Abstract
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 language | English (US) |
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Pages (from-to) | 3616-3628 |
Number of pages | 13 |
Journal | EMBO Journal |
Volume | 18 |
Issue number | 13 |
DOIs | |
State | Published - Jul 1 1999 |
Keywords
- 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