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

P S Lee1, Y Wang, M G Dominguez

  • 1Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.

The EMBO Journal
|July 7, 1999
PubMed

Insights

The Cbl protooncoprotein regulates macrophage proliferation by controlling the ubiquitination and endocytosis of the colony-stimulating factor-1 receptor (CSF-1R). Loss of Cbl leads to faster proliferation due to impaired CSF-1R signaling.

Area of Science:

  • Cell biology
  • Molecular signaling
  • Immunology

Background:

  • Colony-stimulating factor-1 receptor (CSF-1R) signaling is crucial for macrophage proliferation and survival.
  • Cbl protooncoprotein is involved in receptor tyrosine kinase regulation.
  • Understanding Cbl's role in CSF-1R signaling is key to deciphering macrophage responses.

Purpose of the Study:

  • To investigate the role of Cbl protooncoprotein in CSF-1R signaling and macrophage proliferation.
  • To elucidate the mechanisms by which Cbl regulates CSF-1R ubiquitination, endocytosis, and degradation.
  • To determine how Cbl influences macrophage colony formation and proliferation rates.

Main Methods:

  • Utilized primary macrophages from gene-targeted Cbl knockout (Cbl-/-) and wild-type (Cbl+/+) mice.
  • Analyzed CSF-1R tyrosine phosphorylation, Cbl-CSF-1R association, and ubiquitination status.
  • Quantified macrophage colony formation, proliferation rates, and CSF-1R internalization kinetics.

Main Results:

  • Cbl-/- macrophages exhibited faster proliferation and denser colony formation, especially at limiting CSF-1 concentrations.
  • CSF-1R on Cbl-/- macrophages failed to undergo multiubiquitination and a second wave of tyrosine phosphorylation.
  • Internalization of CSF-1R was slower in Cbl-/- macrophages, leading to reduced CSF-1 utilization.
  • Cbl positively regulates CSF-1R multiubiquitination and endocytosis, limiting receptor signaling duration.

Conclusions:

  • Cbl attenuates macrophage proliferation by promoting CSF-1R ubiquitination and endocytosis, thereby reducing cell surface signaling time.
  • These findings establish a paradigm for Cbl's role in modulating proliferative responses to receptor tyrosine kinase activation.
  • Cbl acts as a critical negative regulator of CSF-1R-mediated macrophage proliferation.

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