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Activin signal transduction and its regulation mechanisms

Research Project

Project/Area Number 10480170
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field Functional biochemistry
Research InstitutionUniversity of Tokushima

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)

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)
Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥12,000,000 (Direct Cost: ¥12,000,000)
Fiscal Year 2000: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1999: ¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 1998: ¥5,400,000 (Direct Cost: ¥5,400,000)
Keywordsactivin / follistatin / ARIP / PDZ domain / WW domain / FLRG / FLRG / フォリスタチン / アクチビン受容体 / Smad / 神経シナプス / 神経細胞 / 神経幹細胞 / 分化
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 … More 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

Report

(4 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (67 results)

All Other

All Publications (67 results)

  • [Publications] Yamane,Y. et al.: "Molecular characterization of Xenopus embryo heparan sulfate : Differential structural requirements for the specific binding to basic fibroblast growth factor and follistatin."J.Biol.Chem.. 273. 7375-7381 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yamaoka,T. et al.: "Hypoplasia of pancreatic islets in transgenic mice expressing activin receptor mutants."J.Clin.Invest.. 102. 294-301 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Iemura,S. et al.: "Direct binding of follistatin to a complex of bone morphogenetic protein and its receptor inhibits ventral and epidermal cell fates in early Xenopus embryo."Proc.Natl.Acad.Sci.U.S.A.. 95. 9337-9342 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shoji,H. et al.: "Identification of a novel type II activin receptor, type IIA-N, induced during the neural differentiation of murine P19 embryonal carcinoma cells."Biochem.Biophys.Res.Commun.. 246. 320-324 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohguchi,M. et al.: "Activin A regulates the production of mature interleukin-1β and interleukin-1 receptor antagonist in human monocytic cells."J.Inter.Cyto.Res.. 18. 491-498 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hashimoto,O. et al.: "The role of activin type I receptors in activin A-induced growth arrest and apoptosis in mouse B cell hybridoma cells."Cell.Signal.. 10. 743-749 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okabayashi,K. et al.: "cDNA cloning and distribution of the Xenopus follistatin-related protein."Biochem.Biophys.Res.Commun.. 254. 42-48 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ishisaki,A. et al.: "Differential inhibition of Smad6 and Smad7 on bone morphogenetic protein- and activin-mediated growth arrest and apoptosis in B cells."J.Biol.Chem.. 274. 13637-13642 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Miyamoto,S. et al.: "Effects of activin on hormone secretion by single female rat pituitary cells : Analysis by cell immunoblot aasay."J.Endocrinol.. 161. 375-382 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shoji,H. et al.: "Identification and characterization of a PDZ protein that interacts with activin type II receptors."J.Biol.Chem.. 275. 5485-5492 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tamura,N. et al.: "Effect of activin on production and secretion of prolactin and growth hormone in cultured rat GH3 cells."Eur.J.Endocrinol.. 142. 506-511 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sumitomo,K. et al.: "Expression of a TCF-β1 inducible gene, TSC-36, causes growth inhibition in human lung cancer cell line."Cancer Lett.. 155. 37-46 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Satoh,M. et al.: "Activin promotes astrocytic differentiation of a multipotent neural stem cell line and an astrocyte progenitor cell line from murine central nervous system. "Neurosci.Lett.. 284. 143-146 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Florio,P. et al.: "Activin A stimulates insulin secretion in cultured human pancreatic islets."J.Endocrinol.Invest.. 23. 231-234 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] de Groot,E. et al.: "Expression patterns of follistatin and two follistatin-related proteins during mouse development."Int.J.Dev.Biol.. 44. 327-330 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hashimoto,O. et al.: "Differentiation between follistatin isoforms in the inhibition of activin signalling : Activin neutralizing activity of follistatin isoforms is dependent on their affinity for activin."Cellular Signalling. 12. 565-571 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tsuchida,K. et al.: "Identification and characterizaiton of a novel follistatin-like protein as a binding protein for the TCF-β family."J.Biol.Chem.. 275. 