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 proliferati on and differentiation of cells belonging to the monocytic lineage. We have investigated the nature and origin of the proliferation and diff erentiation 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-P1 clone. Wild-type Fms stimulated both growth and differentiation of FDC-P1 cells in response to M-CSF stimul ation. In contrast, both proliferation and differentiation were differ entially disrupted by mutations affecting the four tyrosine autophosph orylation sites. These analyses revealed that: (a) none of the four au tophosphorylation sites studied (Y697, Y706, Y721, and Y807) were esse ntial for M-CSF-dependent proliferation of the FDC-P1 clone; (b) Y697, Y706, and Y721 sites, located in the kinase insert region of Fms, wer e not necessary for differentiation, but their presence augmented this process; (c) mutation of the Y807 site totally abrogated the differen tiation of the FDC-P1 clone and simultaneously increased the rate of M -CSF-dependent proliferation; and (d) conversely, increasing the intra cellular cAMP level blocked the growth signal in the FDC-P1 clone but had no effect on differentiation. These results suggest that autophosp horylation of Fms at the Y807 site controls the balance between signal s for growth and differentiation.