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Regulation of activin signal transduction by PDZ domain-containing proteins

含 PDZ 结构域的蛋白对激活素信号转导的调节

基本信息

批准号：
11670127
负责人：
TSUCHIDA Kunihiro
金额：
$ 0.83万
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 (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

Activin signal transduction is regulated through multiple mechanisms. We have identified novel regulatory proteins that control activin functions either intracellularly or extracellularly. As intracellular molecules, PDZ (PSD-95/Dlg/ZO-1) proteins that specifically associate with activin type II receptors (ActRIIs) were identified. We have named the molecules as ARIPs (activin receptor-interacting proteins). ARIP1 has two WW domains at its NH2 terminus and five PDZ domains at its COOH-terminus. ARIP1 associated with Smad proteins via WW domains and associated with ActRIIAs via PDZ domain 5. ARIP1 can recruite Smad 3 as well as binding to activin receptors, thus ARIP1 may be the scaffold of the activin-signaling complex in the cell membrane and in the submembranous region, and participate in a physiological regulation of signal transduction. In accord with this speculation, we have observed that overexpression of ARIP1 suppressed Smad 3-augmented transcription in a mouse hippocampus-derived cells and inhibited Smad 3 nuclear translocation by ligand stimulation. ARIPs are likely to have a role of assembling and/or transporting of activin receptors.As an extracellular regulatory protein, we have identified a novel follistatin-like protein, named FLRG (follistatin-related gene). Like follistatins, FLRG binds activins and BMPs (bone morphogenetic proteins) and controls their functions extracellularly. Interestingly, FLRG contains only two follistatin domains, and second follistatin domain including COOH-terminal acidic region is able to bind activin. This mode of association is different from that of follistatin-activin. Since follistatin and FLRG are expressed in a different manner and they are likely to be local regulators of activin and BMPs, their functions in vivo are likely to be different. Specific monoclonal antibodies recognizing mouse and human FLRG have been made to characterize the functions of FLRG further.

激活素信号转导通过多种机制进行调节。我们已经鉴定出控制细胞内或细胞外激活素功能的新型调节蛋白。作为细胞内分子，PDZ (PSD-95/Dlg/ZO-1) 蛋白与激活素 II 型受体 (ActRII) 特异性相关。我们将这些分子命名为 ARIP（激活素受体相互作用蛋白）。 ARIP1 在其 NH2 末端有两个 WW 结构域，在其 COOH 末端有五个 PDZ 结构域。 ARIP1通过WW结构域与Smad蛋白结合，通过PDZ结构域5与ActRIIAs结合。ARIP1可以招募Smad 3并与激活素受体结合，因此ARIP1可能是细胞膜和膜下区激活素信号复合物的支架，参与信号转导的生理调节。根据这一推测，我们观察到 ARIP1 的过度表达抑制了小鼠海马来源细胞中 Smad 3 增强的转录，并通过配体刺激抑制了 Smad 3 核转位。 ARIPs很可能具有组装和/或运输激活素受体的作用。作为一种细胞外调节蛋白，我们发现了一种新型的卵泡抑素样蛋白，命名为FLRG（卵泡抑素相关基因）。与卵泡抑素一样，FLRG 结合激活素和 BMP（骨形态发生蛋白）并在细胞外控制它们的功能。有趣的是，FLRG仅包含两个卵泡抑素结构域，并且包括COOH末端酸性区域的第二个卵泡抑素结构域能够结合激活素。这种结合模式不同于卵泡抑素激活素的结合模式。由于卵泡抑素和 FLRG 以不同的方式表达，并且它们可能是激活素和 BMP 的局部调节因子，因此它们在体内的功能可能不同。已制备出识别小鼠和人 FLRG 的特异性单克隆抗体，以进一步表征 FLRG 的功能。