The carboxy-terminal catalytic domain of the GTPase-activating protein inhibits nuclear signal transduction and morphological transformation mediated by the CSF-1 receptor.
To determine whether ras p21 products are necessary for signal transduction mediated by the colony stimulating factor-1 receptor (CSF-1R, the c-fms proto-oncogene product), we determined whether CSF-1R and ras activate a common nuclear target and whether the interruption of ras action affects CSF-1R signal transduction. Expression of the NVL3 retrotransposon was activated to the same extent in NIH-3T3 cells by both ras and v-fms oncogenes, and the ras-responsive element located in the long terminal repeat of NVL3 was demonstrated to be a common target for oncogene action. Human recombinant CSF-1 stimulated expression of the NVL3 element 30-fold in NIH-3T3 cells that contained human CSF-1R. Expression of the carboxy-terminal 374 amino acid residues of the human ras GTPase-activating protein (GAP) in cells containing CSF-1R was able to inhibit CSF-1 induction of NVL3 expression by 90%. Expression of the catalytic domain of GAP was also able to suppress transformation by either v-fms or ligand-activated CSF-1R. Expression of the c-jun proto-oncogene was activated by CSF-1R but was insensitive to the action of the catalytic domain of GAP. These results provide genetic evidence that in NIH-3T3 cells, ras p21 is involved in signal transduction mediated by CSF-1R.
Bortner
D M
DM
Department of Microbiology and Immunology, Duke University Medical Center, Durham, North Carolina 27710.
Ulivi
M
M
Roussel
M F
MF
Ostrowski
M C
MC
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000502:physiology*; D020690:GTPase-Activating Proteins; D016236:Genes, fms; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D010957:Plasmids; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D014162:Transfection; D020703:ras GTPase-Activating Proteins
D020690:GTPase-Activating Proteins; C000715470:MAS1 protein, human; D009838:Oligodeoxyribonucleotides; D011506:Proteins; D000090063:Proto-Oncogene Mas; D011994:Recombinant Proteins; D020703:ras GTPase-Activating Proteins; D012313:RNA; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor