Positive and negative regulation of Fcϵ receptor I‐mediated signaling events by Lyn kinase C‐terminal tyrosine phosphorylation

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Abstract
Although it is known that the Src family tyrosine kinase Lyn initiates Fcϵ receptor I (FcϵRI) signaling by phosphorylation of the receptor subunits, regulation of Lyn kinase activity and its consequences for receptor signaling are incompletely understood. Using a phospho‐Lyn‐specific antiserum, we show an increased phosphorylation of the Lyn C‐terminal regulatory tyrosine and decreased Lyn kinase activity during FcϵRI‐mediated mast cell activation. Mutant Lyn, defective in the C‐terminal tyrosine, constitutively phosphorylated several substrates in resting cells, but did not cause FcϵRI internalization or spontaneous degranulation. FcϵRI‐induced signaling in the presence of constitutively active Lyn exhibited enhanced phosphorylation of the receptor subunits, Syk, LAT, Gab2, phospholipase C (PLC)γ1 and PLCγ2, and production of phosphatidylinositol 3,4,5‐trisphosphate. Although enzymatic activities of PLCγ1 and PLCγ2 were also up‐regulated, amounts of inositol 1,4,5‐trisphosphate, mobilization of intracellular calcium and degranulation were suppressed. Additionally, constitutively active Lyn was strikingly less efficient than wild‐typeLyn in restoring the receptor‐mediated calcium responses in bone marrow mast cells derived from Lyn–/– mice. These findings pinpoint the tight regulation of Lyn kinase activity as a critical event in mast cell degranulation.