title: Distinct and Overlapping Functions of TEC Kinase and BTK in B Cell Receptor Signaling.
abstract: The Tec tyrosine kinase is expressed in many cell types, including hematopoietic cells, and is a member of the Tec kinase family that also includes Btk. Although the role of Btk in B cells has been extensively studied, the role of Tec kinase in B cells remains largely unclear. It was previously shown that Tec kinase has the ability to partly compensate for loss of Btk activity in B cell differentiation, although the underlying mechanism is unknown. In this study, we confirm that Tec kinase is not essential for normal B cell development when Btk is present, but we also found that Tec-deficient mature B cells showed increased activation, proliferation, and survival upon BCR stimulation, even in the presence of Btk. Whereas Tec deficiency did not affect phosphorylation of phospholipase Cγ or Ca2+influx, it was associated with significantly increased activation of the intracellular Akt/S6 kinase signaling pathway upon BCR and CD40 stimulation. The increased S6 kinase phosphorylation in Tec-deficient B cells was dependent on Btk kinase activity, as ibrutinib treatment restored pS6 to wild-type levels, although Btk protein and phosphorylation levels were comparable to controls. In Tec-deficient mice in vivo, B cell responses to model Ags and humoral immunity upon influenza infection were enhanced. Moreover, aged mice lacking Tec kinase developed a mild autoimmune phenotype. Taken together, these data indicate that in mature B cells, Tec and Btk may compete for activation of the Akt signaling pathway, whereby the activating capacity of Btk is limited by the presence of Tec kinase.
authors.affiliation: Department of Pulmonary Medicine, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.
authors.forename: Marjolein J W
authors.initials: MJ
authors.lastname: de Bruijn
authors.affiliation: Department of Pulmonary Medicine, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.
authors.forename: Jasper
authors.initials: J
authors.lastname: Rip
authors.affiliation: Department of Pulmonary Medicine, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.
authors.forename: Esmee K
authors.identifier: 0000-0002-7468-4527
authors.initials: EK
authors.lastname: van der Ploeg
authors.affiliation: Department of Pulmonary Medicine, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.
authors.forename: Lars W
authors.identifier: 0000-0002-0316-5674
authors.initials: LW
authors.lastname: van Greuningen
authors.affiliation: Department of Pulmonary Medicine, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.
authors.forename: Van T B
authors.initials: VT
authors.lastname: Ta
authors.affiliation: Department of Pulmonary Medicine, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.
authors.forename: Laurens P
authors.initials: LP
authors.lastname: Kil
authors.affiliation: Department of Immunology, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.
authors.forename: Anton W
authors.identifier: 0000-0002-2078-3220
authors.initials: AW
authors.lastname: Langerak
authors.affiliation: Department of Viroscience, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands; and.
authors.forename: Guus F
authors.initials: GF
authors.lastname: Rimmelzwaan
authors.affiliation: Division of Immunobiology, Institute of Immunology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Ellmeier
authors.affiliation: Department of Pulmonary Medicine, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands; r.hendriks@erasmusmc.nl.
authors.forename: Rudi W
authors.identifier: 0000-0003-4506-2531
authors.initials: RW
authors.lastname: Hendriks
authors.affiliation: Department of Pulmonary Medicine, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.
authors.forename: Odilia B J
authors.initials: OB
authors.lastname: Corneth
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007251:Influenza, Human; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology
chemical_list: D011947:Receptors, Antigen, B-Cell; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human