Nakao A, Afrakhte M, Morén A, Nakayama T, Christian J L, Heuchel R, Itoh S, Kawabata M, Heldin N E, Heldin C H, ten Dijke P
Ludwig Institute for Cancer Research, Uppsala, Sweden.
Nature. 1997 Oct 9;389(6651):631-5. doi: 10.1038/39369.
TGF-beta signals from the membrane to the nucleus through serine/threonine kinase receptors and their downstream effectors, termed SMAD proteins. The activated TGF-beta receptor induces phosphorylation of two such proteins, Smad2 and Smad3, which form hetero-oligomeric complex(es) with Smad4/DPC4 that translocate to the nucleus, where they then regulate transcriptional responses. However, the mechanisms by which the intracellular signals of TGF-beta are switched off are unclear. Here we report the identification of Smad7, which is related to Smad6. Transfection of Smad7 blocks responses mediated by TGF-beta in mammalian cells, and injection of Smad7 RNA into Xenopus embryos blocks activin/TGF-beta signalling. Smad7 associates stably with the TGF-beta receptor complex, but is not phosphorylated upon TGF-beta stimulation. TGFbeta-mediated phosphorylation of Smad2 and Smad3 is inhibited by Smad7, indicating that the antagonistic effect of Smad7 is exerted at this important regulatory step. TGF-beta rapidly induces expression of Smad7 mRNA, suggesting that Smad7 may participate in a negative feedback loop to control TGF-beta responses.
转化生长因子-β（TGF-β）通过丝氨酸/苏氨酸激酶受体及其下游效应分子（称为SMAD蛋白）从细胞膜向细胞核传递信号。活化的TGF-β受体诱导两种此类蛋白Smad2和Smad3的磷酸化，它们与Smad4/DPC4形成异源寡聚复合物并转运至细胞核，在细胞核中它们随后调节转录反应。然而，TGF-β的细胞内信号被关闭的机制尚不清楚。在此我们报告了与Smad6相关的Smad7的鉴定。在哺乳动物细胞中，转染Smad7可阻断由TGF-β介导的反应，并且将Smad7 RNA注射到非洲爪蟾胚胎中可阻断激活素/TGF-β信号传导。Smad7与TGF-β受体复合物稳定结合，但在TGF-β刺激下不被磷酸化。Smad7抑制TGF-β介导的Smad2和Smad3的磷酸化，表明Smad7的拮抗作用在这一重要调节步骤发挥作用。TGF-β迅速诱导Smad7 mRNA的表达，提示Smad7可能参与负反馈环以控制TGF-β反应。
