Selection of activating mutations of c-fms in FDC-P1 cells.
FDC-P1 haemopoietic cells were used to select mutations of c-fms that constitutively activate the receptor for macrophage-colony stimulating factor (M-CSF or CSF-1). One mutation changed Ser 929 to Gly within a Ser/Gly rich region of the C-terminal tail and a second changed a nearby, highly conserved Leu 926 for Pro. A third mutation (D802V) changed Asp 802 to Val within the alpha L12/beta 9 region of the tyrosine kinase domain, so supporting the crystallographic evidence that this region triggers kinase activation. A c-kit mutation exactly equivalent to D802V was previously identified in a leukamic cell line and was demonstrated here to be transforming. Surprisingly, although D802V potently transformed FDC-P1 cells, it could not induce Rat-2 fibroblast foci, even in the presence of M-CSF. It is suggested that the accelerated receptor degradation induced by D802V may account for its cell specific effect.
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D018076:DNA, Complementary; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009838:Oligodeoxyribonucleotides; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism; D016415:Sequence Alignment; D019089:Stem Cell Factor / Q000235:genetics
D018076:DNA, Complementary; D009838:Oligodeoxyribonucleotides; D011956:Receptors, Cell Surface; D019089:Stem Cell Factor; D016173:Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D016186:Receptor, Macrophage Colony-Stimulating Factor