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.
Division of Proteomics and Division of Microbiology, Department of Genome Sciences, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
Xiujuan
X
Qu
S M Shahjahan
SM
Miah
Tomoko
T
Hatani
Mami
M
Okazaki
Naoko
N
Hori-Tamura
Hirohei
H
Yamamura
Hak
H
Hotta
Kiyonao
K
Sada
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D047468:Immunoprecipitation; D008407:Mast Cells / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl; D051381:Rats; D017455:Receptors, IgE / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C492213:Cblb protein, rat; D017455:Receptors, IgE; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D001619:beta-N-Acetylhexosaminidases