Balancing the activation state of the endothelium via two distinct TGF-β type I receptors
Balancing the activation state of the endothelium via two distinct TGF-β type I receptors
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DOI：
10.1093/emboj/21.7.1743
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发表时间：
2002-04-02
期刊：
影响因子：
11.4
通讯作者：
ten Dijke, P
中科院分区：
文献类型：
--
作者：
Goumans, MJ;Valdimarsdottir, G;ten Dijke, P
缺乏转化生长因子-β信号转导通路特定成分的小鼠的产生表明，转化生长因子-β在心血管系统的发育和生理中起着关键作用。促血管生成和抗血管生成的特性都归因于转化生长因子-β，其分子机制尚不清楚。在此，我们报道了转化生长因子-β可以激活两个截然不同的I型受体/Smad信号通路，但作用相反。转化生长因子-β可诱导内皮细胞Smad1/5和Smad2的磷酸化，选择性抑制ALK1或Alk5的表达可分别阻断这些作用。转化生长因子-β/碱性磷酸酶5途径抑制细胞迁移和增殖，转化生长因子-β/碱性磷酸酶1途径诱导内皮细胞迁移和增殖。我们确定了由转化生长因子-β介导的ALK1或ALK5激活而特异诱导的基因。ID1介导了转化生长因子-β/碱性磷酸酶1诱导的(且依赖于Smad的)迁移，而激活的碱性磷酸酶5诱导的纤溶酶原激活物抑制物-1可能有助于转化生长因子-β诱导的血管成熟。我们的结果表明，转化生长因子-β通过Alk5和ALK1信号之间的微妙平衡来调节内皮细胞的激活状态。
The generation of mice lacking specific components of the transforming growth factor-beta (TGF-beta) signal tranduction pathway shows that TGF-beta is a key player in the development and physiology of the cardiovascular system. Both pro- and anti-angiogenic properties have been ascribed to TGF-beta, for which the molecular mechanisms are unclear. Here we report that TGF-beta can activate two distinct type I receptor/Smad signalling pathways with opposite effects. TGF-beta induces phosphorylation of Smad1/5 and Smad2 in endothelial cells and these effects can be blocked upon selective inhibition of ALK1 or ALK5 expression, respectively. Whereas the TGF-beta/ALK5 pathway leads to inhibition of cell migration and proliferation, the TGF-beta/ ALK1 pathway induces endothelial cell migration and proliferation. We identified genes that are induced specifically by TGF-beta-mediated ALK1 or ALK5 activation. Id1 was found to mediate the TGF-beta/ALK1-induced (and Smad-dependent) migration, while induction of plasminogen activator inhibitor-1 by activated ALK5 may contribute to the TGF-beta-induced maturation of blood vessels. Our results suggest that TGF-beta regulates the activation state of the endothelium via a fine balance between ALK5 and ALK1 signalling.