40788-40796 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 杉野弘,土田邦博: "サイトカイン・増殖因子"羊土社. 2 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 土田邦博,杉野弘: "サイトカイン・増殖因子"羊土社. 2 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 杉野弘,土田邦博: "サイトカイン・増殖因子"羊土社. 1 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 杉野弘: "医学のあゆみ"医歯薬出版株式会社. 4 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 土田邦博: "生化学"日本生化学会. 6 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sugino,H. et al.: "Activin and Follistatin. In Skeletal Growth Factors"Lippincott Williams & Willkins, Philadelphia.. 13 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yamane, Y.et al.: "Molecular characterization of Xenopus embryo heparan sulfate : Differential structural requirements for the specific binding to basic fibroblast growth factor and follistatin."J.Biol.Chem.. 273. 7375-7381 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yamaoka, T.et al.: "Hypoplasia of pancreatic islets in transgenic mice expressing activin receptor mutants."J.Clin.Invest.. 102. 294-301 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Iemura, S.et al.: "Direct binding of follistatin to a complex of bone morphogenetic protein and its receptor inhibits ventral and epidermal cell fates in early Xenopus embryo."Proc.Natl.Acad.Sci.U.S.A.. 95. 9337-9342 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shoji, H.et al.: "Identification of a novel type II activin receptor, type IIA-N, induced during the neural differentiation of murine P19 embryonal carcinoma cells."Biochem, Biophys.Res.Commun.. 246. 320-324 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohguchi, M.et al.: "Activin A regulates the production of mature interleukin-1β and interleukin-1 receptor antagonist in human monocytic cells."J.Inter.Cyto.Res.. 18. 491-498 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hashimoto, O.et al.: "The role of activin type I receptors in activin A-induced growth arrest and apoptosis in mouse B cell hybridoma cells."Cell.Signal.. 10. 743-749 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okabayashi, K.et al.: "cDNA cloning and distribution of the Xenopus follistatin-related protein."Biochem.Biophys.Res.Commun.. 254. 42-48 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ishisaki, A.et al.: "Differential inhibition of Smad6 and Smad7 on bone morphogenetic protein- and activin-mediated growth arrest and apoptosis in B cells."J.Biol.Chem.. 274. 13637-13642 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Miyamoto, S.et al.: "Effects of activin on hormone secretion by single female rat pituitary cells : analysis by cell immunoblot aasay."J.Endocrinol.. 161. 375-382 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shoji, H.et al.: "Identification and characterization of a PDZ protein that interacts with activin type II receptors."J.Biol.Chem.. 275. 5485-5492 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tamura, N.et al.: "Effect of activin on production and secretion of prolactin and growth hormone in cultured rat GH3 cells."Eur.J.Endocrinol.. 142. 506-511 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sumitomo, K.et al.: "Expression of a TGF-β1 inducible gene, TSC-36, causes growth inhibition in human lung cancer cell line."Cancer Lett.. 155. 37-46 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Satoh, M.et al.: "Activin promotes astrocytic differentiation of a multipotent neural stem cell line and an astrocyte progenitor cell line from murine central nervous system."Neurosci.Lett.. 284. 143-146 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Florio, P.et al.: "Activin A stimulates insulin secretion in cultured human pancreatic islets."J.Endocrinol.Invest.. 23. 231-234 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] de Groot, E.et al.: "Expression patterns of follistatin and two follistatin-related proteins during mouse development."Int.J.Dev.Biol.. 44. 327-330 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hashimoto, O.et al.: "Differentiation between follistatin isoforms in the inhibition of activin signalling : Activin neutralizing activity of follistatin isoforms is dependent on their affinity for activin."Cellular Signalling. 12. 565-571 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tsuchida, K.et al.: "Identification and characterizaiton of a novel follistatin-like protein as a binding protein for the TGF-β family."J.Biol.Chem.. 275. 40788-40796 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sugino, H.et al.: "Activin and inhibin"Cytokines and Growth Factors. 148-149 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tsuchida, K.et al.: "Activin receptors (ActR)"Cytokines and Growth Factors. 150-151 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sugino, H.et al.: "Follistatin (FS)"Cytokines and Growth Factors. 154 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sugino, H.: "Follistatin - Its molecular heterogeneity and regulation of activin action"J.Clin.Expe.Med.. 185. 