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 antiglycophorin 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. In the past year, we have continued our studies on the mechanism of signal transduction by the receptor for the colony stimulating factor-1 (CSF-lR), encoded by the proto-oncogene c-fms. In particular, we have focused on the identification of intracellular substrates for this receptor, since an understanding of the biological action of CSF-1 requires knowledge of the elements of its downstream signalling pathway. To date, only the phosphatidyl inositol 3-kinase has been shown to be associated with CSF-1R upon CSF-1 stimulation. The precise role of this lipid enzyme, however, remains to be determined. We have examined two candidate components of the CSF-1R signalling pathway. The first is p2lras, the c-ras gene product, and the second is the microtubule associated protein 2 (MAP2) kinase.
