title: Grb2 regulates B-cell maturation, B-cell memory responses and inhibits B-cell Ca2+ signalling.
abstract: Grb2 is a ubiquitously expressed adaptor protein, which activates Ras and MAP kinases in growth factor receptor signalling, while in B-cell receptor (BCR) signalling this role is controversial. In B cell lines it was shown that Grb2 can inhibit BCR-induced Ca(2+) signalling. Nonetheless, the physiological role of Grb2 in primary B cells is still unknown. We generated a B-cell-specific Grb2-deficient mouse line, which had a severe reduction of mature follicular B cells in the periphery due to a differentiation block and decreased B-cell survival. Moreover, we found several changes in important signalling pathways: enhanced BCR-induced Ca(2+) signalling, alterations in mitogen-activated protein kinase activation patterns and strongly impaired Akt activation, the latter pointing towards a defect in PI3K signalling. Interestingly, B-cell-specific Grb2-deficient mice showed impaired IgG and B-cell memory responses, and impaired germinal centre formation. Thus, Grb2-dependent signalling pathways are crucial for lymphocyte differentiation processes, as well as for control of secondary humoral immune responses.
authors.affiliation: Department of Biology, University of Erlangen, Erlangen, Germany.
authors.forename: Jochen A
authors.initials: JA
authors.lastname: Ackermann
authors.forename: Daniel
authors.initials: D
authors.lastname: Radtke
authors.forename: Anna
authors.initials: A
authors.lastname: Maurberger
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Winkler
authors.forename: Lars
authors.initials: L
authors.lastname: Nitschke
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D053265:B-Cell Activation Factor Receptor; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D051380:GRB2 Adaptor Protein / Q000502:physiology*; D007114:Immunization; D007156:Immunologic Memory; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction
chemical_list: D053265:B-Cell Activation Factor Receptor; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; C486662:Tnfrsf13c protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium