A novel potential effector of M-Ras and p21 Ras negatively regulates p21 Ras-mediated gene induction and cell growth

Oncogene. 2001 Jan 11;20(2):188-97. doi: 10.1038/sj.onc.1204053.

Abstract

Here, we report the identification and characterization of a new member of the RalGDS-family, which is widely expressed and interacts strongly and selectively with the GTP-bound forms of M-Ras and p21 Ras. This Ras pathway modulator (RPM), also termed RGL3, exhibited Ras-binding and catalytic domains typical of the RalGDS-family of guanine nucleotide exchange factors, and was most similar to Rlf (RalGDS-like factor), but was distinguished by a unique proline-rich region with multiple candidate SH3-domain binding sites. RPM/RGL3 resembled AF-6 and Nore1 in interacting strongly with constitutively active M-Ras and p21 Ras. In contrast to Rlf, transiently expressed RPM/RGL3 did not activate an Elk-1-inducible reporter gene alone or in combination with activated p21 Ras, but strongly inhibited induction of this reporter gene by co-expression of activated H-Ras or MEKK-1. This inhibitory effect was independent of the Ras binding domain and required a second signal provided by p21 Ras or MEKK-1, but not Raf-1 or M-Ras. Expression of RPM/RGL3 also strongly inhibited cell growth of fibroblasts transformed by an activated Src Y527F. Thus, RPM/RGL3 is a novel potential effector of both p21 Ras and M-Ras with the novel function of negatively regulating Elk-1-dependent gene induction downstream of p21 Ras or MEKK-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cell Division / genetics
  • Cells, Cultured
  • DNA-Binding Proteins*
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1*
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Sequence Data
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-raf / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Sequence Homology, Amino Acid
  • Transcription Factors*
  • ets-Domain Protein Elk-1
  • p38 Mitogen-Activated Protein Kinases
  • ral Guanine Nucleotide Exchange Factor / genetics*
  • ral Guanine Nucleotide Exchange Factor / metabolism*
  • src Homology Domains
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism

Substances

  • DNA-Binding Proteins
  • ELK1 protein, human
  • Elk1 protein, mouse
  • Proto-Oncogene Proteins
  • Rgl3 protein, mouse
  • Transcription Factors
  • ets-Domain Protein Elk-1
  • ral Guanine Nucleotide Exchange Factor
  • src-Family Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-raf
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • Map3k1 protein, mouse
  • Mras protein, mouse
  • HRAS protein, human
  • Monomeric GTP-Binding Proteins
  • Proto-Oncogene Proteins p21(ras)

Associated data

  • GENBANK/AF239661