Abstract
Stimulation of the mast cell line, RBL-2H3, with antigen via the tetrameric (alpha beta gamma 2) immunoglobulin E receptor (Fc epsilon R1) leads to the activation of cytosolic phospholipase A2 and the release of arachidonic acid. This pathway is dependent on the activation of the mitogen-activated protein (MAP) kinase. In this paper, we show that the MAP kinase/cytosolic phospholipase A2 pathway is linked to Fc epsilon R1 via the cytosolic tyrosine kinase, Syk, and that the GDP/GTP exchange factor, Vav, might be one candidate for accomplishing this link. Cross-linking of transmembrane chimeras containing the Fc epsilon R1 gamma motif, which is known to activate Syk, results in the tyrosine phosphorylation of Vav, activation of MAP kinase, and release of arachidonic acid. Cross-linking of chimeras containing the Fc epsilon R1 beta motif does not cause these events. Furthermore, stimulation of these events by antigen is enhanced by transient overexpression of a wild-type form of Syk and blocked by overexpression of a dominant negative form of Syk. By contrast, stimulation via the transfected, G protein-coupled, muscarinic m1 receptor is not influenced by either form of Syk and does not result in tyrosine phosphorylation of Vav. These data establish unequivocally that the two types of receptor are independently linked to the two types of receptor are independently linked to the MAP kinase/cytosolic phospholipase A2 pathway and demonstrate the existence of the Fc epsilon R1-Syk-MAP kinase pathway.
Highlights
Stimulation of the mast cell line, RBL-2H3, with antigen via the tetrameric (a/3Y2) immunoglobulin E receptor (FceRl) leads to the activation of cytosolic phospholipase A2 and the release of arachidonic acid
We show that the mitogenactivated protein (MAP) kinase/cytosolic phospholipase ~ pathway is linked to FceRl via the cytosolic tyrosine kinase, Syk, and that the GDP/GTP exchange factor, Vav, might be one candidate for accomplishing this link
Studies in a cultured mast cell (RBL-2H3) cell line indicate that the phospholipase C'Y and the MAP kinase pathways subserve different functions
Summary
Vol 270, No 18, Issue of May 5, pp. 10960-10967, 1995 Printed in U.S.A. A Requirement for Syk in the Activation of the Microtubuleassociated Protein KinaselPhospholipase ~ Pathway by FceRI Is Not Shared by a G Protein-coupled Receptor*. Stimulation of the mast cell line, RBL-2H3, with antigen via the tetrameric (a/3Y2) immunoglobulin E receptor (FceRl) leads to the activation of cytosolic phospholipase A2 and the release of arachidonic acid This pathway is dependent on the activation of the mitogenactivated protein (MAP) kinase. Studies with chimeras of the extracellular and transmembrane domains of the ex subunit of the IL-2 receptor and the cytosolic, carboxyl-terminal portion of the {3 (TTf3) or the cytosolic domain of the I' (TTl') chains of Fc€Rl [25], as well as other studies [26, 27], indicate that aggregation of Fc€Rl causes tyrosine phosphorylation of the {3 and I' chains of Fcelcl, and the recruitment ofSyk and additional Lyn. Cross-linking of the TTl' chimeras with biotinylated anti-Tac antibody and avidin suffice for full expression of responses in RBL-2H3 cells including the activation of Syk [25], mobilization of Ca2+, and release of secretory granules [25].
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