Trends in Immunology
Volume 25, Issue 5, 1 May 2004, Pages 266-273
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The ins and outs of IgE-dependent mast-cell exocytosis

https://doi.org/10.1016/j.it.2004.03.005Get rights and content

Abstract

Mast cells (MCs) are able to secrete the contents of preformed cytoplasmic secretory granules (SGs) on encountering certain stimulants. For MCs, this process is fundamental to their role in innate and acquired immunity. Immunological adaptation through the production of IgE antibodies, to normally innocuous substances, has kidnapped the MC exocytotic response to cause allergic disease. Thus, understanding the molecular events in IgE-dependent MC exocytosis holds promise for therapeutic intervention. Recent advances, in deciphering the coupling of the high affinity IgE receptor (FcεRI) to the secretory machinery, promote a new paradigm of the molecular coordination of MC exocytosis. A clearer picture of the link between FcεRI stimulation and SG exocytosis is emerging.

Section snippets

Regulation of SG exocytosis by FcεRI

The FcεRI is a multisubunit receptor with a ligand-binding α subunit, a signal-amplifying membrane-tetraspanning β subunit and a homodimeric disulfide-linked γ subunit that provides the signaling ability of this receptor (reviewed in Ref. [7]) (Figure 1). Initiation of signaling is mediated through the immunoreceptor tyrosine-based activation motif (ITAM) encoded in the cytoplasmic tails of the β and γ subunits. Monomeric IgE binding to FcεRI, in the absence of antigen, increases expression of

Protein tyrosine kinases and their relative importance to SG exocytosis

Several Src family protein tyrosine kinases (PTKs) are expressed in MCs (Table 2). These and other PTKs, such as Syk and Btk, rapidly respond to FcεRI engagement by localizing to the appropriate site of function and/or by increasing their activity (reviewed in Ref. [13]). The Src PTK, Lyn, which is weakly associated with FcεRI [14], phosphorylates the canonical ITAM-tyrosines of the β and γ subunits (reviewed in Ref. [7]) (Figure 1). Although all the steps required to initiate phosphorylation

The importance of adaptor molecules in SG exocytosis

MCs express numerous adaptor proteins that coordinate and assemble the molecular apparatus of cell signaling (reviewed in Ref. [20]). However, only a few of these adapters, such as Grb2-associated binder-like protein 2 (Gab2), SLP-76 (Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa) and the linker for activation of T cells (LAT), showed considerable involvement in SG exocytosis. Some (SLP-76 and LAT) appear to influence SG exocytosis through their essential role in calcium

MC apparatus for secretion

MCs contain the molecular machinery that drives membrane fusion during SG exocytosis. Essential to this process are SNARE [soluble NSF (N-ethyl-maleimide-sensitive factor) attachment protein receptor] proteins that lie on opposing cellular membranes to form a stable multimeric complex that catalyzes fusion (reviewed in Ref. [25]). A typical SNARE complex includes a vesicular SNARE (R-SNARE), such as the vesicle-associated membrane protein (VAMP), which pairs with two PM-localized SNAREs

Regulation of the secretory apparatus by calcium

MC exocytosis and SNARE complex formation in regulated-secretion competent cells requires calcium (reviewed in Refs 21, 36). During the last decade, a family of calcium sensors, the synaptotagmins (syt), emerged as molecular targets of the calcium fusion machinery (Figure 3). Syt are membrane-anchored proteins (vesicular- or PM-bound) that bind calcium by conserved tandem C2 domains (C2A and C2B), albeit the affinity differs among the various family members. Calcium binding promotes

PKC and other Ser–Thr kinases in the regulation of fusion and exocytosis

PKC activation has been established as a prerequisite for MC exocytosis (reviewed in Ref. [50]). PKC is partly controlled by the PI3-K-dependent kinase 1 (PDK1) [51], whose activity requires both Fyn and Gab2 16, 22. Both a calcium-dependent, PKCβ, and a calcium-independent, PKCδ, PKC were implicated in degranulation using depletion–reconstitution or mutational studies that addressed the calcium–PKC relationship or the consequences of PKC phosphorylation of cellular substrates (reviewed in Ref.

Role of phosphatases in the regulation of fusion

Dephosphorylation of cellular proteins by phosphatases also has a central role in the activated state. For example, the protein tyrosine phosphatases, Src homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1) and SHP-2, and the lipid phosphatase Src homology 2-containing 5′-inositol phosphatase (SHIP) (reviewed in Ref. [61]), function in early FcεRI-dependent events that initiate and regulate exocytosis. Recently, a role for Ser–Thr phosphatase PP1 in the homotypic fusion of yeast

Concluding remarks

As becomes evident from this brief Review, MC exocytosis is a complex process that requires a signal input and a sophisticated molecular machinery for output. A molecular architecture is also required for coordination of both early and late signaling events. Not only must the exocytotic machinery be mobilized but signals must coordinately promote the activation of multiple enzymes, generate second messengers, activate specific molecular targets, cause cytoskeletal changes and promote movement

Acknowledgements

We thank members of our respective laboratories, collaborators and colleagues who contributed to the work described herein. We also wish to acknowledge the important contribution of colleagues whose work was not included due to space constraints. The work of J.R. was supported by the Department of Health and Human Services, National Institutes of Health, National Institute of Arthritis and Musculoskelelatal and Skin Diseases, and Grant No. 2000016 from the United States-Israel Binational

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