Activin signal transduction and its regulation mechanisms

在这方面，我们已经确定了新的调节蛋白，控制激活素功能的细胞内或细胞外。(1)细胞内控制我们已经鉴定了与激活素IIA型受体（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（ARIP 1）。利用酵母双杂交技术，从小鼠脑cDNA文库中克隆了ARIP 1基因。ARIP 1在NH_2端有一个鸟苷酸激酶结构域，其次是两个WW结构域和五个PDZ结构域（PDZ-1-5）。ARIP 1-short在NH_2-末端区域缺失，缺少鸟苷酸激酶结构域。这两种形式通过PDZ 5与ActRIIA相互作用。ARIP 1与转化生长因子β家族受体中的ActRIIA特异性相互作用。有趣的是，ARIP 1也与Smad 3相互作用。ARIP 1 mRNA在脑组织中的表达量高于其它组织。ARIP 1过表达控制激活素和Smad 3诱导的转录 ...更多信息 激活素响应细胞系中的作用。这些发现表明，ARIP 1在特定的亚细胞位点组装激活素信号分子和调节神经细胞的信号转导中具有重要作用。(2)细胞外调控卵泡抑素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。卵泡抑素还结合骨形态发生蛋白（BMP）。在本研究中，我们从小鼠中鉴定了一种新的卵泡抑素样蛋白。小鼠的cDNA编码最有可能是小鼠同源的人FLRG。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。与卵泡抑素类似，FLRG对激活素的亲和力高于对BMP-2的亲和力。FLRG蛋白以剂量依赖性方式抑制激活素诱导的和BMP-2诱导的转录反应。使用β <125>I-激活素的配体印迹显示，含有第二卵泡抑素结构域的COOH末端区域能够结合激活素。我们的发现表明激活素和BMP的细胞信号传导受到卵泡抑素家族多个成员的严格调控。少

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