title: The role of the Syk/Shp-1 kinase-phosphatase equilibrium in B cell development and signaling.
abstract: Signal transduction from the BCR is regulated by the equilibrium between kinases (e.g., spleen tyrosine kinase [Syk]) and phosphatases (e.g., Shp-1). Previous studies showed that Syk-deficient B cells have a developmental block at the pro/pre-B cell stage, whereas a B cell-specific Shp-1 deficiency promoted B-1a cell development and led to autoimmunity. We generated B cell-specific Shp-1 and Syk double-knockout (DKO) mice and compared them to the single-knockout mice deficient for either Syk or Shp-1. Unlike Syk-deficient mice, the DKO mice can generate mature B cells, albeit at >20-fold reduced B cell numbers. The DKO B-2 cells are all Syk-negative, whereas the peritoneal B1 cells of the DKO mice still express Syk, indicating that they require this kinase for their proper development. The DKO B-2 cells cannot be stimulated via the BCR, whereas they are efficiently activated via TLR or CD40. We also found that in DKO pre-B cells, the kinase Zap70 is associated with the pre-BCR, suggesting that Zap70 is important to promote B cell maturation in the absence of Syk and SHP-1. Together, our data show that a properly balanced kinase/phosphatase equilibrium is crucial for normal B cell development and function.
authors.affiliation: Department of Molecular Immunology, Max-Planck-Institut of Immunobiology and Epigenetics, Freiburg 79108, Germany; Biology III, Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg 79108, Germany Spemann Graduate School of Biology and Medicine, Albert-Ludwigs-University Freiburg, Freiburg 79108, Germany; and BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg 79108, Germany.
authors.forename: Ameera
authors.initials: A
authors.lastname: Alsadeq
authors.affiliation: Department of Molecular Immunology, Max-Planck-Institut of Immunobiology and Epigenetics, Freiburg 79108, Germany; Biology III, Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg 79108, Germany.
authors.forename: Elias
authors.initials: E
authors.lastname: Hobeika
authors.affiliation: Department of Molecular Immunology, Max-Planck-Institut of Immunobiology and Epigenetics, Freiburg 79108, Germany; Biology III, Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg 79108, Germany BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg 79108, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Medgyesi
authors.affiliation: Department of Molecular Immunology, Max-Planck-Institut of Immunobiology and Epigenetics, Freiburg 79108, Germany; Biology III, Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg 79108, Germany BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg 79108, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kläsener
authors.affiliation: Department of Molecular Immunology, Max-Planck-Institut of Immunobiology and Epigenetics, Freiburg 79108, Germany; Biology III, Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg 79108, Germany Spemann Graduate School of Biology and Medicine, Albert-Ludwigs-University Freiburg, Freiburg 79108, Germany; and BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg 79108, Germany michael.reth@bioss.uni-freiburg.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Reth
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000276:immunology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse