The CSF-1 receptor is the cell surface receptor for the macrophage colony stimulating factor. It is found on cells of the monocyte-macrophage lineage and placental trophoblasts. The interaction of CSF-1 with its receptor mediates all its biological actions. We have investigated the mechanism whereby ligand binding activates the tyrosine kinase function of the murine receptor. Using a hybrid receptor composed of the external domain of glycophorin A, an erythrocyte structural protein, and the transmembrane and cytoplasmic domains of the CSF-1 receptor, we have shown that it is possible to activate the kinase domain by the cross-linking properties of anti-glycophorin antibodies. Once activated as a kinase, this hybrid receptor is able to support mitogenesis and associate with a known intracellular substrate for the wildtype receptor (phosphatidyl inositol-3-kinase). However, unlike the wildtype receptor, it is not downregulated, indicating that the external domain must contain signals that target the CSF-1 receptor for lysosomal degradation.