Premium
Btk/Tec kinases regulate sustained increases in intracellular Ca 2+ following B‐cell receptor activation
Author(s) -
Fluckiger AnneCatherine,
Li Zuomei,
Kato Roberta M.,
Wahl Matthew I.,
Ochs Hans D.,
Longnecker Richard,
Kinet JeanPierre,
Witte Owen N.,
Scharenberg Andrew M.,
Rawlings David J.
Publication year - 1998
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/17.7.1973
Subject(s) - biology , bruton's tyrosine kinase , tec , kinase , intracellular , microbiology and biotechnology , receptor , protein serine threonine kinases , signal transduction , phosphorylation , tyrosine kinase , biochemistry , protein kinase a , ionosphere , physics , astronomy
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 Ca 2+ 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 (IP 3 ) 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, IP 3 ‐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 IP 3 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 IP 3 levels and calcium store depletion.