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Screening and characterization of BMP-specific R-Smads binding proteins

Research Project

Project/Area Number 13671554
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Orthopaedic surgery
Research InstitutionJapanese Foundation for Cancer Research

Principal Investigator

IMAMURA Takeshi  The JFCR Cancer Institute, Dept. Biochem., Associate member, 癌研究所・生化学部, 主任研究員 (70264421)

Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsBMPs / Smads / Signal transduction
Research Abstract

Bone morphogenetic proteins (BMPs), members of the transforming growth factor-β (TGF-β) superfamily, were originally identified as osteoinductive proteins in bone that induce ectopic bone and cartilage formation in vivo. BMPs bind to type I and type II serine/threonine kinase receptors, BMPR-I and II. Smad proteins play central roles in intracellular signaling by BMPs. Eight different Smad proteins have been identified in mammals, and are classified into three subgroups, i. e. receptor-regulated Smads (R-Smads), a common-partner Smad (Co-Smad), and inhibitory Smads (I-Smads). BMP-specific R-Smads, Smads 1,5 and 8, transiently and directly interact with activated BMPR-Is, and become phosphorylated. Smad1/5/8 then form heteromeric complexes with Co-Smad, Smad4, and translocate into the nucleus where they regulate transcription of various target genes. In contrast, I-Smads, including Smad6 and Smad7, stably bind to BMPR-Is and compete with Smad1/5/8 for activation, resulting in inhibition of BMP signaling.
In this project, we examined the function of Smad ubiquitin regulatory factor(Smurf) 1 as a Smad binding protein. Smurf1 was originally identified as an E3 ubiquitin ligase for Smad1/5. We demonstrated that Smurf1 associates with type I receptors for BMPs through the I-Smads, and induced their ubiquitination and degradation. Smurf1 thus controls BMP signaling with and without I-Smads through multiple mechanisms.
Next, we clarified the mechanism of nuclear export and membrane localization of Smurf1-I-Smad complex. Smurf1 binds to CRM1, and Smurf1-I-Smad complex translocates from the nucleus to the cytoplasm. Then Smurf1-I-Smad complex locates to cell membrane through C2 domain of Smurf1.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (29 results)

All Other

All Publications (29 results)

