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

Pierre S.W. Lee, Yun Wang, Melissa G. Dominguez, Yee Guide Yeung, Maria A. Murphy, David D.L. Bowtell, E. Richard Stanley

Research output: Contribution to journalArticlepeer-review

257 Scopus citations


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 ~ 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.

Original languageEnglish (US)
Pages (from-to)3616-3628
Number of pages13
JournalEMBO Journal
Issue number13
StatePublished - Jul 1 1999


  • CSF-1 receptor tyrosine kinase
  • Cbl
  • Cell proliferation
  • Endocytosis
  • Multiubiquitination

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology


Dive into the research topics of 'The Cbl protooncoprotein stimulates CSF-1 receptor multiubiquitination and endocytosis, and attenuates macrophage proliferation'. Together they form a unique fingerprint.

Cite this