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

我们已经通过相关的衔接蛋白和结合蛋白分析了肌抑素和激活素信号的调节。 Myostatin和activin属于TGF-β超家族，并通过激活素II型受体（ACTRIIS）是丝氨酸/苏氨酸激酶的信号。 Actriis在TGF-β家族的其他受体丝氨酸激酶中是独一无二的，因为它们在其羧基末端具有PDZ蛋白的共识结合基序。我们已经鉴定出多种PDZ蛋白，称为与ACTRIIS关联的活化素受体相互作用蛋白（ARIPS）。 ARIP1是一种具有五个PDZ结构域和两个WW结构域的大蛋白，不仅与Actriis，而且与谷氨酸受体和酪氨酸激酶的SRC家族相关。 ARIP2是一种仅具有一个PDZ结构域的小蛋白质。我们已经确定ARIP2至少具有四个剪接变体Arip2、2B，2C和OMP25，这些变体是由一个基因的替代RNA剪接事件形成的。而ARIP2增强了Actrii Thr的内吞作用……更多的RAL/RALBP1依赖性途径并抑制了激活素/肌抑素信号传导，ARIP2B和2C与RALBP1不关联。 ARIP 2B/2C提高了ACTRIIS的细胞表面水平和增强信号传导。我们还分析了肌蛋白和激活素的结合蛋白的Follistatin和flRG。像Follistatin一样，FLRG在子宫和plapeta中也表达，但是性别立体体对FLRG表达的调节方式与Follistatin不同。在小鼠骨骼肌中，FLRG在慢速肌肉纤维中特异性表达。 FLRG可能会调节血清以及骨骼肌组织中的肌生抑素活性。我们制作了各种人造蛋白质，这些蛋白质源自Follistatin，并鉴定出了几种肌生抑素特异性抑制剂。我们制造了过表达肌抑制素特异性抑制剂之一的转基因小鼠。小鼠显示骨骼肌质量的增加。当与MDX营养不良模型小鼠交叉时，可以预防MDX小鼠中看到的病理变化，例如纤维化和脂肪重塑，这表明我们的肌生抑制剂抑制剂将是治疗肌肉营养不良和其他肌肉浪费疾病的好药物。较少的

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：

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。

DOI：
发表时间：
2005
期刊：
Hepato-Gastroenterology (印刷中)
影响因子：
0
作者：
Takahashi T;et al.;K.Tsuchida et al.
通讯作者：
K.Tsuchida et al.

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