Negative regulation of FcepsilonRI-mediated mast cell activation by a ubiquitin-protein ligase Cbl-b.
Aggregation of the high-affinity immunoglobulin E (IgE) receptor (FcepsilonRI) on mast cells induces a number of biochemical events, including protein-tyrosine phosphorylation leading to degranulation and multiple cytokine gene transcription. Here, we have demonstrated that a second member of the Cbl family of ubiquitin-protein ligase Cbl-b translocates into the lipid raft ... after FcepsilonRI engagement. Overexpression of Cbl-b in the lipid raft inhibits FcepsilonRI-mediated degranulation and cytokine gene transcription through the distinct mechanism. A point mutation of Cys373 in the RING finger domain of Cbl-b abrogates the suppression of FcepsilonRI-mediated degranulation but not cytokine gene transcription. The antigen-induced tyrosine phosphorylation of FcepsilonRI, Syk, phospholipase C-gamma (PLC-gamma), activation of c-Jun N-terminal kinase (JNK), extracellular signal regulated kinase (ERK), inhibitor of nuclear factor kappaB kinase (IKK), and Ca++ influx were all suppressed in the cells overexpressing Cbl-b in the lipid raft. In particular, the expression amount of Gab2 protein and thereby its FcepsilonRI-mediated tyrosine phosphorylation were dramatically down-regulated by ubiquitin-protein ligase activity of Cbl-b. These results suggest that Cbl-b is a negative regulator of both Lyn-Syk-LAT and Gab2mediated complementary signaling pathways in FcepsilonRI-mediated mast cell activation.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Calcium, Carrier Proteins, Cell Line, Tumor, Down-Regulation, Enzyme Precursors, Gene Expression Regulation, Humans, I-kappa B Kinase, Intracellular Signaling Peptides and Proteins, JNK Mitogen-Activated Protein Kinases, Lipid Metabolism, MAP Kinase Kinase 4, Mast Cells, Membrane Microdomains, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinases, Mutation, Phospholipase C gamma, Phosphoproteins, Phosphorylation, Precipitin Tests, Protein Structure, Tertiary, Protein Transport, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-cbl, Rats, Receptors, IgE, Ribonucleases, Signal Transduction, Subcellular Fractions, Time Factors, Transcription, Genetic, Transfection, Type C Phospholipases, Tyrosine, Ubiquitin, Ubiquitin-Protein Ligases, beta-N-Acetylhexosaminidases
Adaptor Proteins, Signal Transducing, Animals, Calcium, Carrier Proteins, Cell Line, Tumor, Down-Regulation, Enzyme Precursors, Gene Expression Regulation, Humans, I-kappa B Kinase, Intracellular Signaling Peptides and Proteins, JNK Mitogen-Activated Protein Kinases, Lipid Metabolism, MAP Kinase Kinase 4, Mast Cells, Membrane Microdomains, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinases, Mutation, Phospholipase C gamma, Phosphoproteins, Phosphorylation, Precipitin Tests, Protein Structure, Tertiary, Protein Transport, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-cbl, Rats, Receptors, IgE, Ribonucleases, Signal Transduction, Subcellular Fractions, Time Factors, Transcription, Genetic, Transfection, Type C Phospholipases, Tyrosine, Ubiquitin, Ubiquitin-Protein Ligases, beta-N-Acetylhexosaminidases
Blood
Date: Mar. 01, 2004
PubMed ID: 14604964
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