Article
- The EMBO Journal (2007) 26, 1140 - 1149
- doi:10.1038/sj.emboj.7601557
Published online: 8 February 2007
Subject Categories:
Subcellular localization of Grb2 by the adaptor protein Dok-3 restricts the intensity of Ca2+ signaling in B cells
Björn Stork1,a, Konstantin Neumann1,a, Ingo Goldbeck1,a, Sebastian Alers1, Thilo Kähne2, Michael Naumann2, Michael Engelke1 and Jürgen Wienands1
- Institute of Cellular and Molecular Immunology, Georg August University of Göttingen, Göttingen, Germany
- Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg, Germany
Correspondence to:
Jürgen Wienands, Institute of Cellular and Molecular Immunology, Georg August University of Göttingen, Humboldtallee 34, 37073 Göttingen, Germany. Tel.: +49 (0)551 39 5812; Fax: +49 (0)551 39 5843, E-mail: jwienan@uni-goettingen.de
aThese authors contributed equally to this work
Received 17 October 2006; Accepted 19 December 2006
Abstract
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-
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.
Keywords:
- adaptor proteins,
- B-cell activation,
- Ca2+ mobilization,
- plasma membrane recruitment,
- tyrosine phosphorylation
