Abstract
Antigen interaction with specific IgE bound to the high-affinity Fc receptor for IgE, constitutively expressed on the cell-surface of mast cells, generates signals that cause a shift in the resting state equilibrium of phosphorylation and dephosphorylation events that serves to maintain homeostasis. The outcome of this activated state is the release of a wide array of preformed and newly synthesized pro-inflammatory mediators. During the past few years, the existence of a negative feedback loop initiated upon FcεRI engagement has also been envisaged. This negative signal involves the coordinated action of adaptors, phosphatases and ubiquitin ligases that limits the intensity and duration of positive signals, thus modulating mast cell functions. Relevant to this, others and we have demonstrated that Cbl family proteins control the amplitude of FcεRI-generated signals by specific ubiquitin modification of activated receptor subunits and associated protein tyrosine kinases. In this article, we review advances in our understanding of the molecular mechanisms through which Cbl proteins regulate FcεRI expression and signaling.
Highlights
Mast cells have long been recognized, together with basophils, as the critical effector cells in IgE-mediated allergic diseases [1,2].Mast cells and basophils share the presence of basophilic granules in their cytoplasm and the surface expression of a high affinity receptor for the Fc fragment of IgE (FcεRI).FcεRI belongs to a family of multisubunit immunoreceptors that lack intrinsic enzymatic activity but transduces intracellular signals through association with cytoplasmic protein tyrosine kinases (PTKs) [3,4]
Others and we have demonstrated that Cbl family proteins control the amplitude of FcεRI-generated signals by specific ubiquitin modification of activated receptor subunits and associated protein tyrosine kinases
The Cbl family belongs to the E3 Ub ligases characterized by the presence of a RING finger domain [37]: tyrosine kinase-binding (TKB) domain, as well as additional domains located in the C-terminal region of both c-Cbl and Cbl-b, determine Cbl substrate specificity serving as a docking site for tyrosine phosphorylated proteins that are ubiquitinated by the RING-finger associated E2 enzyme (Figure 1(b))
Summary
Mast cells have long been recognized, together with basophils, as the critical effector cells in IgE-mediated allergic diseases [1,2]. In rodent and human mast cells and basophils, the intracellular signalling generated upon engagement of receptor-bound IgE with the corresponding allergens are responsible for the release of preformed and newly synthesized mediators including histamine, leukotrienes, IL-4 and IL-13 [4,5,6]. Besides these positive signals, FcεRI aggregation has been understood to generate negative intracellular signals capable of limiting mast cell functional responses through the action of a variety of multidomain adaptor proteins [7]. This review is aimed at providing an overview on the mechanisms through which Cbl proteins, acting as Ub ligases, negatively regulate mast cell and basophil functional responses
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