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Signal transduction mechanism mediated by small G protein Ras and its disorder.

Research Project

Project/Area Number 07457041
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionHIROSHIMA UNIVERSITY

Principal Investigator

KIKUCHI Akira  Hiroshima University School of Medicine, Professor, 医学部, 教授 (10204827)

Co-Investigator(Kenkyū-buntansha) KOYAMA Shinya  Hiroshima University School of Medicine, Associate professor, 医学部, 助教授 (00186834)
Project Period (FY) 1995 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥7,400,000 (Direct Cost: ¥7,400,000)
Fiscal Year 1996: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1995: ¥5,300,000 (Direct Cost: ¥5,300,000)
Keywordssmall G proteins / Ras / signal transduction / cancer / RalGDS / Raf
Research Abstract

Small G protein superfamily consists of more than 50 members such as Ras, Ral, and Rac, and regulates important cellular functions including proliferation, differentiation, motion, and vesicle transport. Ras has been shown to possess multiple effector proteins including Raf and phosphatidylinositol-3 kinase. We have found that Ral GDP dissociation stimulator (RalGDS), a GDP/GTP exchange protein of Ral, is an effector protein of Ras and proposed that there is a Ras-signaling pathway through RalGDS.RalGDS interacted with Ras in response to EGF.Protein kinase A inhibited EGF-dependent Raf activation but not interaction of RalGDS and Ras. Furthermore, RalGDS bound to a Ras effector loop mutant with which Raf did not interact, and RalGDS synergized with Raf to stimulate c-fos promoter activity. These results indicate that RalGDS acts downstream of Ras in response to extracellular signal and that it constitutes a Ras-signaling pathway distinct from Raf. It is known that small G proteins undergo post-translational lipid modifications and that the modifications are important for their membrane localization and functions. The modified form of Ras bound to RalGDS more effectively than the unmodified form, and induced the translocation of RalGDS from the cytosol to membrane fractions. The modification of Ral enhanced the RalGDS action. Furthermore, the modified form of Ral bound to RalBP1, a putative effector protein of Ral, more effectively than the unmodified form, and induced the translocation of RalBP1 from the cytosol to membrane fractions. The modification of Rac enhanced the GAP activity of RalBP1 for Rac. Taken together with the observations that Ras, Ral, and Rac are localized to the membranes through their modification, these results suggest that the post-translational modifications of small G proteins play roles for transmitting the signal effectively on the membranes in the signal transduction pathway of Ras/RalGDS/Ral/RalBP1/Rac.

Report

(3 results)
  • 1996 Annual Research Report   Final Research Report Summary
  • 1995 Annual Research Report
  • Research Products

    (40 results)

All Other

All Publications (40 results)

