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 FcepsilonRI signaling, mast cell cultures from wild-type, c-Cbl(-/-), and Cbl-b(-/-) mice were generated. Cell growth rates and cell surface expression of FcepsilonRI were similar in the different cell populations. Compared with control cells, Cbl-b inactivation resulted in increases in FcepsilonRI-induced Ca2+ response and histamine release. FcepsilonRI-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 FcepsilonRI-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 Ca2+ response. These results suggest that Cbl-b and c-Cbl have divergent effects on FcepsilonRI signal transduction and that Cbl-b, but not c-Cbl, functions as a negative regulator of FcepsilonRI-induced degranulation.