The Cbl protooncoprotein stimulates CSF-1 receptor multiubiquitination and endocytosis, and attenuates macrophage proliferation

EMBO J. 1999 Jul 1;18(13):3616-28. doi: 10.1093/emboj/18.13.3616.


Colony-stimulating factor-1 (CSF-1) activation of the CSF-1 receptor (CSF-1R) causes Cbl protooncoprotein tyrosine phosphorylation, Cbl-CSF-1R association and their simultaneous multiubiquitination at the plasma membrane. The CSF-1R is then rapidly internalized and degraded, whereas Cbl is deubiquitinated in the cytoplasm without being degraded. We have used primary macrophages from gene-targeted mice to study the role of Cbl. Cbl-/- macrophages form denser colonies and, at limiting CSF-1 concentrations, proliferate faster than Cbl+/+ macrophages. Their CSF-1Rs fail to exhibit multiubiquitination and a second wave of tyrosine phosphorylation previously suggested to be involved in preparation of the CSF-1-CSF-1R complex for endocytosis. Consistent with this result, Cbl-/- macrophage cell surface CSF-1-CSF-1R complexes are internalized more slowly, yet are still lysosomally degraded, and the CSF-1 utilization by Cbl-/- macrophages is reduced approximately 2-fold. Thus, attenuation of proliferation by Cbl is associated with its positive regulation of the coordinated multiubiquitination and endocytosis of the activated CSF-1R, and a reduction in the time that the CSF-1R signals from the cell surface. The results provide a paradigm for studies of the mechanisms underlying Cbl attenuation of proliferative responses induced by ligation of receptor tyrosine kinases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Division
  • Cell Size
  • Cell Survival
  • Cell Transformation, Neoplastic
  • Down-Regulation / drug effects
  • Endocytosis* / drug effects
  • Gene Deletion
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Macrophage Colony-Stimulating Factor / pharmacology
  • Macrophages / cytology*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Mice, Inbred C57BL
  • Peptide Hydrolases / physiology
  • Phosphorylation
  • Proteasome Endopeptidase Complex*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-cbl
  • Receptor, Macrophage Colony-Stimulating Factor / metabolism*
  • Signal Transduction / drug effects
  • Tyrosine / metabolism
  • Ubiquitin-Protein Ligases*
  • Ubiquitins / metabolism*
  • ras Proteins / metabolism


  • Proto-Oncogene Proteins
  • Ubiquitins
  • Tyrosine
  • Macrophage Colony-Stimulating Factor
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases
  • Receptor, Macrophage Colony-Stimulating Factor
  • Peptide Hydrolases
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease
  • ras Proteins
  • Cbl protein, mouse