The CSF-1 receptor (CSF-1R), encoded by the proto-oncogene, c-fms, is the receptor for the macrophage colony stimulating factor, also known as colony stimulating factor-1 (CSF-1). It is a transmembrane glycoprotein, consisting of an excellent ligand-binding domain, a membrane-spanning region and a cytoplasmic domain that has a tyrosine kinase active site. We are interested in (a) the mechanism of ligand- induced kinase activation and (b) the roles of the different domains. Previously, we have demonstrated with insertional mutations of CSF-1R that ligand activation is unlikely to occur via an intramolecular mechanism, in which ligand binding induces a conformational change in the extracellular domain that is transmitted across the transmembrane region to the cytoplasmic tyrosine kinase site. Using glycophorin-CSF- 1R chimerae, we showed that a more likely mechanism involves ligand- induced oligomerization which allows the cytoplasmic domains to be juxtaposed and critical interactions such as transphosphorylation to occur resulting in kinase activation. Our work during the past year has continued to focus on the identification of intracellular substrates for CSF-1R and intermediates along its signalling pathway. In particular we will describe progress on the elucidation of the involvement of p21ras in CSF-1 signalling.
