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A CSF-1 receptor phosphotyrosine 559 signaling pathway regulates receptor ubiquitination and tyrosine phosphorylation.

http://www.ncbi.nlm.nih.gov/pubmed/21041311

Receptor tyrosine kinase (RTK) activation involves ligand-induced receptor dimerization and transphosphorylation on tyrosine residues. Colony-stimulating factor-1 (CSF-1)-induced CSF-1 receptor (CSF-1R) tyrosine phosphorylation and ubiquitination were studied in mouse macrophages. Phosphorylation of CSF-1R Tyr-559, required for the binding of Src family kinases (SFKs), was both necessary and sufficient for these responses and for c-Cbl tyrosine phosphorylation and all three responses were inhibited by SFK inhibitors. In c-Cbl-deficient macrophages, CSF-1R ubiquitination and tyrosine phosphorylation were substantially inhibited. Reconstitution with wild-type, but not ubiquitin ligase-defective C381A c-Cbl rescued these responses, while expression of C381A c-Cbl in wild-type macrophages suppressed them. Analysis of site-directed mutations in the CSF-1R further suggests that activated c-Cbl-mediated CSF-1R ubiquitination is required for a conformational change in the major kinase domain that allows amplification of receptor tyrosine phosphorylation and full receptor activation. Thus the results indicate that CSF-1-mediated receptor dimerization leads to a Tyr-559/SFK/c-Cbl pathway resulting in receptor ubiquitination that permits full receptor tyrosine phosphorylation of this class III RTK in macrophages.

Pubmed ID: 21041311 RIS Download

Mesh terms: HEK293 Cells | Humans | Macrophage Colony-Stimulating Factor | Macrophages | Mutagenesis, Site-Directed | Phosphorylation | Phosphotyrosine | Protein Binding | Protein Structure, Tertiary | Receptor, Macrophage Colony-Stimulating Factor | Signal Transduction | Tyrosine | Ubiquitin-Protein Ligases | Ubiquitination | src-Family Kinases

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Associated grants

  • Agency: NCI NIH HHS, Id: 5P30-CA13330
  • Agency: NCI NIH HHS, Id: CA26504
  • Agency: NCI NIH HHS, Id: P01 CA 100324
  • Agency: NIDDK NIH HHS, Id: P60 DK020541
  • Agency: NCI NIH HHS, Id: R37 CA026504

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