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Cited by 69Protein Kinase Regulation and GTPase SignalingT-cell and B-cell ImmunologyIon Channels and Receptors

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

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Stork, Björn, Neumann, Konstantin, Goldbeck, Ingo, Alers, Sebastian, Kähne, Thilo, Naumann, Michael, Engelke, Michael, Wienands, Jürgen·2007·The EMBO Journal
DOI 10.1038/sj.emboj.7601557PMC PMC1852829
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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-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.

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  • Several biochemical pathways and processes negatively regulate PLCγ2 activity and calcium flux after BCR engagement, including RasGRP3, Bam32, Dok-3 with Grb2, Themis2, BLNK, and SFRP2.

    “Several biochemical pathways and processes were shown to negatively regulate PLCγ2 activity and the resulting calcium flux after BCR engagement. These include RasGRP3 (39, 40), Bam32 (41), hematopoietic adaptor protein Dok-3 (downstream of kinase-3) with Grb2 (42), Themis2, an adaptor protein with no known enzymatic activity, via constitutive binding to Lyn, Grb2, and PLCγ2 to mediate its function”

    From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [42]

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Cited by

Sorted by citations

Authors
Stork, B., Neumann, K., Goldbeck, I., Alers, S., Kähne, T., Naumann, M., Engelke, M., & Wienands, J.
Affiliations
  • University of Göttingen (DE)
  • Otto-von-Guericke-Universität Magdeburg (DE)
Corresponding author
Wienands, Jürgen
ORCID
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2007-02-08
Volume
26
Issue
4
Pages
1140-1149
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
DOI
10.1038/sj.emboj.7601557
PMC
PMC1852829
OpenAlex
W2087578663
Cited by
69
References
3
Citations by year
2026: 1 · 2023: 1 · 2021: 1 · 2020: 3 · 2019: 5 · 2018: 4 · 2017: 2 · 2016: 7 · 2015: 6 · 2014: 6 · 2013: 3 · 2012: 6
FWCI
2.12
Type
journal article
Language
en
Open access
Licence
Locations
  • The EMBO Journal (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • GRO (submittedVersion)
Funders
Deutsche Forschungsgemeinschaft
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords
Grb2, subcellular localization, calcium signaling, B cells, B cell receptor, negative feedback regulation, Lyn kinase, Bruton's tyrosine kinase, PLCγ2, inositol trisphosphate, adaptor proteins
MeSH terms
Agammaglobulinaemia Tyrosine Kinase, Animals, B-Lymphocytes, Calcium, Cell Line, Chickens, Protein-Tyrosine Kinases, Mass Spectrometry, Signal Transduction, DNA Primers, Microscopy, Confocal, src-Family Kinases, Feedback, Physiological, Adaptor Proteins, Signal Transducing, Mice, GRB2 Adaptor Protein

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