Subcellular localization of Grb2 by the adaptor protein Dok-3 restricts the intensity of Ca2+ signaling in B cells.
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.
Stork
Björn
B
Institute of Cellular and Molecular Immunology, Georg August University of Göttingen, Göttingen, Germany.
Neumann
Konstantin
K
Goldbeck
Ingo
I
Alers
Sebastian
S
Kähne
Thilo
T
Naumann
Michael
M
Engelke
Michael
M
Wienands
Jürgen
J
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002645:Chickens; D017931:DNA Primers; D025461:Feedback, Physiological / Q000502:physiology; D051380:GRB2 Adaptor Protein / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D018613:Microscopy, Confocal; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; C406768:Dok3 protein, mouse; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D002118:Calcium