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

EMBO J. 2007 Feb 21;26(4):1140-9. doi: 10.1038/sj.emboj.7601557. Epub 2007 Feb 8.


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-gamma2 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Agammaglobulinaemia Tyrosine Kinase
  • Animals
  • B-Lymphocytes / metabolism*
  • Calcium / metabolism*
  • Cell Line
  • Chickens
  • DNA Primers
  • Feedback, Physiological / physiology
  • GRB2 Adaptor Protein / metabolism*
  • Mass Spectrometry
  • Mice
  • Microscopy, Confocal
  • Protein-Tyrosine Kinases / metabolism
  • Signal Transduction / physiology*
  • src-Family Kinases / metabolism


  • Adaptor Proteins, Signal Transducing
  • DNA Primers
  • Dok3 protein, mouse
  • GRB2 Adaptor Protein
  • Grb2 protein, mouse
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • Btk protein, mouse
  • lyn protein-tyrosine kinase
  • src-Family Kinases
  • Calcium