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Integrated signalling pathways for mast-cell activation

Key Points

  • Mast cells have a central role in the initiation of allergic inflammatory reactions that are associated with disease states such as asthma.

  • These reactions are generally a consequence of the aggregation of IgE-occupied high-affinity receptors for IgE (FcεRIs), which is induced by multivalent antigen.

  • There is emerging evidence, however, that other receptors expressed by mast cells ? such as the receptors for stem-cell factor (that is, KIT), adenosine, complement component 3a, chemokines, sphingosine 1-phosphate and pathogen-associated molecular patterns ? might also markedly influence these responses either by potentiating FcεRI-dependent mediator release or by themselves inducing mast-cell activation. So, in vivo, these receptors might prime mast cells for subsequent activation by antigen, or ligands for these receptors might be co-activators for antigen-mediated mast-cell responses.

  • Two main signalling pathways seem to regulate FcεRI-mediated mast-cell activation: first, the 'principle' pathway, which is regulated by the transmembrane adaptor molecule LAT (linker for activation of T cells) and is mediated by phospholipase Cγ; and second, the complementary pathway (also termed the amplification pathway), which is mediated by the SRC-family kinase FYN and phosphatidylinositol 3-kinase and might be regulated by the transmembrane adaptor molecule NTAL (non-T-cell activation linker).

  • The existence of these interacting pathways might help to explain how the signals that are initiated by receptors such as KIT could be integrated with the signals that are mediated by FcεRI, leading to a synergistic increase in antigen-dependent release of mediators by mast cells.

  • The ability of these receptors to modify FcεRI-mediated mast-cell signalling and activation might have important implications for the treatment of mast-cell-driven disorders.

Abstract

Mast-cell activation mediated by the high-affinity receptor for IgE (FcεRI) is considered to be a key event in the allergic inflammatory response. However, in a physiological setting, other receptors, such as KIT, might also markedly influence the release of mediators by mast cells. Recent studies have provided evidence that FcεRI-dependent degranulation is regulated by two complementary signalling pathways, one of which activates phospholipase Cγ and the other of which activates phosphatidylinositol 3-kinase, using specific transmembrane and cytosolic adaptor molecules. In this Review, we discuss the evidence for these interacting pathways and describe how the capacity of KIT, and other receptors, to influence FcεRI-dependent mast-cell-mediator release might be a function of the relative abilities of these receptors to activate these alternative pathways.

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Figure 1: Influence of environmental and/or physiological stimuli on the release of pro-inflammatory mediators by mast cells.
Figure 2: The 'principle' signalling cascade in activated mast cells.
Figure 3: Amino-acid sequences and protein?protein interaction sites of human LAT and NTAL.
Figure 4: The 'complementary' (amplification) signalling cascade in activated mast cells.
Figure 5: The signal-transduction molecules that are recruited and/or activated by KIT.
Figure 6: Integration of the signalling pathways induced by the G-protein-coupled receptors FcεRI and KIT.

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Acknowledgements

Work in the authors' laboratory has been supported, in part, by funding from the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (United States). The authors thank J. Rivera and anonymous reviewers for their comments and suggestions. Owing to space limitations, all pertinent literature could not be cited. This does not imply that other relevant studies that were not quoted are of less merit.

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DATABASES

Signaling Gateway

FYN

KIT

LAT

LYN

NTAL

S1P1

S1P2

FURTHER INFORMATION

Alasdair Gilfillan's laboratory

NIAID Laboratory of Allergic Diseases

NIAID Mast Cell Biology Section

Glossary

Pathogen-associated molecular patterns

(PAMPs). Molecular motifs that are characteristic of prokaryotes and are thereby recognized by the mammalian innate immune system.

Eicosanoids

A family of lipid mediators with diverse biological activities. These metabolites are the products of the lipoxygenase and cyclooxygenase pathways ? which produce leukotrienes and prostaglandins, respectively ? and they are important mediators of the allergic inflammatory response.

Lipid rafts

This term conceptually describes detergent-resistant membrane fractions that are separated on sucrose gradients. These fractions contain heterogeneous plasma-membrane microdomains that are enriched in sphingolipids, cholesterol and glycosylphosphatidylinositol-anchored proteins, as well as several membrane-associated signalling molecules, such as LYN. These microdomains are thought to be important sites for protein-tyrosine-kinase-mediated protein?protein interactions that are involved in the initiation of receptor signalling pathways.

SRC-family kinases

A family of closely related protein tyrosine kinases ? including SRC, LYN, LCK, FYN and BLK (B-lymphoid kinase) ? each member of which has a SRC homology 2 (SH2) domain, an SH3 domain, a single catalytic domain, a carboxy-terminal regulatory domain and a unique amino-terminal region. These proteins are anchored at the plasma membrane and targeted to lipid rafts as a result of myristoylation and palmitoylation.

