Goumans Marie-José, Valdimarsdottir Gudrun, Itoh Susumu, Rosendahl Alexander, Sideras Paschalis, ten Dijke Peter
Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
EMBO J. 2002 Apr 2;21(7):1743-53. doi: 10.1093/emboj/21.7.1743.
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.
缺乏转化生长因子-β（TGF-β）信号转导途径特定成分的小鼠模型表明，TGF-β在心血管系统的发育和生理过程中起着关键作用。TGF-β兼具促血管生成和抗血管生成特性，但其分子机制尚不清楚。在此，我们报告TGF-β可激活两条具有相反作用的不同I型受体/Smad信号通路。TGF-β在内皮细胞中诱导Smad1/5和Smad2磷酸化，这些效应可分别通过选择性抑制ALK1或ALK5表达而被阻断。TGF-β/ALK5通路导致细胞迁移和增殖受到抑制，而TGF-β/ALK1通路则诱导内皮细胞迁移和增殖。我们鉴定了由TGF-β介导的ALK1或ALK5激活特异性诱导的基因。Id1被发现介导TGF-β/ALK1诱导的（且依赖Smad的）迁移，而活化的ALK5诱导纤溶酶原激活物抑制剂-1可能有助于TGF-β诱导的血管成熟。我们的结果表明，TGF-β通过ALK5和ALK1信号之间的精细平衡来调节内皮细胞的激活状态。
