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Molecular Pharmacology

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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

Takaaki Hiragun, Ze Peng and Michael A. Beaven
Molecular Pharmacology March 2005, 67 (3) 598-603; DOI: https://doi.org/10.1124/mol.104.008607
Takaaki Hiragun
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Ze Peng
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Michael A. Beaven
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Abstract

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.

  • Received October 21, 2004.
  • Accepted December 17, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 67 (3)
Molecular Pharmacology
Vol. 67, Issue 3
1 Mar 2005
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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

Takaaki Hiragun, Ze Peng and Michael A. Beaven
Molecular Pharmacology March 1, 2005, 67 (3) 598-603; DOI: https://doi.org/10.1124/mol.104.008607

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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

Takaaki Hiragun, Ze Peng and Michael A. Beaven
Molecular Pharmacology March 1, 2005, 67 (3) 598-603; DOI: https://doi.org/10.1124/mol.104.008607
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