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 nea rby, highly conserved Leu 926 for Pro. A third mutation (D802V) change d Asp 802 to Val within the alpha L12/beta 9 region of the tyrosine ki nase domain, so supporting the crystallographic evidence that this reg ion triggers kinase activation, A c-kit mutation exactly equivalent to D802V was previously identified in a leukamic cell line and was demon strated 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 re ceptor degradation induced by D802V may account for its cell specific effect.