Elsevier

Biochemical Pharmacology

Volume 58, Issue 12, 15 December 1999, Pages 1841-1850
Biochemical Pharmacology

Commentaries
Molecular consequences of human mast cell activation following immunoglobulin E–high-affinity immunoglobulin E receptor (IgE–FcϵRI) interaction

https://doi.org/10.1016/S0006-2952(99)00226-9Get rights and content

Abstract

The cross-linking by immunoglobulin E of its high-affinity receptor, FcϵRI, on mast cells initiates a complex series of biochemical events leading to degranulation and the synthesis and secretion of eicosanoids and cytokines through the action of transcription factors, such as nuclear factor-κB. The initial activation involves the phosphorylation of FcϵRI β- and γ-subunits through the actions of the tyrosine kinases lyn and syk. For the purposes of description, the subsequent events may be grouped in three cascades characterized by the key proteins involved. First, the phospholipase C–inositol phosphate cascade activates protein kinase C and is largely responsible for calcium mobilization and influx. Second, activation of Ras and Raf via mitogen-activated protein kinase causes the production of arachidonic acid metabolites. Third, the generation of sphingosine and sphingosine-1-phosphate occurs through activation of sphingomyelinase. While the early signaling events tend to be specific for the cited cascades, there is an increasing overlap of activated proteins with the downstream propagation of the signal. It is the balanced interaction between these proteins that culminates in degranulation, synthesis, and release of eicosanoids and cytokines.

Section snippets

FcϵRI expression

FcϵRI belongs to the family of multi-subunit immune response receptors that do not have intrinsic kinase activity, but associate reversibly with PTK 8, 9. In its “classical” form, FcϵRI is expressed on the mast cell as a heterotetramer comprising α-, β-, and two γ-chains (Fig. 1). The binding site for IgE lies within the α-chain, which therefore confers ligand recognition and constitutes the major extracellular component of FcϵRI. The α-chain carries seven N-linked glycosylation sites, which

FcϵRI signal transduction

In the following we attempt to give a concise summary of the signaling pathways activated through FcϵRI cross-linking and their possible interactions. We will discuss the pathways separately FIG. 1, FIG. 2, FIG. 3, FIG. 4 and then bring them together in a summary (Fig. 5). This review is based essentially on findings in the rat basophilic leukemia (RBL) cell line, which is the predominant model system for studies on FcϵRI signal transduction. It remains to be shown how well the signaling

Conclusion

Finally, the signaling pathways discussed above are brought together in Fig. 5, providing a summary of ways in which the cascades may interact. However, since the parts of this mosaic are pieced together from results obtained with various experimental models, the relative contributions and importance of the individual components in human mast cells remain to be determined.

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