Persson U, Souchelnytskyi S, Franzén P, Miyazono K, ten Dijke P, Heldin C H
Ludwig Institute for Cancer Research, Box 595, S-751 24 Uppsala, Sweden.
J Biol Chem. 1997 Aug 22;272(34):21187-94. doi: 10.1074/jbc.272.34.21187.
Members of the transforming growth factor-beta (TGF-beta) superfamily signal via different heteromeric complexes of two sequentially acting serine/threonine kinase receptors, i.e. type I and type II receptors. We generated two different chimeric TGF-beta superfamily receptors, i.e. TbetaR-I/BMPR-IB, containing the extracellular domain of TGF-beta type I receptor (TbetaR-I) and the intracellular domain of bone morphogenetic protein type IB receptor (BMPR-IB), and TbetaR-II/ActR-IIB, containing the extracellular domain of TGF-beta type II receptor (TbetaR-II) and the intracellular domain of activin type IIB receptor (ActR-IIB). In the presence of TGF-beta1, TbetaR-I/BMPR-IB and TbetaR-II/ActR-IIB formed heteromeric complexes with wild-type TbetaR-II and TbetaR-I, respectively, upon stable transfection in mink lung epithelial cell lines. We show that TbetaR-II/ActR-IIB restored the responsiveness upon transfection in mutant cell lines lacking functional TbetaR-II with respect to TGF-beta-mediated activation of a transcriptional signal, extracellular matrix formation, growth inhibition, and Smad phosphorylation. Moreover, TbetaR-I/BMPR-IB and TbetaR-II/ActR-IIB formed a functional complex in response to TGF-beta and induced phosphorylation of Smad1. However, complex formation is not enough for signal propagation, which is shown by the inability of TbetaR-I/BMPR-IB to restore responsiveness to TGF-beta in cell lines deficient in functional TbetaR-I. The fact that the TGF-beta1-induced complex between TbetaR-II/ActR-IIB and TbetaR-I stimulated endogenous Smad2 phosphorylation, a TGF-beta-like response, is in agreement with the current model for receptor activation in which the type I receptor determines signal specificity.
转化生长因子-β（TGF-β）超家族成员通过两种相继作用的丝氨酸/苏氨酸激酶受体（即I型和II型受体）形成的不同异源复合物进行信号传导。我们构建了两种不同的嵌合TGF-β超家族受体，即TβR-I/BMPR-IB，它包含TGF-β I型受体（TβR-I）的细胞外结构域和骨形态发生蛋白IB型受体（BMPR-IB）的细胞内结构域；以及TβR-II/ActR-IIB，它包含TGF-β II型受体（TβR-II）的细胞外结构域和激活素IIB型受体（ActR-IIB）的细胞内结构域。在存在TGF-β1的情况下，将TβR-I/BMPR-IB和TβR-II/ActR-IIB稳定转染到貂肺上皮细胞系后，它们分别与野生型TβR-II和TβR-I形成了异源复合物。我们发现，在缺乏功能性TβR-II的突变细胞系中，转染TβR-II/ActR-IIB可恢复对TGF-β介导的转录信号激活、细胞外基质形成、生长抑制和Smad磷酸化的反应能力。此外，TβR-I/BMPR-IB和TβR-II/ActR-IIB在TGF-β作用下形成功能性复合物，并诱导Smad1磷酸化。然而，复合物的形成对于信号传导来说并不足够，这一点通过TβR-I/BMPR-IB无法在缺乏功能性TβR-I的细胞系中恢复对TGF-β的反应能力得以证明。TβR-II/ActR-IIB与TβR-I之间由TGF-β1诱导形成的复合物刺激内源性Smad2磷酸化，这是一种类似TGF-β的反应，这一事实与当前的受体激活模型一致，即I型受体决定信号特异性。
