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European Cytokine Network

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Arg 777 plays a major role in the conformation of the colony-stimulating factor-1 receptor intracellular kinase domain Volume 9, issue 1, March 1998

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A point mutation substituting Arg 777 by Gln was obtained in a highly conserved region of the human colony-stimulating factor-1 receptor (CSF-1R) sequence. Constitutive expression of wild-type receptors in CHO cells confers susceptibility to CSF-1 for proliferation whereas the mutated receptors exhibited a 90% reduced efficiency in proliferation. We sought to determine the alterations intervening in the CSF-1 signal transduction of the Arg 777 Gln mutated receptor. We found that ligand binding and ligand-induced CSF-1R internalization were unaffected. CSF-1-induced receptor dimerization and autophosphorylation were impaired to the same extent as mitogen-activated protein kinase activation (90%). However, only phosphatidylinositol 3-kinase activation and ligand-induced receptor ubiquitination were abrogated by the mutation. These features probably reflect the inability of the mutated CSF-1R kinase domain to fold properly and hence to autophos-phorylate and/or to associate correctly with transduction proteins. These data may indicate a role for the conserved regions of the RTK kinase domains in the stabilization of the intracellular domain conformation.