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.
Qu
Xiujuan
X
Division of Proteomics, Department of Genome Sciences, Kobe University Graduate School of Medicine, Kobe, Japan.
Sada
Kiyonao
K
Kyo
Shinkou
S
Maeno
Koichiro
K
Miah
S M Shahjahan
SM
Yamamura
Hirohei
H
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004792:Enzyme Precursors / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051550:I-kappa B Kinase; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D050356:Lipid Metabolism; D048670:MAP Kinase Kinase 4; D008407:Mast Cells / Q000166:cytology*; D021962:Membrane Microdomains / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D051381:Rats; D017455:Receptors, IgE / Q000096:biosynthesis* / Q000235:genetics; D012260:Ribonucleases / Q000378:metabolism; D015398:Signal Transduction; D013347:Subcellular Fractions; D000072377:Syk Kinase; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D010738:Type C Phospholipases / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C492213:Cblb protein, rat; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D017455:Receptors, IgE; D025801:Ubiquitin; D014443:Tyrosine; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606898:Syk protein, rat; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D012260:Ribonucleases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D001619:beta-N-Acetylhexosaminidases; D002118:Calcium