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Activin signal transduction and its regulation mechanisms

激活素信号转导及其调控机制

基本信息

批准号：
10480170
负责人：
SUGINO Hiromu
金额：
$ 7.68万
依托单位：
University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10480170/
关键词：
activin follistatin ARIP PDZ domain WW domain FLRG FLRG フォリスタチンアクチビン受容体 Smad 神経シナプス神経細胞神経幹細胞分化

项目摘要

In this term, we have identified novel regulatory proteins that control activin functions either intracellularly or extracellularly.(1) Intracellular controlWe have identified a mouse PDZ protein that interacts with the activin type IIA receptor (ActRIIA), which we named activin receptor-interacting protein 1 (ARIP1). By using yeast two-hybrid screening, we isolated a cDNA clone of ARIP1 from a mouse brain cDNA library. ARIP1 had one guanylate kinase domain in the NH_2-terminal region, followed by two WW domains and five PDZ domains (PDZ-1-5). ARIP1-short had a deletion in the NH_2-terminal region and lacked the guanylate kinase domain. Both forms interacted with ActRIIA through PDZ5. ARIP1 interacted specifically with ActRIIA among the receptors for the transforming growth factor β family. Interestingly, ARIP1 also interacted with Smad3. The mRNA of ARIP1 was more abundant in the brain than in other tissues. Overexpression of ARIP1 controled activin-induced and Smad3-induced transcrip … More tion in activin-responsive cell lines. These findings suggest that ARIP1 has a significant role in assembling activin signaling molecules at specific subcellular sited and in regulating signal transduction in neuronal cells.(2) Extracellular controlFollistatin is an activin-binding protein that prevents activin from binding to its receptors and neutralizes its activity. Follistatin also binds bone morphogenetic proteins (BMPs). In this study, we identified a novel follistatin-like protein from mouse. The mouse cDNA encoded most likely a mouse homologue of human FLRG.Whereas follistatin has three follistatin domains, FLRG possessed only two follistatin domains. Like follistatin, FLRG had higher affinity for activin than for BMP-2. The FLRG protein inhibited activin-induced and BMP-2-induced transcriptional responses in a dose-dependent manner. Ligand blotting using ^<125>I-activin revealed that the COOH-terminal region containing the second follistatin domain was able to bind activin. Our finding implies that cellular signaling by activin and BMPs is tightly regulated by multiple members of the follistatin family. Less

在这个术语中，我们已经确定了新的调节蛋白，控制激活蛋白在细胞内或细胞外的功能。(1)细胞内控制我们已经鉴定出一种与激活素型IIA受体（ActRIIA）相互作用的小鼠PDZ蛋白，我们将其命名为激活素受体相互作用蛋白1 （ARIP1）。通过酵母双杂交筛选，从小鼠脑cDNA文库中分离出一个ARIP1 cDNA克隆。ARIP1在nh_2末端有1个鸟苷酸激酶结构域，随后有2个WW结构域和5个PDZ结构域（PDZ-1-5）。ARIP1-short在nh_2末端缺失，缺乏鸟苷酸激酶结构域。这两个表单都通过PDZ5与ActRIIA交互。在转化生长因子β家族受体中，ARIP1与ActRIIA特异性相互作用。有趣的是，ARIP1也与Smad3相互作用。ARIP1 mRNA在脑中的表达量高于其他组织。在激活素应答细胞系中，ARIP1的过表达可控制激活素诱导和smad3诱导的转录。这些发现表明，ARIP1在特定亚细胞位点组装激活素信号分子和调节神经元细胞的信号转导中具有重要作用。(2)胞外控制follistatin是一种激活素结合蛋白，可阻止激活素与其受体结合并中和其活性。Follistatin还能结合骨形态发生蛋白（BMPs）。在这项研究中，我们从小鼠中鉴定了一种新的卵泡抑素样蛋白。小鼠cDNA编码最有可能是人类FLRG的小鼠同源物。而卵泡抑素有三个卵泡抑素结构域，FLRG只有两个卵泡抑素结构域。与卵泡抑素一样，FLRG对激活素的亲和力高于对BMP-2的亲和力。FLRG蛋白以剂量依赖的方式抑制激活素诱导和bmp -2诱导的转录反应。使用^<125>I-activin进行配体印迹显示，含有第二个卵泡抑素结构域的cooh末端区域能够结合激活素。我们的发现表明激活素和bmp的细胞信号受到卵泡抑素家族多个成员的严格调节。少