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RI Signaling in RBL 2H3 Mast Cells1
*
Institut für Pharmakologie und Toxikologie der Universität Freiburg, Freiburg, Germany;
Institut für Pharmakologie und Toxikologie der Universität des Saarlandes, Homburg (Saar), Germany; and
Institute for Research in Biomedicine, Bellinzona, Switzerland
Fc
RI signaling in rat basophilic leukemia cells depends on
phosphatidylinositol 3-kinase (PI3-kinase) and the small GTPase Rac.
Here, we studied the functional relationship among PI3-kinase, its
effector protein kinase B (PKB), and Rac using inhibitors of PI3-kinase
and toxins inhibiting Rac. Wortmannin, an inhibitor of PI3-kinase,
blocked FcRI-mediated tyrosine phosphorylation of phospholipase
C
, inositol phosphate formation, calcium mobilization, and secretion
of hexosaminidase. Similarly, Clostridium difficile
toxin B, which inactivates all Rho GTPases including Rho, Rac and
Cdc42, and Clostridium sordellii lethal toxin, which
inhibits Rac (possibly Cdc42) but not Rho, blocked these responses.
Stimulation of the FcRI receptor induced a rapid increase in the
GTP-bound form of Rac. Whereas toxin B inhibited the Rac activation,
PI3-kinase inhibitors (wortmannin and LY294002) had no effect on
activation of Rac. In line with this, wortmannin had no effect on
tyrosine phosphorylation of the guanine nucleotide exchange factor Vav.
Wortmannin, toxin B, and lethal toxin inhibited phosphorylation of PKB
on Ser473. Similarly, translocation of the pleckstrin
homology domain of PKB tagged with the green fluorescent protein to the
membrane, which was induced by activation of the FcRI receptor, was
blocked by inhibitors of PI3-kinase and Rac inactivation. Our results
indicate that in rat basophilic leukemia cells Rac and PI3-kinase
regulate PKB and suggest that Rac is functionally located upstream
and/or parallel of PI3-kinase/PKB in FcRI
signaling.
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