Colony-stimulating factor 1-mediated regulation of a chimeric c-fms/v-fms receptor containing the v-fms-encoded tyrosine kinase domain.
A chimeric gene specifying the 308 N-terminal amino acids of the extracellular ligand binding domain of the human c-fms protooncogene joined to the remainder of the feline v-fms oncogene product encodes a functional colony-stimulating factor 1 (CSF-1) receptor. When expressed in mouse NIH 3T3 fibroblasts, the chimeric gene product was rapidly transported to the cell surface, was autophosphorylated on tyrosine only in response to human recombinant CSF-1, underwent ligand-induced but not phorbol ester-induced down-modulation, and stimulated CSF-1-dependent cell proliferation. By contrast, the C-terminally truncated glycoprotein encoded by the v-fms oncogene is partially inhibited in its transport to the plasma membrane, is constitutively phosphorylated on tyrosine, and is relatively refractory to both ligand-induced and phorbol ester-induced down-modulation. Although the v-fms oncogene can transform cells in the absence of CSF-1, its tyrosine kinase activity and turnover can be appropriately regulated by the human c-fms-encoded ligand binding domain. The results confirm that C-terminal truncation of the c-fms gene is insufficient to activate its transforming potential and suggest that an additional mutation in its distal extracellular domain is required for oncogenic activation.
Roussel
M F
MF
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38101.
Downing
J R
JR
Ashmun
R A
RA
Rettenmier
C W
CW
Sherr
C J
CJ
D000818:Animals; D002471:Cell Transformation, Neoplastic; D003001:Cloning, Molecular; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D004247:DNA / Q000032:analysis; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011519:Proto-Oncogenes; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics*; D016184:Receptors, Colony-Stimulating Factor; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D003115:Colony-Stimulating Factors; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D016184:Receptors, Colony-Stimulating Factor; D004247:DNA; D011505:Protein-Tyrosine Kinases; D013755:Tetradecanoylphorbol Acetate