Selective inhibition of Fcepsilon RI-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 (FcepsilonRI)-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. FcepsilonRI-mediated tyrosine phosphorylation of Syk, Gab2, and phospholipase C-gamma1, 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 kappaB kinase (IKK), and generation of Rac1 are unaffected in cells overexpressing the truncated Cbl-b in the lipid raft. On the other hand, FcepsilonRI-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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Cells, Cultured, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Down-Regulation, Gene Expression Regulation, Immunoprecipitation, Mast Cells, Proto-Oncogene Proteins c-cbl, Rats, Receptors, IgE, Transcription, Genetic, Transfection, Ubiquitin-Protein Ligases, beta-N-Acetylhexosaminidases
J. Biochem.
Date: Jun. 01, 2005
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