Selective Inhibition of FcεRI-Mediated Mast Cell Activation by a Truncated Variant of Cbl-b Related to the Rat Model of Type 1 Diabetes Mellitus

Ubiquitin-protein ligase Cbl-b negatively regulates high affinity IgE receptor (FcεRI)–mediated degranulation and cytokine gene transcription in mast cells. In this study, we have examined the role of a truncated variant of Cbl-b related to the rat model of type 1 diabetes mellitus using the mast cell signaling model. Overexpression of the truncated Cbl-b that lacks the C-terminal region did not suppress the activation of proximal and distal signaling molecules leading to degranulation. FcεRI-mediated tyrosine phosphorylation of Syk, Gab2, and phospholipase C-γ1, and activation of c-Jun N-terminal kinase (JNK), extracellular signal–regulated kinase (ERK), p38 mitogen–activated protein kinase (MAP kinase), and inhibitor of nuclear factor κB kinase (IKK), and generation of Rac1 are unaffected in cells overexpressing the truncated Cbl-b in the lipid raft. On the other hand, FcεRI-mediated transcriptional activation of nuclear factor of activated T cells (NFAT), and transcription of interleukin-3 (IL-3) and IL-4 mRNA are inhibited by overexpression of the truncated variant of Cbl-b. This suppression parallels the re-compartmentalization of specific effector molecules in the lipid raft. These structural and functional analyses reveal the mechanism underlying the selective inhibition of cellular signaling by the truncated variant of Cbl-b related to insulin-dependent diabetes mellitus.