Btk/Tec kinases regulate sustained increases in intracellular Ca2+ following B-cell receptor activation

Anne Catherine Fluckiger, Zuomei Li, Roberta M. Kato, Matthew I. Wahl, Hans D. Ochs, Richard Longnecker, Jean Pierre Kinet, Owen N. Witte, Andrew M. Scharenberg, David J. Rawlings*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

342 Scopus citations

Abstract

Bruton's tyrosine kinase (Btk) is essential for B-lineage development and represents an emerging family of non-receptor tyrosine kinases implicated in signal transduction events initiated by a range of cell surface receptors. Increased dosage of Btk in normal B cells resulted in a striking enhancement of extracellular calcium influx following B-cell antigen receptor (BCR) cross-linking. Ectopic expression of Btk, or related Btk/Tec family kinases, restored deficient extracellular Ca2+ influx in a series of novel Btk-deficient human B-cell lines. Btk and phospholipase Cγ (PLCγ) co-expression resulted in tyrosine phosphorylation of PLCγ and required the same Btk domains as those for Btk-dependent calcium influx. Receptor-dependent Btk activation led to enhanced peak inositol trisphosphate (IP3) generation and depletion of thapsigargin (Tg)-sensitive intracellular calcium stores. These results suggest that Btk maintains increased intracellular calcium levels by controlling a Tg-sensitive, IP3-gated calcium store(s) that regulates store-operated calcium entry. Overexpression of dominant-negative Syk dramatically reduced the initial phase calcium response, demonstrating that Btk/Tec and Syk family kinases may exert distinct effects on calcium signaling. Finally, co-cross-linking of the BCR and the inhibitory receptor, FcγRIIb1, completely abrogated Btk-dependent IP3 production and calcium store depletion. Together, these data demonstrate that Btk functions at a critical crossroads in the events controlling calcium signaling by regulating peak IP3 levels and calcium store depletion.

Original languageEnglish (US)
Pages (from-to)1973-1985
Number of pages13
JournalEMBO Journal
Volume17
Issue number7
DOIs
StatePublished - Apr 1 1998

Keywords

  • Calcium stores
  • FcγRIIb1
  • Phospholipase Cγ
  • Syk
  • Thapsigargin

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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