Stork, BjoernBjoernStorkNeumann, KonstantinKonstantinNeumannGoldbeck, IngoIngoGoldbeckAlers, SebastianSebastianAlersKaehne, ThiloThiloKaehneNaumann, MichaelMichaelNaumannEngelke, MichaelMichaelEngelkeWienands, JuergenJuergenWienands2018-11-072018-11-072007https://resolver.sub.uni-goettingen.de/purl?gro-2/51949Spatial and temporal modulation of intracellular Ca2+ 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 Ca2+ 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 Ca2+ 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-gamma 2 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 Ca2+-mobilizing enzymes.journal_article10.1038/sj.emboj.760155717290227000244387500021