FMIP, a novel Fms-interacting protein, affects granulocyte/macrophage differentiation

Hematopoietic cell growth, differentiation, and commitment to a restricted lineage are guided by a set of cytokines acting exclusively on cells expres sing the corresponding cytokine receptor. The macrophage colony stimulating factor (M-CSF, also termed CSF-1) and its cognate receptor, the tyrosine k inase c-Fms, are essential for monocyte and macrophage development. The und erlying molecular mechanism, however, is poorly understood. Here we identif ied a novel Fms-interacting protein (FMIP, MW 78 kDa) which binds transient ly via its N-terminal 144 residues to the cytoplasmic domain of activated F ms-molecules. Binding of FMIP was paralleled by rapid tyrosine phosphorylat ion within the binding domain which drastically reduced its ability to asso ciate with Fms. Binding was specific as evidenced by co-immunoprecipitation and association with recombinant GST-Fms fusion proteins. No binding was o bserved with the tyrosine phosphorylated cytoplasmic domains of c-Kit, TrkA , c-Met, and the insulin receptor. The role of FMIP in hematopoietic differ entiation was studied in the bipotential myeloid progenitor cell line, FDC- P1Mac11. Overexpression of FMIP prevented M-CSF induced macrophage differen tiation. Instead, cells differentiated into granulocytes. Our data suggest that the level of FMIP expression could form a threshold that decides about differentiation either into macrophages or into granulocytes.