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.
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Department of Developmental Biology and Cancer, Albert Einstein College of Medicine, Bronx, NY 10461.
Stanley
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D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D007461:Iodoacetates / Q000494:pharmacology; D019807:Iodoacetic Acid; D007700:Kinetics; D046911:Macromolecular Substances; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008264:Macrophages; D008954:Models, Biological; D008970:Molecular Weight; D010766:Phosphorylation; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism*; D015398:Signal Transduction
D007461:Iodoacetates; D046911:Macromolecular Substances; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D019807:Iodoacetic Acid