title: The immunoglobulin tail tyrosine motif upgrades memory-type BCRs by incorporating a Grb2-Btk signalling module.
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.
authors.affiliation: Institute of Cellular and Molecular Immunology, Georg-August-University of Göttingen, Medical Faculty, Humboldtallee 34, 37073 Göttingen, Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Engels
authors.affiliation: Institute of Cellular and Molecular Immunology, Georg-August-University of Göttingen, Medical Faculty, Humboldtallee 34, 37073 Göttingen, Germany.
authors.forename: Lars M
authors.initials: LM
authors.lastname: König
authors.affiliation: Institute of Cellular and Molecular Immunology, Georg-August-University of Göttingen, Medical Faculty, Humboldtallee 34, 37073 Göttingen, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Schulze
authors.affiliation: Chair of Genetics, Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Staudtstrasse 5, 91058 Erlangen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Radtke
authors.affiliation: Institute of Cellular and Molecular Immunology, Georg-August-University of Göttingen, Medical Faculty, Humboldtallee 34, 37073 Göttingen, Germany.
authors.forename: Kanika
authors.initials: K
authors.lastname: Vanshylla
authors.affiliation: Institute of Cellular and Molecular Immunology, Georg-August-University of Göttingen, Medical Faculty, Humboldtallee 34, 37073 Göttingen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Lutz
authors.affiliation: Hematopoiesis Unit, Department of Biology, Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Glückstrasse 6, 91054 Erlangen, Germany.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Winkler
authors.affiliation: Chair of Genetics, Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Staudtstrasse 5, 91058 Erlangen, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Nitschke
authors.affiliation: Institute of Cellular and Molecular Immunology, Georg-August-University of Göttingen, Medical Faculty, Humboldtallee 34, 37073 Göttingen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wienands
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D020816:Amino Acid Motifs; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D005260:Female; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*
chemical_list: D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D007074:Immunoglobulin G; D011947:Receptors, Antigen, B-Cell; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D002118:Calcium