Btk plays a crucial role in the amplification of FcεRI-mediated mast cell activation by Kit

Shoko Iwaki, Christine Tkaczyk, Anne B. Satterthwaite, Kristina Halcomb, Michael A. Beaven, Dean D. Metcalfe, Alasdair M. Gilfillan

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

Stem cell factor (SCF) acts in synergy with antigen to enhance the calcium signal, degranulation, activation of transcription factors, and cytokine production in human mast cells. However, the underlying mechanisms for this synergy remain unclear. Here we show, utilizing bone marrow-derived mast cells (BMMCs) from Btk and Lyn knock-out mice, that activation of Btk via Lyn plays a key role in promoting synergy. As in human mast cells, SCF enhanced degranulation and cytokine production in BMMCs. In Btk-/- BMMCs, in which there was a partial reduction in the capacity to degranulate in response to antigen, SCF was unable to enhance the residual antigen-mediated degranulation. Furthermore, as with antigen, the ability of SCF to promote cytokine production was abrogated in the Btk-/- BMMCs. The impairment of responses in Btk-/- cells correlated with an inability of SCF to augment phospholipase Cγ1 activation and calcium mobilization, and to phosphorylate NFκB and NFAT for cytokine gene transcription in these cells. Similar studies with Lyn-/- and Btk-/-/ Lyn-/- BMMCs indicated that Lyn was a regulator of Btk for these responses. These data demonstrate, for the first time, that Btk is a key regulator of a Kit-mediated amplification pathway that augments FcεRI-mediated mast cell activation.

Original languageEnglish (US)
Pages (from-to)40261-40270
Number of pages10
JournalJournal of Biological Chemistry
Volume280
Issue number48
DOIs
StatePublished - Dec 2 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Iwaki, S., Tkaczyk, C., Satterthwaite, A. B., Halcomb, K., Beaven, M. A., Metcalfe, D. D., & Gilfillan, A. M. (2005). Btk plays a crucial role in the amplification of FcεRI-mediated mast cell activation by Kit. Journal of Biological Chemistry, 280(48), 40261-40270. https://doi.org/10.1074/jbc.M506063200