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

J Biochem. 2005 Jun;137(6):711-20. doi: 10.1093/jb/mvi088.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / metabolism*
  • Down-Regulation
  • Gene Expression Regulation*
  • Immunoprecipitation
  • Mast Cells / physiology*
  • Proto-Oncogene Proteins c-cbl
  • Rats
  • Receptors, IgE / metabolism*
  • Transcription, Genetic
  • Transfection
  • Ubiquitin-Protein Ligases / metabolism*
  • beta-N-Acetylhexosaminidases / metabolism


  • Adaptor Proteins, Signal Transducing
  • Cblb protein, rat
  • Receptors, IgE
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases
  • beta-N-Acetylhexosaminidases