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

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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.