Accumulation of c-Cbl and rapid termination of colony-stimulating factor 1 receptor signaling in interferon consensus sequence binding protein-deficient bone marrow-derived macrophages.
Mice deficient for the transcription factor interferon consensus sequence binding protein (ICSBP) are immunodeficient and develop granulocytic leukemia. Further analyses indicated that ICSBP is a molecular switch factor directing the differentiation of bipotential myeloid precursors to the monocytic lineage. To reveal the molecular mechanisms responsible for the deregulation of myelopoiesis, we examined the signaling of the colony-stimulating factor 1 receptor (CSF-1R) in bone marrow-derived macrophages (BMMs) from ICSBP(-/-) mice. We found that in the absence of ICSBP, CSF-1R signaling is attenuated as seen from an accelerated termination of Erk phosphorylation and reduced cell growth. This finding coincides with an increased CSF-1R ubiquitination and an enhanced accumulation of c-Cbl. c-Cbl is an ubiquitin-ligase known to down-regulate activated CSF-1R by targeting it to the endocytic pathway. Our results indicate that upon CSF-1R activation, c-Cbl itself is partly proteolytically degraded in ICSBP(+/+) but not in ICSBP(-/-) BMMs. Congruently, the expression of a major endosomal/lysosomal protease, cathepsin B, is strongly reduced in ICSBP(-/-) BMMs.
Kallies
Axel
A
Department of Molecular Genetics, Institute of Molecular Pharmacology, Medical Center Benjamin Franklin, Free University of Berlin, Germany.
Rosenbauer
Frank
F
Scheller
Marina
M
Knobeloch
Klaus-Peter
KP
Horak
Ivan
I
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002401:Cathepsin B / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D050835:Interferon Regulatory Factors; D019891:Leukopoiesis / Q000187:drug effects; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000378:metabolism* / Q000502:physiology; D050721:Proto-Oncogene Proteins c-cbl; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D000099185:Interferon Regulatory Factor-8
D002401:Cathepsin B; D050835:Interferon Regulatory Factors; D016173:Macrophage Colony-Stimulating Factor; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D016186:Receptor, Macrophage Colony-Stimulating Factor; D012097:Repressor Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000099185:Interferon Regulatory Factor-8; C493849:Cbl protein, mouse