Uncoupling of the proliferation and differentiation signals mediated by the murine macrophage colony-stimulating factor receptor expressed in myeloid FDC-P1 cells

The macrophage colony-stimulating factor (M-CSF) regulates proliferation and differentiation of cells belonging to the monocytic lineage. We have investigated the nature and origin of the proliferation and differentiation signals derived from the M-CSF receptor (Fms) by mutating Fms at the four tyrosine autophosphorylation sites and examining their biological effects in an FDC-Pt clone. Wild-type Fms stimulated both growth and differentiation of FDC-P1 cells in response to M-CSF stimulation. In contrast, both proliferation and differentiation were differentially disrupted by mutations affecting the fear tyrosine autophosphorylation sites. These analyses revealed that: (a) none of the four autophosphorylation sites studied (Y697, Y706, Y721, and Y807) were essential for M-CSF-dependent proliferation of the FDC-P1 clone; (b) Y697, Y706, and Y721 sites, located in the kinase insert region of Fms, were not necessary for differentiation, but their presence augmented this process; (c) mutation of the Y807 site totally abrogated the differentiation of the FDC-P1 clone and simultaneously increased the rate of M-CSF-dependent proliferation; and (d) conversely, increasing the intracellular cAMP level blocked the growth signal in the FDC-P1 clone but had no effect on differentiation. These results suggest that autophosphorylation of Fms at the Y807 site controls the balance between signals for growth and differentiation.