169-172 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tsuchida, K.: "Signal transduction through receptor serine/threonine kinase and its regulation."J.Med.. 70. 1430-1435 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sugino, H.et al.: "Activin and follistatin"Skeletal Growth Factors (Canalis, E.ed). 251-262 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tsuchida,K. et al.: "Identification and characterization of a novel follistatin-like protein as a binding protein for the TGF-β family."J.Bjol.Chem.. 275. 40788-40796 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Shoji,H. et al.: "Identification and characterization of a PDZ protein that interacts with activin type II receptors."J.Biol.Chem.. 275. 5485-5492 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sumitomo,K. et al.: "Expression of a TGF-β1 inducible gene, TSC-36, causes growth inhibition in human lung cacer cell lines."Cancer Letters. 155. 37-46 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tamura,N. et al.: "Effect of activin on production and secretion of prolactin and growth hormone in cultured rat GH3 cells."Euro.J.Endocrinol.. 142. 506-511 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Satoh,M. et al.: "Activin promotes astrocytic differentiation of a multipotent neural stem cell line and an astrocyte progenitor cell line from murine central nervous system."Neurosci.Lett.. 284. 143-146 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Florio,P. et al.: "Activin A stimulates insulin secretion in cultured human pancreatic islets."J.Endocrinol.Invest.. 23. 231-234 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] de Groot,E. et al.: "Expression patterns of follistatin and two follistatin-related proteins during mouse development."Int.J.Dev.Biol.. 44. 327-330 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hashimoto,O. et al.: "Differentiation between follistatin isoforms in the inhibition of activin signalling. Activin neutralizing activity of follistatin isoforms is dependent on their affinity for activin."Cellular Signalling. 12. 565-571 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sugino,H. et al.: "Activin and Follistatin. In Skeletal Growth Factors"Lippincott Williams & Willkins, Philadelphia. 13 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Okabayashi,K et al.: "cDNA Cloning and Distribution of the Xenopus Follistatin-Related Protein."Biochem.Biophys.Res.Commun.. 254. 42-48 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ishisaki,A.et al.: "Differential Inhibition of Smad6 and Smad7 on Bone Morphogenetic Protein-and Activin-mediated Growth Arrest and Apoptosis in B Cells."J.Biol.Chem.. 274. 13637-13642 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Miyamoto,S.et al.: "Effects of activin on hormone secretion by signal female rat pituitary cells: analysis by cell immunoblot assay."J.Endocrinol.. 161. 375-382 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Shoji,H.et al.: "Identification and characterization of a PDZ protein that interacts with activin type II receptors."J.Biol.Chem.. 275(8). 5485-5492 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sumitomo,K.et al.: "Expression of TGF-β inducible gene,TSC-36,causes growth inhibition in human lung cancer cell lines."Cancer letters. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sugino,H.et al.: "Skeletal Growth Factors (Canalis,E.ed) Chapter I Activin and follistatin"Lippincott Williams & Willkins,Philadelphia.(in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yamane,Y.,et al.: "Molecular Characterization of Xenopus Embryo Heparan Sulfate:Differential Structural Requirements for the Specific Binding to Basic Fibroblast Growth Factor and Follistatin." J.Biol.Chem.273. 7375-7381 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yamaoka,T.,et al.: "Hypoplasia of Pancreatic Islets in Transgenic Mice Expressing Activin Receptor Mutants." J.Clin.Invest.102. 294-301 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Iemura,S.,et al.: "Direct Binding of Follistatin to a Complex of Bone Morphogenetic Protein and its Receptor Inhibits Ventral and Epidermal Cell Fates in Early Xenopus Embryo." Proc.Natl.Acad.Sci.U.S.A.95. 9337-9342 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Shoji,H.,et al.: "Identification of a Novel Type II Activin Receptor,Type IIA-N,Induced During the Neural Differentiation of Murine P19 Embryonal Carcinoma Cells." Biochem.Biophys.Res.Commun.246. 320-324 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ohguchi,M.,et al.: "Activin A Regulates the Production of Mature Interleukin-lβ and Interleukin-l Receptor Antagonist in Human Monocytic Cells." J.Inter.Cyto.Res.18. 491-498 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hashimoto,O.,et al.: "The Role of Activin TypeI Receptors in Activin A-induced Growth Arrest and Apoptosis in Mouse Cell." Cell.Signal.10. 743-749 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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