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J Biol Chem, Vol. 275, Issue 10, 7066-7070, March 10, 2000
From the Laboratory of Molecular Immunology, NHLBI, National
Institutes of Health, Bethesda, Maryland 20892-1760
Antigen stimulation of mast cells via the IgE
receptor, Fc
Disruption of Raf-1/Heat Shock Protein 90 Complex and Raf
Signaling by Dexamethasone in Mast Cells*
RI, results in the recruitment of the cytosolic tyrosine
kinase, Syk, and the activation of various signaling cascades. One of these, the extracellular signal-regulated kinase (ERK2) cascade, is
inhibited by low concentrations of the immunosuppressant drug, dexamethasone, probably at a step prior to the activation of Raf-1 (Rider, L. G., Hirasawa, N., Santini, F., and Beaven, M. A. (1996) J. Immunol. 157, 2374-2380). We now show that
treatment of cultured RBL-2H3 mast cells with nanomolar concentrations
of dexamethasone causes dissociation of the Raf-1·heat shock protein
90 (Hsp90) complex. Raf-1 bereft of this protein fails to associate
with the membrane or Ras in antigen-stimulated cells. Upstream events such as the Syk-dependent phosphorylation of Shc, the
engagement of Shc with the adapter protein, Grb2, and the activation of
Ras itself are unaffected. Interestingly, the counterpart of Raf-1 in
the c-Jun N-terminal kinase (JNK) cascade, MEKK-1
(mitogen-activated protein kinase/ERK kinase), is similarly associated
with Hsp90, and this association as well as the activation of MEKK-1
are disrupted by dexamethasone treatment. Disruption of the ERK and JNK
cascades at the level of Raf-1 and MEKK-1 could account for the
inhibitory action of dexamethasone on the generation of inflammatory
mediators in stimulated mast cells.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Bldg. 10, Rm. 8N109,
National Institutes of Health, Bethesda, MD 20892-1760. Tel.: 301-496-6188; Fax: 301-402-0171; E-mail: beaven@helix.nih.gov.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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