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Nat Commun. 2014 Nov 21;5:5456. doi: 10.1038/ncomms6456.

The immunoglobulin tail tyrosine motif upgrades memory-type BCRs by incorporating a Grb2-Btk signalling module.

Author information

1
Institute of Cellular and Molecular Immunology, Georg-August-University of Göttingen, Medical Faculty, Humboldtallee 34, 37073 Göttingen, Germany.
2
Chair of Genetics, Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Staudtstrasse 5, 91058 Erlangen, Germany.
3
Hematopoiesis Unit, Department of Biology, Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Glückstrasse 6, 91054 Erlangen, Germany.

Abstract

The vigorous response of IgG-switched memory B cells to recurring pathogens involves enhanced signalling from their B-cell antigen receptors (BCRs). However, the molecular signal amplification mechanisms of memory-type BCRs remained unclear. Here, we identify the immunoglobulin tail tyrosine (ITT) motif in the cytoplasmic segments of membrane-bound IgGs (mIgGs) as the principle signal amplification device of memory-type BCRs in higher vertebrates and decipher its signalling microanatomy. We show that different families of protein tyrosine kinases act upstream and downstream of the ITT. Spleen tyrosine kinase (Syk) activity is required for ITT phosphorylation followed by recruitment of the adaptor protein Grb2 into the mIgG-BCR signalosome. Grb2 in turn recruits Bruton's tyrosine kinase (Btk) to amplify BCR-induced Ca(2+) mobilization. This molecular interplay of kinases and adaptors increases the antigen sensitivity of memory-type BCRs, which provides a cell-intrinsic trigger mechanism for the rapid reactivation of IgG-switched memory B cells on antigen recall.

PMID:
25413232
PMCID:
PMC4263166
DOI:
10.1038/ncomms6456
[Indexed for MEDLINE]
Free PMC Article

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