Mathematical Modeling of Syk Activation in Allergen-Stimulated Mast Cells and Basophils

Abstract

Mast cells and basophils play major roles in allergic responses of the immediate type (Rivera & Gilfillan, 2006). Allergic individuals produce IgE that is specific for the multivalent foreign molecules (allergens) that trigger their allergic responses. IgE binds with high affinity through its constant region to a monovalent receptor, FcǫRI, that is expressed on the surface of basophils and mast cells and that mediates much of mast cell activation in allergic reactions. Upon exposure to the allergen, the bridging of multiple IgEs by the allergen results in the aggregation of FcǫRI receptors on the cell surface, which in turn triggers a cascade of biochemical reactions that results in the release of preformed mediators from granules together with the synthesis and release of lipid mediators and cytokines. The cytosolic protein tyrosine kinase Syk plays a crucial role in FcǫRI-mediated signaling cascade in mast cells. A clone of the syk gene was first isolated on the basis of partial sequenced information of a 40 kDa kinase from porcine spleen (de Castro, 2011; Taniguchi et al., 1991). The product of this gene was identified as a nonreceptor-type protein tyrosine kinase of 72 kDa (Yang et al., 1994) and was named Spleen Tyrosine Kinase (Syk). Syk has two Src-homology 2 domains (SH2) which are separated by a linker region from the kinase domain (Siraganian et al., 2002). FcǫRI is a tetrameric complex composed of an α-chain that binds IgE to form a long-lived complex, and three subunits, a β-chain and two disulfide-linked γ-chains (Blank et al., 1989) that contain immunoreceptor tyrosine-based activation motifs (ITAMs). The FcǫRI receptor lacks intrinsic enzymatic acitivity and requires non-receptor protein tyrosine kinase activity in propagating cellular signals in allergen-stimulated mast cells and basophils. The unphosphorylated β-chain of the FcǫRI receptor associates weakly with the Src family kinase Lyn, which is anchored to the inner layer of the plasma membrane (Vonakis et al., 1997; 2001). Upon receptor aggregation, Lyn transphosphorylates tyrosines in the β and γ ITAMs. Syk from the cytosol binds with high affinity through its two SH2 domains to the doubly phosphorylated γ ITAM (Benhamou et al., 1993; Hutchcroft et al., 1992). Recent experimental