Cbl family proteins: balancing FcεRI-mediated mast cell and basophil activation

Int Arch Allergy Immunol. 2011;156(1):16-26. doi: 10.1159/000322236. Epub 2011 Mar 29.

Abstract

The binding of IgE to high-affinity IgE receptors (FcεRI) expressed on the surface of mast cells and basophils initiates a cascade of signaling events that results in the release of a wide array of proinflammatory mediators. In order to limit the intensity and duration of cell activation, FcεRI aggregation has been understood to additionally generate negative signals through the coordinated action of adapters, phosphatases, and ubiquitin ligases. Among them, Cbl family proteins negatively regulate FcεRI-mediated signals mainly by promoting ubiquitination of the activated receptor subunits and associated protein tyrosine kinases. Notably, FcεRI ubiquitination has become recognized as an important signal for the internalization and delivery of engaged receptor complexes to lysosomes for degradation. The surface expression of activated FcεRI complexes is further downregulated through a pathway that is functionally separable from Cbl ligase activity and is dependent on the interaction of Cbl proteins with adapters involved in clathrin-dependent endocytosis. In this article, we review recent advances in our understanding of the molecular mechanisms through which Cbl proteins negatively regulate FcεRI-mediated mast cell and basophil functions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Basophils / immunology*
  • Basophils / metabolism
  • Gene Expression Regulation*
  • Humans
  • Mast Cells / immunology*
  • Mast Cells / metabolism
  • Proto-Oncogene Proteins c-cbl / metabolism*
  • Receptors, IgE / metabolism*
  • Signal Transduction*
  • Ubiquitin / metabolism

Substances

  • Receptors, IgE
  • Ubiquitin
  • Proto-Oncogene Proteins c-cbl
  • CBL protein, human