Passive cutaneous anaphylaxis

An experimental technique that reflects in situ mast-cell degranulation. Mice or rats are passively sensitized by intradermal injection of antigen-specific IgE, then antigen and the dye Evans Blue are injected into the tail vein. Mediators that are released from the activated mast cells increase vascular permeability, resulting in leakage of the dye into the skin at the site of injection of IgE.

Passive systemic anaphylaxis

An experimental technique that, similar to passive cutaneous anaphylaxis, reflects mast-cell degranulation. Mice or rats are passively sensitized by intravenous injection of antigen-specific IgE, then antigen is injected into the tail vein. The concentration of histamine in the plasma, which indicates systemic mast-cell activation, is then assessed.

SRC-homology-2 domain

(SH2 domain). A protein?protein interaction domain that is commonly found in signal-transduction molecules. It specifically interacts with phosphotyrosine-containing sequences.

Immunoreceptor tyrosine-based activation motif

(ITAM). A structural motif that contains tyrosine residues and is found in the cytoplasmic tail of several signalling molecules. The motif has the form YXXL/I (where X denotes any amino acid), and the tyrosine residue is a target for phosphorylation by protein tyrosine kinases of the SRC family and, subsequently, for the binding of proteins that contain SRC-homology-2 domains.

Adaptor molecule

A signalling molecule that has one or more binding motifs and/or tyrosine residues that can be phosphorylated by SRC-family kinases, SYK (spleen tyrosine kinase) and/or ZAP70 (ζ-chain-associated protein kinase of 70 kDa). These molecules mainly function as components of a 'molecular scaffold' that organizes activated receptor signalling complexes.

Palmitoylation site

A juxtamembrane sequence (CXXC, where X denotes any amino acid) that is found in signalling proteins, including SRC-family kinases and transmembrane adaptor molecules. It allows binding of these proteins to plasma-membrane palmitic acid and thereby targets these proteins to lipid rafts.

Small interfering RNA

(siRNA). Short, double-stranded RNA molecules of 19?23 nucleotides that induce RNA interference (RNAi), a post-transcriptional process that leads to gene silencing in a sequence-specific manner.

Protein kinase C

(PKC). A family of serine/threonine kinases that is composed of 12 isozymes in 3 distinct classes: conventional (which consists of PKCα, PKCβI, PKCβII and PKCγ), novel (which consists of PKCδ, PKCε, PKCη, PKCθ (and PKCμ) and atypical (which consists of PKCζ, PKCι and PKCλ). The activation of these enzymes is either calcium dependent (for conventional family members) or calcium independent (for novel and atypical family members). They all have a regulatory and a catalytic domain, as well as a conserved and a variable region.

Pleckstrin-homology domain

An amino-acid sequence that is present in several signalling proteins that mediate their actions through binding phosphoinositides. A subset of these domains selectively binds phosphatidylinositol-3-kinase products. Pleckstrin-homology domains also anchor proteins to membranes through the binding of membrane lipids.

TEC-family kinases

One of the three classes of protein tyrosine kinases that are required for the activation of haematopoietic cells, the other classes being the SRC- and SYK (spleen tyrosine kinase)-family kinases. The TEC-family-kinase prototypes are ITK (interleukin-2-inducible T-cell kinase) in T cells and BTK (Bruton's tyrosine kinase) in B cells. Among other functions, TEC-family kinases seem to have an important role in the activation of phospholipase Cγ after immunoreceptor ligation.

Single-nucleotide polymorphism

Typically biallelic base-pair substitutions, which are the most common forms of genetic polymorphism.

W/Wv, W/Wsh and Sl/Sld mice

Mast-cell-deficient mice. These deficiencies result from a defect in cell-surface expression of KIT. W/Wv mice have a point mutation (known as viable, v) in the Kit gene at the dominant spotting (W) locus, on chromosome 5. W/Wsh mice have an inversion and a breakpoint mutation (known as sash, sh) between the genes that encode platelet-derived-growth-factor receptor and KIT. Unlike the W/Wv mice, the W/Wsh mice are fertile. For Sl/Sld mice, mast-cell deficiency arises from a mutation (known as Dickie, d) in the gene that encodes stem-cell factor (previously known as steel, Sl).

G-protein-coupled receptor

(GPCR). One of a large group of receptors that bind a diverse set of molecules, including chemokines, complement components, bioactive amines and neurotransmitters. GPCRs are seven-transmembrane-spanning receptors and are coupled to heterotrimeric, GTP-regulated signalling proteins.

Mastocytosis

A disease that affects both adults and children and is associated with dysfunctional KIT. It is characterized by mast-cell hyperplasia in the bone marrow and peripheral tissues. The most common form is linked to an activating mutation in KIT (in which valine replaces aspartic acid at residue 816).

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Gilfillan, A., Tkaczyk, C. Integrated signalling pathways for mast-cell activation. Nat Rev Immunol 6, 218–230 (2006). https://doi.org/10.1038/nri1782

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