TY - JOUR T1 - Dexamethasone Up-Regulates the Inhibitory Adaptor Protein Dok-1 and Suppresses Downstream Activation of the Mitogen-Activated Protein Kinase Pathway in Antigen-Stimulated RBL-2H3 Mast Cells JF - Molecular Pharmacology JO - Mol Pharmacol SP - 598 LP - 603 DO - 10.1124/mol.104.008607 VL - 67 IS - 3 AU - Takaaki Hiragun AU - Ze Peng AU - Michael A. Beaven Y1 - 2005/03/01 UR - http://molpharm.aspetjournals.org/content/67/3/598.abstract N2 - The glucocorticoid dexamethasone suppresses antigen-induced degranulation, cytokine production, and intermediate signaling events in RBL-2H3 mast cells, although the exact mechanisms are uncertain. By microarray analysis, we discovered that expression of the inhibitory adaptor protein, downstream of tyrosine kinase (Dok)-1, was up-regulated 4-fold in dexamethasone-treated RBL-2H3 cells. The up-regulation was apparent with as little as 1 to 10 nM dexamethasone. Treatment with dexamethasone also enhanced tyrosine phosphorylation of Dok-1, augmented recruitment of Ras GTPase-activating protein (RasGAP) by Dok-1, and inhibited activation of the mitogen-activated protein (MAP) kinase pathway in antigen-stimulated cells. The same effects were obtained by transient overexpression of Dok-1 but not by overexpression of Dok-1 that was mutated in RasGAP-binding domain. The negative regulatory role of Dok-1 was further validated by the expression of small interfering RNA directed against Dok-1, which enhanced activation of MAP kinase and subsequent release of arachidonic acid and tumor necrosis factor-α. These findings identify Dok-1 as mediator of the antiallergic actions of dexamethasone and as a negative regulator of the MAP kinase pathway and downstream release of inflammatory mediators. ER -