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1996 Fiscal Year Final Research Report Summary

The Significance of Posttranslational Modification (Farnesylation) of Ras Protein in Activation of Its Effectors

Research Project

Project/Area Number 08457038
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General medical chemistry
Research InstitutionKobe University School of Medicine

Principal Investigator

KATAOKA Tohru  Kobe Univ.Sch.Med., Dept.Physiology II,Professor, 医学部, 教授 (40144472)

Co-Investigator(Kenkyū-buntansha) KATAOKA Yuriko  Kobe Univ.Sch.Med., Dept.Physiology II,Instructor, 医学部, 助手 (50233739)
KARIYA Ken-ichi  Kobe Univ.Sch.Med., Dept.Physiology II,Associate Professor, 医学部, 助教授 (40263371)
Project Period (FY) 1996
Keywordsras Oncogene / GTP-Binding Protein / Posttranslational Modification / Rap1A / Anti-Oncogene / raf Oncogene / Adenylyl Cyclase / Adenylyl Cyclase-Associated Protein
Research Abstract

1. Based on our discovery of the second Ras-binding site of Raf-1 corresponding to the cysteine-rich region (CRR), whose interaction with Ras is abolished by mutations in the activator region of Ras and requires posttranslational modification of Ras, we elucidated the mechanism by which the anti-oncogene product Rap1A antagonizes the Ras function. Rap1A has a high affinity for CRR,forms a ternary complex with Raf-1 and Ras, and thereby inhibits the binding of Ras to CRR,resulting in inhibition of Ras-dependent Raf-1 activation. The binding of Rap1A to Raf-1 CRR also requires posttranslational modification (geranylgeranylation) of RaplA.The antagonistic function of RaplA is determined by the nature of its 31th amino acid residue, which is converted to lysine compared to glutamic acid of Ras.
2. We elucidated the molecular mechanism by which posttranslational modification (especially farnesylation) of Ras is required for activation of yeast adenylyl cyclase. Farnesylation of Ras is required for activation of adenylyl cyclase, whereas it has no effect on the binding affinity of cyclase for Ras. The stimulatory effect of farnesylation depends on the association of adenylyl cyclase with the adenylyl cyclase-associated protein CAP.This implies that CAP may be an acceptor for the farnesyl moiety of Ras and mediate the effect of Ras farnesylation. These results led us to propose a new concept of "isoprenyl group acceptor sites".
3. By employing the fluorescence polarization method, we were able to show that a synthetic peptide corresponding to the C-terminus of Ras which was chemically attached with farnesyl group bound specifically to CAP,suggesting that CAP is really an acceptor molecule for the farnesyl moiety of Ras. However, we failed to detect similar interaction of the farnesylated peptide with Raf-1 CRR.This is presumably due to vary low affinity of their interaction.

  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] M. Shinkai et al.: "Difference in the mechanism of interaction of Raf-1 and B-raf with H-Ras." Biochem. Biophys. Res. Comm.223巻3号. 729-734 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] F. Shima et al.: "Effect of association with adenylyl cyclase-associated protein on the interaction of yeast adenlylyl cyclase with Ras protein." Mol. Cell. Biol.17巻3号. 1057-1064 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K. Kariya et al.: "C. elegans homologs of ralGDS, AF-6, Cdc25 and phospholipase Cβ interact with Let-60." Worm Breeder's Gazette. 14巻5号. 34-35 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M. Okazaki et al.: "Synergistic activation of c-fospromoter activity by Raf and Ral GDP dissociation stimulator." Oncogene. 14巻3号. 515-521 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] C-D. Hu et al.: "Coassociation of Rap1A and Ha-Ras with Raf-1 N-terminal region interferes with Ras-dependent activation of Raf-1." J. Biol. Chem.272巻 (発表予定). (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] C. Yanagihara et al.: "Association of elongation factor 1alpha and ribosomal protein L3 with the proline-rich region of yeast adenylyl cyclase-associated protein." Biochem. Biophys. Res. Comm.233または234巻 (発表予定). (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M.Shinkai et al.: "Difference in the mechanism of interaction of Raf-1 and B-raf with H-Ras." Biochem.Biophys.Res.Comm.223. 729-734 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] F.Shima et al.: "Effect of association with adenylyl cyclase-associated protein on the interaction of yeast adenylyl cyclase with Ras protein." Mol.Cell.Biol.17. 1057-1064 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K.Kariya et al.: "C.elegans homologs of ralGDS,AF-6, Cdc25 and phospholipase Cbeta interact with Let-60." Worm Breed.Gazet.14(5). 34-35 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] M.Okazaki et al.: "Synergistic activation of c-fos promoter activity by Raf and Ral GDP dissociation stimulator." Oncogene. 14. 515-521 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] C-D.Hu et al.: "Coassociation of Rap1A and Ha-Ras with Raf-1 N-terminal region interferes with Ras-dependent activation of Raf-1." J.Biol.Chem.272. 11702-11705 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] C.Yanagihara et al.: "Association of elongation factor 1a and ribosomal protein protein L3 with the proline-rich region of yeast adenylyl cyclase-associated protein." Biochem.Biophys.Res.Comm.233 or 234. (in press). (1997)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-03-09  

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