Adapters in the organization of mast cell signaling

Abstract

Summary Mast cells are pivotal in innate immunity and play an important role in amplifying adaptive immunity. Nonetheless, they have long been known to be central to the initiation of allergic disorders. This results from the dysregulation of the immune response whereby normally innocuous substances are recognized as non-self, resulting in the production of IgE antibodies to these ‘allergens’. Preformed and newly synthesized inflammatory (allergic) mediators are released from the mast cell following allergen-mediated aggregation of allergen-specific IgE bound to the high-affinity receptors for IgE (FcεRI). Thus, the process by which the mast cell is able to interpret the engagement of FcεRI into the molecular events necessary for release of their allergic mediators is of considerable therapeutic interest. Unraveling these molecular events has led to the discovery of a functional class of proteins that are essential in organizing activated signaling molecules and in coordinating and compartmentalizing their activity. These so-called ‘adapters’ bind multiple signaling proteins and localize them to specific cellular compartments, such as the plasma membrane. This organization is essential for normal mast cell responses. Here, we summarize the role of adapter proteins in mast cells focusing on the most recent advances toward understanding how these molecules work upon FcεRI engagement.

Human mast cell line-1 (HMC-1) cells transfected with FcεRIα are sensitive to IgE/antigen-mediated stimulation demonstrating selectivity towards cytokine production

“…In mouse bone marrow-derived mast cells, low valency ligands, which may have strong pathobiological relevance, have been shown to favor cytokine production as opposed to degranulation [37]. Ability to phosphorylate the adapter protein linker of activated T-cells-1 (LAT1) has been suggested to underlie this selectivity [38]. Whilst the IgE and antigen used to activate HMCα cells was able to elicit degranulation in RBLα cells, the latter cells express higher levels of human FcεRI and so larger receptor aggregates with 'stronger' signaling capacity may have been generated in this case.…”

Signaling in Innate Immunity and Inflammation

“…PIP 3 produced by PI3Kd retains proteins containing plextrin homology (PH) domains at the plasma membrane, such as PLCg, Gab2, Akt, and Btk. The kinase Btk phosphorylates and enhances the activity of PLCg (Alvarez-Errico et al 2009). …”

Characterization of a Phospho-Specific Antibody to the Fcε Receptor γ Chain, Reveals Differences in the Regulation of Syk and Akt Phosphorylation

“…Mast cells express high levels of the high affinity receptor for IgE, FcεRI, which is comprised of four non-covalently associated polypeptides, the IgE-binding α-chain, the signal transduction amplifying β-chain, and the signal inducing γ-chain [1,2]. Both the β-and γ-chain contain an immunoreceptor tyrosine-based activation motif (ITAM) that encodes the consensus sequence (D/E)XXYXXLX 7-11 -YXXL(L/I) [3].…”