This project aims to elucidate the biological function(s) of the c-fps/fes proto-oncogene and to understand the molecular basis of its oncogenic potential. We have previously shown that the c-fps/fes proto-oncogene, when expressed at sufficiently high levels, can cause tumorigenic transformation of cells that do not express c-fps/fes, such as murine fibroblasts. We have now shown that introduction of c-fps/fes into a differentiated factor-dependent macrophage cell line where c-fps/fes is normally expressed, can relieve their dependence of CSF-1 for their growth. The release of these cells from CSF-1 dependence did not result from a direct action of the c-fps/fes product (NCP92) on targets of the CSF-1 receptor. Biochemical analysis showed that the phosphotyrosine substrates of NCP92 were different from those that are phosphorylated by CSF-1 receptor upon CSF-1 treatment of the cells. Neither was endogenous or ectopically expressed c-fps/fes a substrate of CSF-1 receptor kinase during ligand-activated signal transduction in these cells. Further analysis showed that in cells that overexpressed NCP92 there was no change in the rate of synthesis, the number of CSF-1 receptors at the cell surface, or in the ability of receptors to bind CSF- 1. We conclude that 1) overexpression of c-fps/fes can subvert the mechanisms of normal growth control in mature macrophages by acting on targets that are different from those of the CSF-1 receptor pathway, 2) the c-fps/fes product does not mediate CSF-1 -activated signal transduction, and 3) overexpressed c-fps/fes does not up- or down-regulate CSF-1 receptor expression, nor does it affect the binding of ligand to its receptor.
