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Functional analysis on follistatin domain-containing proteins and activin signaling

含卵泡抑素结构域的蛋白质和激活素信号的功能分析

基本信息

批准号：
09680626
负责人：
NAKAMURA Takanori
金额：
$ 2.05万
依托单位：
Kagawa Medical Univ.
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

1. Follistatin-related protein (FRP, TSC-36), a follistatin domain-containing protein was originally isolated as a cDNA that was up-regulated by TGF-β in mouse osteogenic MC3T3E1 cells. We have isolated a homologue (xFRP) of the cDNA from Xenopus laevis to clarify the function in early embryogenesis. In the Xenopus embryos, xFRP mRNA expression started at the onset of gastrulation, and sustained through the tail-bud stage. The mRNAs Were localized in the Spemann organizer, notochord, neural floor plate, hypochord and somite. The similarities with the pattern of expression of Xenopus follistain mRNA suggests that xFRP may play a role in neuralization. Follistatin is an activin-binding protein and binds to heparin/heparansulfate carbohydrate moieties on the cell surface proteoglycans. Thus, a function of follistain on the neuralization may be performed by the inhibition of activin actions. We have also found that follistatin can mediate the activin metabolization after the internalization via surface heparansulfate-proteoglycans in various cultured cell lines.2. We have identified a mouse PDZ protein that interacts with the activin type IIA receptor (ActRIIA), which we named activin receptor-interacting protein 1 (ARIP1). ARlP1 had one guanylate kinase domain in the NH(2)-terminal region, followed by two WW domains and five PDZ domains (PDZ1-5), and interacted with ActRIIA through PDZ5. ARIP1 interacts specifically with ActRIIA among the receptors for the transforming growth factor beta family. Interestingly, ARIP1 also interacted with Smad3, which is an activin/transforming growth factor beta intracellular signaling molecule. The mRNA of ARIPI was more abundant in the brain than in other tissues. These findings suggest that ARIP1 has a significant role in assembling activin signaling molecules at specific subcellular sites and in regulating signal transduction in neuronal cells.

1.卵泡抑素相关蛋白（FRP，TSC-36）是一种含有卵泡抑素结构域的蛋白质，最初在小鼠成骨细胞MC 3 T3 E1中被TGF-β上调表达。我们已经从非洲爪蟾的cDNA中分离出一个同源物（xFRP），以阐明其在早期胚胎发生中的功能。在非洲爪蟾胚胎中，xFRP mRNA的表达开始于原肠胚形成的开始，并持续通过尾芽阶段。mRNA定位于Spemann组织器、脊索、神经底板、下索和体节。与非洲爪蟾卵泡抑素mRNA的表达模式的相似性表明，xFRP可能在神经化中发挥作用。卵泡抑素是一种激活素结合蛋白，与细胞表面蛋白聚糖上的肝素/硫酸乙酰肝素碳水化合物部分结合。因此，卵泡抑素对神经化的功能可以通过抑制激活素作用来实现。我们还发现卵泡抑素在各种培养细胞系中通过表面硫酸乙酰肝素-蛋白聚糖内化后，可以介导激活素的代谢.我们已经确定了小鼠PDZ蛋白与激活素IIA型受体（ActRIIA）相互作用，我们命名为激活素受体相互作用蛋白1（ARIP 1）。ARIP 1在NH（2）-末端区域具有一个鸟苷酸激酶结构域，随后是两个WW结构域和五个PDZ结构域（PDZ 1 -5），并且通过PDZ 5与ActRIIA相互作用。ARIP 1与转化生长因子β家族的受体中的ActRIIA特异性相互作用。有趣的是，ARIP 1还与Smad 3相互作用，Smad 3是一种激活素/转化生长因子β细胞内信号分子。ARIPI mRNA在脑组织中的表达量高于其它组织。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元细胞中的信号转导中具有重要作用。