Inactivation of c-Cbl or Cbl-b differentially affects signaling from the high affinity IgE receptor.
The Cbl family of proteins negatively regulate signaling from tyrosine kinase-coupled receptors. Among the three members of this family, only c-Cbl and Cbl-b are expressed in hemopoietic cells. To examine the role of c-Cbl and Cbl-b in Fc epsilon RI signaling, mast cell cultures from wild-type, c-Cbl(-/-), and Cbl-b(-/-) mice were generated. Cell growth rates and cell surface expression of Fc epsilon RI were similar in the different cell populations. Compared with control cells, Cbl-b inactivation resulted in increases in Fc epsilon RI-induced Ca(2+) response and histamine release. Fc epsilon RI-induced tyrosine phosphorylation of total cellular proteins, Syk, and phospholipase C-gamma was also enhanced by Cbl-b deficiency, whereas receptor-initiated phosphorylation of Vav, JNK, and p38 kinases was not changed in these cells. In contrast to Cbl-b, c-Cbl deficiency had no detectable effect on Fc epsilon RI-induced histamine release or on the phosphorylation of total cellular proteins or Syk. The absence of c-Cbl increased the phosphorylation of ERK after receptor stimulation, but resulted in slightly reduced p38 phosphorylation and Ca(2+) response. These results suggest that Cbl-b and c-Cbl have divergent effects on Fc epsilon RI signal transduction and that Cbl-b, but not c-Cbl, functions as a negative regulator of Fc epsilon RI-induced degranulation.
Zhang
Juan
J
Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Chiang
Yungping J
YJ
Hodes
Richard J
RJ
Siraganian
Reuben P
RP
D000818:Animals; D000941:Antigens / Q000276:immunology; D020013:Calcium Signaling; D004792:Enzyme Precursors / Q000378:metabolism; D006636:Histamine Release; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl; D011940:Receptor Aggregation / Q000502:physiology*; D017455:Receptors, IgE / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D000072377:Syk Kinase; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000502:physiology*
D000941:Antigens; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D017455:Receptors, IgE; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C067419:CBL protein, human; C493849:Cbl protein, mouse