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*
Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121;
Department of Microbiology and Molecular Genetics, University of California, Los Angeles, CA 90095;
Department of Pediatrics, University of California, Los Angeles, CA 90095;
§
National Research Institute of Vegetables, Ornamental Plants and Tea, Kanaya, Shizuoka, Japan;
¶
Department of Laboratory Medicine, University of California, San Francisco, CA 94143; and
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Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095
Protein-tyrosine kinases play crucial roles in mast cell activation
through the high-affinity IgE receptor (Fc
RI). In this study, we
have made the following observations on growth properties and
FcRI-mediated signal transduction of primary cultured mast cells
from Btk-, Lyn-, and Btk/Lyn-deficient mice. First, Lyn deficiency
partially reversed the survival effect of Btk deficiency. Second,
FcRI-induced degranulation and leukotriene release were almost
abrogated in Btk/Lyn doubly deficient mast cells while singly deficient
cells exhibited normal responses. Tyrosine phosphorylation of cellular
proteins including phospholipases C-
1 and C-2 was reduced in
Btk/Lyn-deficient mast cells. Accordingly, FcRI-induced elevation of
intracellular Ca2+ concentrations and activation of protein
kinase Cs were blunted in the doubly deficient cells. Third, in
contrast, Btk and Lyn demonstrated opposing roles in cytokine secretion
and mitogen-activated protein kinase activation. Lyn-deficient cells
exhibited enhanced secretion of TNF-
and IL-2 apparently through the
prolonged activation of extracellular signal-related kinases and c-Jun
N-terminal kinase. Potentially accounting for this phenomenon and
robust degranulation in Lyn-deficient cells, the activities of protein
kinase C and protein kinase CßII, low at basal levels, were
enhanced in these cells. Fourth, cytokine secretion was severely
reduced and c-Jun N-terminal kinase activation was completely abrogated
in Btk/Lyn-deficient mast cells. The data together demonstrate that Btk
and Lyn are involved in mast cell signaling pathways in distinctly
different ways, emphasizing that multiple signal outcomes must be
evaluated to fully understand the functional interactions of individual
signaling components.
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J. Kitaura, K. Asai, M. Maeda-Yamamoto, Y. Kawakami, U. Kikkawa, and T. Kawakami Akt-Dependent Cytokine Production in Mast Cells J. Exp. Med., September 5, 2000; 192(5): 729 - 740. [Abstract] [Full Text] [PDF]
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T.-T. Ching, A.-L. Hsu, A. J. Johnson, and C.-S. Chen Phosphoinositide 3-Kinase Facilitates Antigen-stimulated Ca2+ Influx in RBL-2H3 Mast Cells via a Phosphatidylinositol 3,4,5-Trisphosphate-sensitive Ca2+ Entry Mechanism J. Biol. Chem., April 27, 2001; 276(18): 14814 - 14820. [Abstract] [Full Text] [PDF]
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