle cells increases the expression of biglycan and causes marked elongation of its glycosaminoglycan (GAG) chains. We investigated the role of MAP kinases and Smad transcription factors in this response. TGF-beta-stimulated phosphorylation of p38, ERK, and JNK as well as Smad2 at both its carboxy terminal (phospho-Smad2C) and in the linker region (phospho-Smad2L). Pharmacological inhibition of ERK and p38 blocked TGF-beta-mediated GAG elongation and expression of biglycan whereas inhibition of JNK had no effect. Inhibition of ERK and p38 but not JNK attenuated the effect of TGF-beta to increase phospho-Smad2L. High levels of phospho-Smad2L were detected in a nuclear fraction of TGF-beta treated cells. Thus, MAP kinase signaling through ERK and p38 and via phosphorylation of the linker region of Smad2 mediates the effects of TGF-beta on biglycan synthesis in vascular smooth-muscle cells.
转化生长因子 (TGF)-β 处理人血管平滑肌细胞会增加 biglycan 的表达,并使其糖胺聚糖 (GAG) 链明显延长。我们研究了 MAP 激酶和 Smad 转录因子在此反应中的作用。TGF-β 刺激 p38、ERK 和 JNK 的磷酸化以及 Smad2 的羧基末端(磷酸化 Smad2C)和连接区(磷酸化 Smad2L)。ERK 和 p38 的药理学抑制阻断了 TGF-β 介导的 GAG 延长和 biglycan 的表达,而 JNK 的抑制则没有作用。ERK 和 p38 的抑制而不是 JNK 的抑制减弱了 TGF-β 增加磷酸化 Smad2L 的作用。在 TGF-β 处理的细胞的核部分检测到高水平的磷酸化 Smad2L。因此,ERK 和 p38 通过 MAP 激酶信号传导以及 Smad2 连接区的磷酸化介导 TGF-β 对血管平滑肌细胞中 biglycan 合成的影响。