| Project/Area Number |
10480170
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional biochemistry
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| Research Institution | University of Tokushima |
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Principal Investigator |
SUGINO Hiromu University of Tokushima, The Institute for Enzyme Research, Professor, 分子酵素学研究センター, 教授 (50211305)
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| Co-Investigator(Kenkyū-buntansha) |
OGURA Yasunori University of Tokushima, The Institute for Enzyme Research, Research Associate, 分子酵素学研究センター, 助手 (60304557)
NAKAMURA Takanori Kagawa Medical University, Professor, 医学部, 教授 (70183887)
TSUCHIDA Kunihiro University of Tokushima, The Institute for Enzyme Research, Associate Professor, 分子酵素学研究センター, 助教授 (30281091)
SUGINO Hiromu University of Tokushima, The Institute for Enzyme Research, Professor (50211305)
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| Project Period (FY) |
1998 – 2000
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| Keywords | activin / follistatin / ARIP / PDZ domain / WW domain / FLRG / FLRG |
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| Research Abstract |
In this term, we have identified novel regulatory proteins that control activin functions either intracellularly or extracellularly.
(1) Intracellular control
We have identified a mouse PDZ protein that interacts with the activin type IIA receptor (ActRIIA), which we named activin receptor-interacting protein 1 (ARIP1). By using yeast two-hybrid screening, we isolated a cDNA clone of ARIP1 from a mouse brain cDNA library. ARIP1 had one guanylate kinase domain in the NH_2-terminal region, followed by two WW domains and five PDZ domains (PDZ-1-5). ARIP1-short had a deletion in the NH_2-terminal region and lacked the guanylate kinase domain. Both forms interacted with ActRIIA through PDZ5. ARIP1 interacted specifically with ActRIIA among the receptors for the transforming growth factor β family. Interestingly, ARIP1 also interacted with Smad3. The mRNA of ARIP1 was more abundant in the brain than in other tissues. Overexpression of ARIP1 controled activin-induced and Smad3-induced transcrip
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tion in activin-responsive cell lines. These findings suggest that ARIP1 has a significant role in assembling activin signaling molecules at specific subcellular sited and in regulating signal transduction in neuronal cells.
(2) Extracellular control
Follistatin is an activin-binding protein that prevents activin from binding to its receptors and neutralizes its activity. Follistatin also binds bone morphogenetic proteins (BMPs). In this study, we identified a novel follistatin-like protein from mouse. The mouse cDNA encoded most likely a mouse homologue of human FLRG.Whereas follistatin has three follistatin domains, FLRG possessed only two follistatin domains. Like follistatin, FLRG had higher affinity for activin than for BMP-2. The FLRG protein inhibited activin-induced and BMP-2-induced transcriptional responses in a dose-dependent manner. Ligand blotting using ^<125>I-activin revealed that the COOH-terminal region containing the second follistatin domain was able to bind activin. Our finding implies that cellular signaling by activin and BMPs is tightly regulated by multiple members of the follistatin family. Less
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