Abstract
Aggregation of the high-affinity IgE receptor (FcεRI) initiates a cascade of signaling events leading to release of preformed inflammatory and allergy mediators and de novo synthesis and secretion of cytokines and other compounds. The first biochemically well defined step of this signaling cascade is tyrosine phosphorylation of the FcεRI subunits by Src family kinase Lyn, followed by recruitment and activation of spleen tyrosine kinase (Syk). Activity of Syk is decisive for the formation of multicomponent signaling assemblies, the signalosomes, in the vicinity of the receptors. Formation of the signalosomes is dependent on the presence of transmembrane adaptor proteins (TRAPs). These proteins are characterized by a short extracellular domain, a single transmembrane domain, and a cytoplasmic tail with various motifs serving as anchors for cytoplasmic signaling molecules. In mast cells five TRAPs have been identified [linker for activation of T cells (LAT), non-T cell activation linker (NTAL), linker for activation of X cells (LAX), phosphoprotein associated with glycosphingolipid-enriched membrane microdomains (PAG), and growth factor receptor-bound protein 2 (Grb2)-binding adaptor protein, transmembrane (GAPT)]; engagement of four of them (LAT, NTAL, LAX, and PAG) in FcεRI signaling has been documented. Here we discuss recent progress in the understanding of how TRAPs affect FcεRI-mediated mast cell signaling. The combined data indicate that individual TRAPs have irreplaceable roles in important signaling events such as calcium response, degranulation, cytokines production, and chemotaxis.
Highlights
Activation through the high-affinity IgE receptor (FcεRI) and other immunoreceptors is characterized by formation of multiprotein signaling assemblies on the cytoplasmic side of the plasma membrane
spleen tyrosine kinase (Syk) phosphorylates a number of its targets critical for further propagation of the signal, including transmembrane adaptor proteins (TRAPs; see below), SH2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76; Bubeck et al, 1996; Hendricks-Taylor et al, 1997), phospholipase C (PLC)γ (Yablonski et al, 2001), and p85 (Shim et al, 2004)
The SH3 domains serve for constitutive binding to SLP-76 and other proteins with proline-rich domains, whereas SH2 domains bind to tyrosine-phosphorylated motifs on the TRAPs
Summary
Activation through the high-affinity IgE receptor (FcεRI) and other immunoreceptors is characterized by formation of multiprotein signaling assemblies (signalosomes) on the cytoplasmic side of the plasma membrane. NTAL−/− cells exhibited enhanced phosphorylation of LAT, PLCγ1, PLCγ2, extracellular signal-regulated kinase (Erk), calcium mobilization, degranulation, cytokines production, and enzymatic activity of inositol 1,4,5-trisphosphate (Figure 2, NTAL−/−). It is not clear what causes the different outcome of NTAL silencing in mouse and human mast cells, the combined data indicate that NTAL exerts both positive and negative regulatory roles on FcεRI signaling, and reflect the complex nature of regulatory factors involved in this signaling pathway.
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