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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肉生长抑素和激活素信号的调节。Myostatin和激活素属于转化生长因子-β超家族，通过激活素II型受体(ActRII)传递信号，ActRII是丝氨酸/苏氨酸受体。在转化生长因子-β家族的其他受体丝氨酸激酶中，ActRII是独一无二的，因为它们在其羧基末端与PDZ蛋白有共同的结合基序。我们已经鉴定出与ActRIIs相关的多种PDZ蛋白，称为激活素受体相互作用蛋白(ARIP)。ARIP1是一个具有5个PDZ结构域和2个WW结构域的大蛋白，它不仅与ActRIIs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。我们已经确定ARIP2至少有四个剪接变异体，ARIP2，2b，2c和OMP25，它们是由来自一个基因的选择性RNA剪接事件形成的。而ARIP2可增强ActRII Thr…的内吞作用ARIP2b和ARIP2c与RalBP1无关，更多的是依赖Ral/RalBP1途径，抑制激活素/肌肉抑制素信号转导。ARIP 2b/2c增加细胞表面ActRIIs的水平并增强信号。我们还分析了与肌肉生长抑素和激活素结合的卵泡抑素和FlrG。与卵泡抑素一样，FLRG在子宫和胎盘中也有表达，但性激素对其表达的调节方式与卵泡抑素不同。在小鼠骨骼肌中，FLRG在慢型肌纤维中特异表达。FLRG可能调节血清和局部骨骼肌组织中的肌肉生长抑素活性。我们已经从卵泡抑素中制备了各种人工蛋白，并鉴定了几种肌肉生长抑素特异性抑制剂。我们已经获得了过表达一种肌肉生长抑制素特异性抑制物的转基因小鼠。小鼠骨骼肌重增加。当与MDX营养不良模型小鼠杂交时，MDX小鼠出现的纤维化和脂肪重塑等病理变化被预防，这表明我们的肌肉生长抑制素抑制剂将是治疗肌肉营养不良和其他肌肉萎缩疾病的良好药物。较少

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-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。