Ras-interacting domain of Ral GDP dissociation stimulator like (RGL) reverses v-Ras-induced transformation and Raf-1 activation in NIH3T3 cells

Cancer Res. 1996 May 15;56(10):2387-92.

Abstract

Ral GDP dissociation stimulator (RalGDS) and RalGDS like (RGL) are putative effector proteins of Ras and contain the Ras-interacting domain (RID) at their C-terminal regions. v-Ras is known to activate c-fos promoter/enhancer and Raf-1 and to transform NIH3T3 cells. It is also known that v-Raf activates c-fos promoter/enhancer and transforms NIH3T3 cells. In this study, we examined the effect of RID on the phenotype of the cells transformed by v-Ras and v-Raf. Overexpression of RID greatly reduced cell growth in low serum, colony-forming activity in soft agar, c-fos promoter/enhancer activity, and Raf-1 activity of v-Ras-transformed cells. However, overexpression of RID did not affect the phenotype of v-Raf-transformed cells. These results clearly indicate that RID of RGL specifically binds to Ras in mammalian cells, that it blocks the signal from Ras to Raf-1, and that it reverses v-Ras-induced malignant phenotype. It has been reported that Ras-binding domains of Raf-1 and neurofibromatosis type 1 (NF1) reverse v-Ras-induced malignant phenotype. Since there is no homology in primary structures of RGL, Raf-1, and NF1, there may be a similarity of secondary or tertiary structure among RID of RGL and Ras-binding domains of Raf-1 and NF1, and the structure might be useful for developing a potential medicine for human cancers caused by Ras.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Alkyl and Aryl Transferases*
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cell Adhesion
  • Cell Division
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Enhancer Elements, Genetic
  • Farnesyltranstransferase
  • GTP-Binding Proteins / chemistry
  • GTP-Binding Proteins / physiology*
  • Gene Expression Regulation, Neoplastic*
  • Genes, Neurofibromatosis 1
  • Genes, fos
  • Genes, ras
  • Guanine Nucleotide Exchange Factors*
  • Mice
  • Molecular Sequence Data
  • Neoplasm Proteins / antagonists & inhibitors
  • Oncogene Protein p21(ras) / antagonists & inhibitors
  • Oncogene Protein p21(ras) / physiology*
  • Oncogene Proteins v-raf
  • Peptide Fragments / biosynthesis
  • Peptide Fragments / genetics
  • Promoter Regions, Genetic
  • Protein Serine-Threonine Kinases / physiology*
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-raf
  • Recombinant Proteins / metabolism
  • Retroviridae Proteins, Oncogenic / physiology
  • Structure-Activity Relationship
  • Transferases / antagonists & inhibitors
  • ral GTP-Binding Proteins

Substances

  • Guanine Nucleotide Exchange Factors
  • Neoplasm Proteins
  • Peptide Fragments
  • Proto-Oncogene Proteins
  • RGL1 protein, human
  • Recombinant Proteins
  • Retroviridae Proteins, Oncogenic
  • Rgl1 protein, mouse
  • Transferases
  • Alkyl and Aryl Transferases
  • Farnesyltranstransferase
  • Oncogene Proteins v-raf
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-raf
  • GTP-Binding Proteins
  • Oncogene Protein p21(ras)
  • ral GTP-Binding Proteins