Subcellular localization of Grb2 by the adaptor protein Dok‐3 restricts the intensity of Ca2+ signaling in B cells

B Stork, K Neumann, I Goldbeck, S Alers… - The EMBO …, 2007 - embopress.org
B Stork, K Neumann, I Goldbeck, S Alers, T Kähne, M Naumann, M Engelke, J Wienands
The EMBO journal, 2007embopress.org
Spatial 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 …
Spatial 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‐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 Ca2+‐mobilizing enzymes.
embopress.org