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Subcellular localization of Grb2 by the adaptor protein Dok‐3 restricts the intensity of Ca 2+ signaling in B cells
Author(s) -
Stork Björn,
Neumann Konstantin,
Goldbeck Ingo,
Alers Sebastian,
Kähne Thilo,
Naumann Michael,
Engelke Michael,
Wienands Jürgen
Publication year - 2007
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 - 10.1038/sj.emboj.7601557
Subject(s) - biology , signal transducing adaptor protein , grb2 , microbiology and biotechnology , subcellular localization , signal transduction , cytoplasm
Spatial and temporal modulation of intracellular Ca 2+ fluxes controls the cellular response of B lymphocytes to antigen stimulation. Herein, we identify the hematopoietic adaptor protein Dok‐3 (downstream of kinase‐3) as a key component of negative feedback regulation in Ca 2+ signaling from the B‐cell antigen receptor. Dok‐3 localizes at the inner leaflet of the plasma membrane and is a major substrate for activated Src family kinase Lyn. Phosphorylated Dok‐3 inhibits antigen receptor‐induced Ca 2+ elevation by recruiting cytosolic Grb2, which acts at this location as a negative regulator of Bruton's tyrosine kinase. This leads to diminished activation of phospholipase C‐γ2 and reduced production of soluble inositol trisphosphate. Hence, the Dok‐3/Grb2 module is a membrane‐associated signaling organizer, which orchestrates the interaction efficiency of Ca 2+ ‐mobilizing enzymes.