Redundant and opposing functions of two tyrosine kinases, Btk and Lyn, in mast cell activation

Yuko Kawakami, Jiro Kitaura, Anne B. Satterthwaite, Roberta M. Kato, Koichi Asai, Stephen E. Hartman, Mari Maeda-Yamamoto, Clifford A. Lowell, David J. Rawlings, Owen N. Witte, Toshiaki Kawakami

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146 Scopus citations

Abstract

Protein-tyrosine kinases play crucial roles in mast cell activation through the high-affinity IgE receptor (FcεRI). In this study, we have made the following observations on growth properties and FcεRI-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, FcεRI-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-γ1 and C-γ2 was reduced in Btk/Lyn-deficient mast cells. Accordingly, FcεRI-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-α 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 Cα and protein kinase CβII, 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.

Original languageEnglish (US)
Pages (from-to)1210-1219
Number of pages10
JournalJournal of Immunology
Volume165
Issue number3
DOIs
StatePublished - Aug 1 2000

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Kawakami, Y., Kitaura, J., Satterthwaite, A. B., Kato, R. M., Asai, K., Hartman, S. E., Maeda-Yamamoto, M., Lowell, C. A., Rawlings, D. J., Witte, O. N., & Kawakami, T. (2000). Redundant and opposing functions of two tyrosine kinases, Btk and Lyn, in mast cell activation. Journal of Immunology, 165(3), 1210-1219. https://doi.org/10.4049/jimmunol.165.3.1210