Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 97, Issue 13, Pages 7423-7428Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.120175097
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Funding
- NIAID NIH HHS [R01 AI038348, U19 AI42244, AI33617, AI38348] Funding Source: Medline
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Two protein-tyrosine kinases, Bruton's tyrosine kinase (Btk) and Syk, and members of the protein kinase C (PKC) subfamily of serine/threonine kinases play crucial roles in signal transduction through antigen receptors in B lymphocytes and high-affinity IgE receptors (Fc epsilon RI) in mast cells. The present study provides genetic, biochemical, and pharmacological evidence that, on Fc epsilon RI stimulation, Syk regulates Btk, and Btk selectively regulates the membrane translocation and enzymatic activity of PKC beta I among the conventional PKC isoforms (alpha, beta I, and beta II) expressed in mast cells. Syk/Btk-mediated PKC beta I regulation is involved in transcriptional activation of the IL-2 and tumor necrosis factor or genes through the JNK pathway induced by FceRI stimulation. Accordingly, Fc epsilon RI-induced production of these cytokines is inhibited by specific inhibitors of Btk and Syk, as well as broad-specificity inhibitors of PKC and a selective inhibitor of PKC beta. Specific regulation of PKC beta I by Btk is consistent with the selective association of Btk with PKC beta I. Components of this signaling pathway may represent an attractive set of potential targets of pharmaceutical interference for the treatment of allergic and other immunologic diseases.
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