Regulation of protein kinase C beta I by two protein-tyrosine kinases, Btkand Syk

Two protein-tyrosine kinases, Bruton's tyrosine kinase (Btk) and Syk, and m embers of the protein kinase C (PKC) subfamily of serine/threonine kinases play crucial roles in signal transduction through antigen receptors in B ly mphocytes and high-affinity IgE receptors (Fc epsilon RI) in mast cells. Th e 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 transc riptional activation of the IL-2 and tumor necrosis factor or genes through the JNK pathway induced by FceRI stimulation. Accordingly, Fc epsilon RI-i nduced production of these cytokines is inhibited by specific inhibitors of Btk and Syk, as well as broad-specificity inhibitors of PKC and a selectiv e inhibitor of PKC beta. Specific regulation of PKC beta I by Btk is consis tent with the selective association of Btk with PKC beta I. Components of t his signaling pathway may represent an attractive set of potential targets of pharmaceutical interference for the treatment of allergic and other immu nologic diseases.