Regulation of protein kinase CbetaI by two protein-tyrosine kinases, Btk and Syk.
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 (FcepsilonRI) in mast cells. The present study provides genetic, biochemical, and pharmacological evidence that, on FcepsilonRI stimulation, Syk regulates Btk, and Btk selectively regulates the membrane translocation and enzymatic activity of PKCbetaI among the conventional PKC isoforms (alpha, betaI, and betaII) expressed in mast cells. Syk/Btk-mediated PKCbetaI regulation is involved in transcriptional activation of the IL-2 and tumor necrosis factor alpha genes through the JNK pathway induced by FcepsilonRI stimulation. Accordingly, FcepsilonRI-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 PKCbeta. Specific regulation of PKCbetaI by Btk is consistent with the selective association of Btk with PKCbetaI. 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.
Kawakami
Y
Y
Division of Allergy, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA.
Kitaura
J
J
Hartman
S E
SE
Lowell
C A
CA
Siraganian
R P
RP
Kawakami
T
T
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D004792:Enzyme Precursors / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000276:immunology*; D064546:Protein Kinase C beta; D011505:Protein-Tyrosine Kinases / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D000072377:Syk Kinase
D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D011493:Protein Kinase C; D064546:Protein Kinase C beta