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调节。我们已经确定了新型的调节蛋白，这些蛋白质会在细胞内或细胞外控制。作为细胞内分子，鉴定了与激活素II型受体（ACTRIIS）特别关联的PDZ（PSD-95/DLG/ZO-1）蛋白。我们将这些分子命名为ARIPS（激活素受体相互作用蛋白）。 ARIP1在其NH2末端具有两个WW域，其COOH末端具有五个PDZ域。 ARIP1与SMAD蛋白通过WW结构域以及通过PDZ结构域5。ARIP1可以募集Smad 3以及与激活素受体的结合相关的ARIP1，因此ARIP1可以是细胞膜中激活素信号复合物的支架，在细胞膜和甲状腺肿瘤区域中，并参与了脑膜型和脑膜型的信号。根据这种猜测，我们观察到，ARIP1的过表达在小鼠海马衍生的细胞中抑制了SMAD 3型转录，并通过配体刺激抑制了SMAD 3核易位。 ARIP可能在组装和/或转运激活蛋白受体的作用。作为细胞外调节蛋白，我们已经鉴定出一种新型的类似Follistatin的蛋白，称为FLRG（Follistatin与Follistatin相关基因）。像卵泡蛋白一样，FLRG结合了激活素和BMP（骨形态发生蛋白），并细胞外控制其功能。有趣的是，FLRG仅包含两个Follistatin结构域，而包括COOH末端酸性区域（COOH-末端酸性区域）的第二个Follistatin结构域能够结合激活素。这种缔合模式与follistatin-activin不同。由于Follistatin和Flrg以不同的方式表达，并且它们可能是激活素和BMP的局部调节剂，因此它们在体内的功能可能会有所不同。已经制定了识别小鼠和人FLRG的特定单克隆抗体，以进一步表征FLRG的功能。