Modulation of the functional binding sites for TGF-β on the type II receptor leads to suppression of TGF-β signaling
Modulation of the functional binding sites for TGF-β on the type II receptor leads to suppression of TGF-β signaling
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DOI：
10.1038/sj.onc.1210123
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发表时间：
2007-05-17
期刊：
影响因子：
8
通讯作者：
Miyazono, K.
中科院分区：
文献类型：
--
作者：
Shimanuki, T.;Hara, T.;Miyazono, K.
转化生长因子-β（TGF-β）结合两种不同类型的丝氨酸/苏氨酸激酶受体，称为II型（T β R-II）和I型（T β R-I）。TGF-β在缺乏T β R-II的情况下不能与T β R-I结合，并通过与T β R-II的高亲和力结合来启动受体组装。以前对TGF-β 3-T β R-II复合物的结构分析表明，T β R-II的两个带电氨基酸残基D55和E142是TGF-β的结合位点。在本研究中，我们已经表明，T β R-II的氨基酸残基D55和E142的突变导致TGF-β结合和下游信号活性的丧失。此外，我们发现3，5，7，2 '，4'-五羟基黄酮（桑色素）抑制TGF-β与T β R-II的结合，并抑制TGF-β诱导的Smad 2的磷酸化和TGF-β靶基因Smad 7的表达。因此，我们的研究结果可能为设计TGF-β诱导的各种疾病（包括晚期癌症）的治疗药物提供有用的信息。
Transforming growth factor-beta (TGF-beta) binds to two different types of serine/threonine kinase receptors termed type II (T beta R-II) and type I (T beta R-I). TGF-beta is unable to bind to T beta R-I in the absence of T beta R-II, and initiates receptor assembly by binding with high affinity to T beta beta R-II. Previous structural analysis of the TGF-beta 3-T beta R-II complex has suggested that two charged amino acid residues, D55 and E142 of T beta R-II, are binding sites of TGF-beta. In the present study, we have shown that mutations of the amino-acid residues, D55 and E142 of T beta R-II, resulted in loss of TGF-beta binding and downstream signaling activity. Moreover, we found that 3,5,7,2',4'-pentahydroxyflavone (Morin) inhibits TGF-beta binding to T beta R-II, and suppresses phosphorylation of Smad2 and expression of a TGF-beta target gene Smad7 induced by TGF-beta. Our findings may thus provide useful information for designing therapeutic agents for various diseases induced by TGF-beta, including advanced cancers.