  • [Publications] Tajima Y, Goto K, Yoshida M, Shinomiya K, Sekimoto T, Yoneda Y, Miyazono K, Imamura T.: "Chromosomal Region Maintenance 1 (CRM1)-dependent Nuclear Export of Smad Ubiquitin Regulatory Factor 1 (Smurf1) Is Essential for Negative Regulation of Transforming Growth Factor-beta Signaling by Smad7"J Biol Chem.. 278. 10716-10721 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Midorikawa Y, Ishikawa S, Iwanari H, Imamura T, Sakamoto H, Miyazono K, Kodama T, Makuuchi M, Aburatani H: "Glypican-3, overexpressed in hepatocellular carcinoma, modulates FGF2 and BMP-7 signaling"Int J Cancer.. 103. 455-465 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Mizuide M, Hara T, Furuya T, Takeda M, Kusanagi K, Inada Y, Mori M, Imamura T, Miyazawa K, Miyazono K: "Two short segments of Smad3 are important for specific interaction of Smad3 with c-Ski and SnoN"J Biol Chem.. 278. 531-536 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nishihara A, Watabe T, Imamura T, Miyazono K: "Functional Heterogeneity of Bone Morphogenetic Protein Receptor-II Mutants Found in Patients with Primary Pulmonary Hypertension"Mol Biol Cell.. 13. 3055-3063 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Suzuki C, Murakami G, Fukuchi M, Shimanuki T, Shikauchi Y, Imamura T, Miyazono K: "Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane"J Biol Chem.. 277. 39919-39925 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hanyu A, Ishidou Y, Ebisawa T, Shimanuki T, Imamura T, Miyazono K: "The N domain of Smad7 is essential for specific inhibition of transforming growth factor-beta signaling"J Cell Biol.. 155. 1017-1028 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamato K, Hashimoto S, Imamura T, Uchida H, Okahashi N, Koseki T, Ishisaki A, Kizaki M, Miyazono K, Ikeda Y, Nishihara T: "Activation of the p21 (CIP1/WAF1) promoter by bone morphogenetic protein-2 in mouse B lineage cells"Oncogen.. 20. 4383-4392 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fukuchi M, Imamura T, Chiba T, Ebisawa T, Kawabata M, Tanaka K, Miyazono K: "Ligand-dependent degradation of smad3 by a ubiquitin ligase complex or rocl and associated proteins"Mol Biol Cell.. 12. 1431-1443 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Aoki H, Fujii M, Imamura T, Yagi K, Takehara K, Kato M, Miyazono K: "Synergistic effects of different bone morphogenetic protein type I receptors on alkaline phosphatase induction"J Cell Sci.. 114. 1483-1489 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T, Miyazono K: "Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation"J Biol Chem.. 276. 12477-12480 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nishimori S, Tanaka Y, Chiba T, Fujii M, Imamura T, Miyazono K, Ogasawara T, Kawaguchi H, Igarashi T, Fujita T, Tanaka K, Toyoshima H: "Smad-mediated transcription is required for transforming growth factor-beta 1-induced p57(Kip2) proteolysis in osteoblastic cells"J Biol Chem.. 276. 10700-10705 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tajima Y, Goto K, Yoshida M, Shinomiya K, Sekimoto T, Yoneda Y, Miyazono K, Imamura T: "Chromosomal Region Maintenance 1 (CRM 1)-dependent Nuclear Export of Smad Ubiquitin Regulatory Factor 1 (Smurf1) Is Essential for Negative Regulation of Transforming Growth Factor-beta Signaling by Smad7."J. Biol Chem.. 278. 10716-10721 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Midorikawa Y, Ishikawa S, Iwanari H, Imamura T, Sakamoto H, Miyazono K, Kodama T, Makuuchi M, Aburatani H: "Glypican-3, ova-expressed in hepatocellular carcinoma, modulates FGF2 and BMP-7 signaling."Int J Cancer.. 103. 455-465 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Mzuide M, Hara T, Furuya T, Takeda M, Kusanagi K, Inada Y, Mori M, Imamura T, Miyazawa K, Miyazono K: "Two short segments of Smad3 are important for specific interaction of Smad3 with c-Ski and SnoN."JBiol Chem.. 278. 531-536 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nishihara A, Watabe T, Imamura T, Miyazono K: "Functional Heterogeneity of Bone Mprphogenetic Protein Receptor-n Mutants Found in Patients with Primary Pulmonary Hypertension."Mol Biol Cell.. 13. 3055-3063 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Suzuki C, Murakami G, Fukuchi M, Shimanuki T, Shikauchi Y, Imamura T, Miyazono K: "Smurf1 regulates the inhibitory activity of Srnad7 by targeting Smad7 to the plasma membrane."J Biol Chem.. 277. 39919-39925 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hanyu A, Ishidou Y, Ebisawa T, Shimanuki T, Imamura T, Miyazono K: "The N domain of SmadV is essential for specific inhibition of transforming growth factor-beta signaling."J CeU Biol.. 155. 1017-1028 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamato K, Hashimoto S, Imamura T, Uchida H, Okahashi N, Koseki T, Ishisaki A, Kizaki M, Miyazono K, Ikeda Y, Nishihara T: "Activation of the p21 (CIP1/WAF1) promoter by bone morphogenetic protein-2 in mouse B lineage cells."Oncogene. 20. 4383-4392 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fukuchi M, Imamura T, Chiba T, Ebisawa T, Kawabata M, Tanaka K, Miyazono K: "Ligand-dependent degradation of smad3 by a ubiquitin ligase complex of roc1 and associated proteins."Mol Biol Cell.. 12. 1431-1443 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Aoki H, Fujii M, Imamura T, Yagi K, Takehara K, Kato M, Miyazono K: "Synergistic effects of different bone morphogenetic protein type I receptors on alkaline phosphatase induction."JCell Sci.. 114. 1483-1489 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T, Miyazono K: "Smurf1 interacts with transforming growth factor-beta type I receptor through Smad.7 and induces receptor degradation."JBiol Chem.. 276. 12477-12480 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nishimori S, Tanaka Y, Chiba T, Fujii M, Imamura T, Miyazono K, Ogasawara T, Kawaguchi H, Igarashi T, Fujita T, Tanaka K, Toyoshima H.: "Smad-mediated transcription is required for transforming growth factor-beta 1-induced p57(Kip2) proteolysis in osteoblastic cells."J Biol Chem,. 276. 10700-10705 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tajima, Y.et al.: "Chromosomal Region Maintenance 1(CRM1)-dependent Nuclear Export of Smad Ubiquitin Regulatory Factor 1(Smurf1) Is Essential for Negative Regulation of Transforming Growth Factor-beta Signaling by Smad7"J Biol Chem. 278. 10716-10721 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Midorikawa, Y.et al.: "Glypican-3, overexpressed in hepatocellular carcinoma, modulates FGF2 and BMP-7 signaling"Int J Cancer. 103. 455-465 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Mizuide, M.et al.: "Two short segments of Smad3 are important for specific interaction of Smad3 with c-Ski and SnoN"J Biol Chem. 278. 531-536 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nishihara, A.et al.: "Functional Heterogeneity of Bone Morphogenetic Protein Receptor-II Mutants Found in Patients with Primary Pulmonary Hypertension"Mol Biol Cell. 13. 3055-3063 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Suzuki, C.et al.: "Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane"J Biol Chem. 277. 39919-39925 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hanyu, A. et al.: "The N domain of Smad7 is essential for specific inhibition of transforming growth factor-beta signaling"J Cell Biol.. 155. 1017-1027 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Aoki, H. et al.: "Synergistic effects of different bone morphogenetic protein type I receptors on alkaline phosphatase induction"J Cell Sci.. 114. 1483-1489 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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