Involvement of filamentous actin in setting the threshold for degranulation in mast cells

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Abstract
Previous studies using cytochalasins and latrunculin B, inhibitors of actin polymerization, showed that filamentous (F)‐actin had a negative regulatory role in Fcϵ receptor I (FcϵRI) signaling. How F‐actin is involved in regulating the activation of mast cells is unknown. In this study we investigated the role of F‐actin in mast cell activation induced by aggregation of the glycosylphosphatidylinositol (GPI)‐anchored proteins Thy‐1 and TEC‐21, and compared it to activation via FcϵRI. Pretreatment of rat basophilic leukemia cells with latrunculin B inhibited the Thy‐1‐induced actin polymerization and elevated the Thy‐1‐mediated secretory and calcium responses. Inhibition of actin polymerization followed by Thy‐1 aggregation resulted in an increased tyrosine phosphorylation of Syk, phospholipase Cγ (PLCγ), Gab2 and linker for activation of T cells (LAT) adapters, and some other signaling molecules. Enzymatic activities of phosphatidylinositol 3‐kinase, PLCγ, and phosphatase SHP‐2 were also up‐regulated, but tyrosine phosphorylation of ezrin was inhibited. Similar changes were observed in FcϵRI‐activated cells. Significant changes in intracellular distribution, tyrosine phosphorylation, and/or enzymatic activities of signaling molecules occurred in latrunculin‐pretreated cells before cell triggering. The combined data suggest that actin polymerization is critical for setting the thresholds for mast cell signaling via aggregation of both FcϵRI and GPI‐anchored proteins.