  • [Publications] Murai,H.: "Characterization of Ral GDP dissociation stimulator like (RGL) activities to regulate c-fos promoter and the GDP/GTP exchange of Ral." J.Biol.Chem.(in press). (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Okazaki,M.: "Synergistic activation of c-fos promoter activity by Ral GDP dissociation stimulator and Raf." Oncogene. 14. 515-521 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Murai,H.: "Tyrosine dephosphorylation of glycogen synthase kinese-3 is involved in its extracellular signal-dependent inactivation." FEBS Lett.392. 153-160 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Koyama,S.: "Ras-interacting domain of RGL blocks Ras-dependent signal transduction in Xenopus oocytes" FEBS Lett.380. 113-117 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Okazaki,M.: "Ras-interacting domain of RGL reverses v-Ras-induced transformation and Raf-1 activity in NIH3T3 cells." Cancer Res.56. 2387-2392 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Li,S.: "Baculovirus-based expression of mammalian caveolin in Sf21 insect cells." J.Biol.Chem.,. 271. 28647-28654 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hinoi,T.: "Post-translational modifications of Ras and Ral are important for the action of RalGDS." J.Biol.Chem.271. 19726-19710 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Akasaka,K.: "Differential structure requirements for interaction of Ras protein with its distinct downstream effectors." J.Biol.Chem.271. 5353-5360 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kikuchi,A.: "Regulation of interaction of ras p21 with RalGDS and Raf-1 by Cyclic AMP-dependent protein kinase." J.Biol.Chem.271. 588-594 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] MacNicol,A.M.: "Regulation of Raf-1 dependent signaling during early Xenopus development." Mol.Cell.Biol.15. 6686-6693 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Ikeda,M.: "rap p21 regulates the interaction of ras p21 with RGL,a new effector protein of ras p21." FEBS Lett.375. 37-40 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Koyama,S.: "Characterization of the interaction of Raf-1 to ras p21 and 14-3-3 protein in intact cells" FEBS Lett.368. 321-325 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Murai, H.: "Characterization of Ral GDP dissociation stimulator like (RGL) activities to regulate c-fos promoter and the GDP/GTP exchange of Ral." J.Biol.Chem.(in press). (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Okazaki, H.: "Synergistic activation of c-fos promoter activity by Ral GDP dissociation stimulator and Raf." Oncogene. 14. 515-521 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Murai, H.: "Tyrosine dephosphorylation of glycogen synthase kinase-3 is involved in its extracellular signal-dependent inactivation." FEBS Lett.392. 153-160 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Koyama, S.: "Ras-interacting domain of RGL blocks Ras-dependent signal transduction in Xenopus oocytes" FEBS Lett.380. 113-117 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Okazaki, M.: "Ras-interacting domain of RGL reverses v-Ras-induced transformation and Raf-1 activity in NIH3T3 cells" Cancer Res.56. 2387-2392 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Li, S.: "Baculovirus-based expression of mammalian caveolin in Sf21 insect cells." J.Biol.Chem.271. 28647-28654 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hinoi, T.: "Post-translational modifications of Ras and Ral are important for the action of RalGDS." J.Biol.Chem.271. 19710-19726 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Akasaka, K.: "Differential structure requirements for interaction of Ras protein with its distinct downstream effectors." J.Biol.Chem.271. 5353-5360 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kikuchi, A.: "Regulation of interaction of ras p21 with RalGDS and Raf-1 by Cyclic AMP-dependent protein kinase." J.Biol.Chem.271. 588-594 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] MacNicol, A.M.: "Regulation of Raf-1 dependent signaling during early Xenopus development." Mol.Cell.Biol.15. 6686-6693 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Ikeda, M.: "rap p21 regulates the interaction of ras p21 with RGL,a new effector protein of ras p21." FEBS Lett.375. 37-40 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Koyama, S.: "Characterization of the interaction of Raf-1 to ras p21 and 14-3-3 protein in intact cells" FEBS Lett.368. 321-325 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Murai, H.: "Characterization of Ral GDP dissociation stimulator like (RGL) activities to regulate c-fos promoter and the GDP/GTP exchange of Ral." J. Biol. Chem.(in press). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Okazaki, M.: "Synergistic activation of c-fos promoter activity by Ral GDP dissociation stimulator and Raf." Oncogene. 14. 515-521 (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Murai, H.: "Tyrosine dephosphorylation of glycogen synthase kinase-3 is involved in its extracellular signal-dependent inactivation." FEBS Letters. 392 (2). 153-160 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Koyama, S.: "Ras-interacting domain of RGL blocks Ras-dependent signal transduction in Xenopus oocytes" FEBS Letters. 380 (1-2). 113-117 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Okazaki, M.: "Ras-interacting domain of RGL reverses v-Ras-induced transformation and Raf-1 activity in NIH3T3 cells." Cancer Res.56 (10). 2387-2392 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Li, S.: "Baculovirus-based expression of mammalian caveolin in Sf21 insect cells." J. Biol. Chem.271 (45). 28647-28654 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hinoi, T.: "Post-translational modifications of Ras and Ral are important for the action of RalGDS." J. Biol. Chem.271 (33). 19710-19726 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Akasaka, K.: "Differential structure requirements for interaction of Ras protein with its distinct downstream effectors." J. Biol. Chem.271 (10). 5353-5360 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kikuchi, A.: "Regulation of interaction of ras p21 with RalGDS and Raf-1 by Cyclic AMP-depedent protein kinase." J. Biol. Chem.271 (1). 588-594 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kikuchi, A.: "Regulation of interaction of ras p21 with RalGDS and Raf-1 by cyclic AMP-dependent protein kinase." J. Biol. Chem.271. 588-594 (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Akasaka, K: "Differential structure requirements for interaction of Ras protein with its distinct downstream effectors." J. Biol. Chem.271. 5353-5360 (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Koyama, S.: "Ras-interacting domain of RGL blocks Ras-dependent signal transduction in Xenopus oocytes." FEBS Letters. 380. 113-117 (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Okazaki, M.: "Ras-interacting domain of RGL reverses v-Ras-induced transformation and Raf-1 activation in NIH3T3 cells." Cancer Res.(in press). (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] MacNicol, A. M.: "Regulation of Raf-1 dependent signaling during early Xenopus development." Mol. Cell. Biol.15. 6686-6693 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Ikeda, M.: "rap p21 regulates the interaction of ras p21 with RGL, a new effector protein of ras p21." FEBS Letters. 375. 37-40 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Koyama, S.: "Characterization of the interaction of Raf-1 to ras p21 and 14-3-3 protein in intact cells." FEBS Letters. 368. 321-325 (1995)

    • Related Report
      1995 Annual Research Report

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Published: 1995-04-01   Modified: 2016-04-21  

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