Subcellular localization of Grb2 by the adaptor protein Dok‐3 restricts the intensity of Ca 2+ signaling in B cells

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.