Regulation of signal transduction of TGF-β family by novel adaptor and binding proteins

新型接头蛋白和结合蛋白对 TGF-β 家族信号转导的调节

基本信息

批准号：
15590248
负责人：
TSUCHIDA Kunihiro
金额：
$ 2.3万
依托单位：
The 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：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

We have analyzed the regulation of myostatin and activin signaling by receptor associated adaptor proteins and binding proteins. Myostatin and activin belong to the TGF-β superfamily and signal through activin type II receptors (ActRIIs) that are receptor serine/threonine kinases. ActRIIs are unique among other receptor serine kinases for the TGF-β family in that they have consensus binding motifs for PDZ proteins at their carboxy terminus. We have identified multiple PDZ proteins, called activin receptor-interacting proteins (ARIPs) that associate with ActRIIs. ARIP1 is a large protein having five PDZ domains and two WW domains, and associates not only with ActRIIs but also with glutamate receptors and src family of tyrosine kinases. ARIP2 is a small protein that has only one PDZ domain. We have identified ARIP2 has at least four splicing variants, ARIP2, 2b, 2c and OMP25 that are formed by alternative RNA splicing events from one gene. Whereas ARIP2 enhances endocytosis of ActRII thr … More ough Ral/RalBP1-dependent pathway and inhibit activin/myostatin signaling, ARIP2b and 2c do not associate with RalBP1. ARIP 2b/2c increase cell surface level of ActRIIs and augment signaling.We also analyzed follistatin and FLRG that are binding proteins for myostatin and activin. Like follistatin, FLRG is expressed in uterus and placenta, but mode of regulation of FLRG expression by sex steroids are different from that of follistatin. In mouse skeletal muscles, FLRG is specifically expressed in slow type muscle fibers. FLRG is likely to regulate myostatin activity in serum as well as in skeletal muscle tissues locally. We have made various artificial protein derived from follistatin, and identified several myostatin-specific inhibitors. We have made transgenic mouse that overexpress one of myostatin-specific inhibitors. The mice show increase of skeletal muscle mass. When crossed with mdx dystrophy model mice, pathological changes such as fibrosis and fatty remodeling seen in mdx mice were prevented, suggesting that our myostatin inhibitors would be a good drugs for treatment of muscular dystrophy and other muscle-wasting disorders. Less

我们分析了受体相关接头蛋白和结合蛋白对肌生长抑制素和激活素信号的调节，它们属于 TGF-β 超家族，并通过激活素 II 型受体 (ActRII) 发出信号，而激活素 II 型受体 (ActRII) 是独特的受体丝氨酸/苏氨酸激酶。在 TGF-β 家族的其他受体丝氨酸激酶中，它们在其羧基末端具有 PDZ 蛋白的共有结合基序。 PDZ 蛋白称为激活素受体相互作用蛋白 (ARIP)，与 ActRII 相关，是一种具有 5 个 PDZ 结构域和 2 个 WW 结构域的大蛋白，不仅与 ActRII 相关，还与谷氨酸受体和酪氨酸激酶 src 家族相关。 ARIP2 是一种只有一个 PDZ 结构域的小蛋白，我们已经鉴定出 ARIP2 至少有四种剪接变体：ARIP2、2b、2c 和OMP25 是由一个基因的选择性 RNA 剪接事件形成的，除了 ARIP2 通过 Ral/RalBP1 依赖性途径增强 ActRII 的内吞作用并抑制激活素/肌肉生长抑制素信号传导外，ARIP2b 和 2c 与 RalBP1 的增加无关。 ActRIIs 的细胞表面水平并增强信号传导。我们还分析了卵泡抑素和 FLRG，它们是肌生长抑制素的结合蛋白，与卵泡抑素一样，FLRG 在子宫和胎盘中表达，但性类固醇对 FLRG 表达的调节方式与卵泡抑素不同，在小鼠骨骼肌中，FLRG 可能特异性地在慢型肌纤维中表达。我们已经制备了多种源自卵泡抑素的人工蛋白质，并鉴定了几种肌生长抑制素特异性抑制剂。过度表达一种肌生长抑制素特异性抑制剂的转基因小鼠显示，当与 mdx 营养不良模型小鼠杂交时，mdx 小鼠中出现的纤维化和脂肪重塑等病理变化得到了预防，这表明我们的肌生长抑制素抑制剂可能会被抑制。治疗肌营养不良症和其他肌肉萎缩性疾病的良好药物。

项目成果

期刊论文数量（55）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Activins, myostatin and related TGF-β family members as novel therapeutic targets for endocrine, metabolic and immune disorders.

激活素、肌肉生长抑制素和相关的 TGF-β 家族成员作为内分泌、代谢和免疫疾病的新治疗靶点。

DOI：
发表时间：
2004
期刊：
Current Drug Targets 4
影响因子：
0
作者：
Hiromi Fujii;et al.;K.Tsuchida
通讯作者：
K.Tsuchida

K.Takamura, K.Tsuchida, H.Miyake, S.Tashiro, H.Sugino: "Possible Endocrine Control by Follistatin 315 during Liver Regeneration Based on Changes of Activin Receptor after Partial Hepatectomy in Rat"Hepato-Gastroenterology. (印刷中). (2004)

K.Takamura、K.Tsuchida、H.Miyake、S.Tashiro、H.Sugino：“基于大鼠部分肝切除术后激活素受体的变化，卵泡抑素 315 在肝脏再生过程中可能的内分泌控制”肝胃肠病学（出版中）。 (2004)

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

Activins, myostatin and related TGF-beat family members as novel therapeutic targets for endocrine, metabolic and immune disorders

激活素、肌肉生长抑制素和相关的 TGF-beat 家族成员作为内分泌、代谢和免疫疾病的新治疗靶点

DOI：
发表时间：
2004
期刊：
Current Drug Targets-Immune, Endocrine & Metabolic Disorders 4(2)
影响因子：
0
作者：
Shuji Takahashi;et al.;H.Miyamoto et al.;K.Tsuchida et al.;K.Tsuchida et al.;H.Miyamoto et al.;K.Tsuchida
通讯作者：
K.Tsuchida

Possible endocrine control by follistatin 315 during liver regeneration based on changes of activin receptor after partial hepatectomy in rat.

根据大鼠部分肝切除术后激活素受体的变化，卵泡抑素 315 在肝再生过程中可能对内分泌进行控制。