Role of dimerization and modification of the CSF‐1 receptor in its activation and internalization during the CSF‐1 response.

We have used kinetic and cross‐linking approaches to study CSF‐1‐induced changes in the structure and function of the CSF‐1R. Addition of CSF‐1 to cells stimulates or stabilizes non‐covalent CSF‐1R dimerization resulting in activation of the CSF‐1R kinase and the tyrosine phosphorylation of the receptor and certain cytoplasmic proteins. The non‐covalent dimers become covalently linked via disulfide bonds and/or are subsequently further modified. These modified forms are selectively internalized. Pre‐treatment of cells with the alkylating agent, iodoacetic acid (IAA), selectively inhibits covalent dimerization, modification and internalization but enhances protein tyrosine phosphorylation. It is proposed that ligand‐induced non‐covalent dimerization activates the CSF‐1R kinase, whereas the covalent dimerization and subsequent modification lead to kinase inactivation, phosphotyrosine dephosphorylation and internalization of the receptor–ligand complex.