title: Cutting edge: feed-forward activation of phospholipase Cγ2 via C2 domain-mediated binding to SLP65.
abstract: Ag-mediated B cell stimulation relies on phospholipase Cγ2 (PLCγ2) for Ca(2+) mobilization. Enzymatic activity of PLCγ2 is triggered upon Src homology 2 domain-mediated binding to the tyrosine-phosphorylated adaptor SLP65. However, SLP65 phosphorylation outlasts the elevation of cytosolic Ca(2+) concentration suggesting additional levels of PLCγ2 regulation. We show in this article that the functionality of the PLCγ2/SLP65 complex is controlled by the weakly characterized C2 domain of PLCγ2. Usually C2 domains bind membrane lipids, but that of PLCγ2 docks in a Ca(2+)-regulated manner to a distinct phosphotyrosine of SLP65. Hence, early Ca(2+) fluxing provides feed-forward signal amplification by promoting anchoring of the PLCγ2 C2 domain to phospho-SLP65. As the cellular Ca(2+) resources become exhausted, the concomitant decline of Ca(2+) dampens the C2-phosphotyrosine interaction so that PLCγ2 activation terminates despite sustained SLP65 phosphorylation.
authors.affiliation: Institute of Cellular and Molecular Immunology, Georg August University of Göttingen, 37073 Göttingen, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Engelke
authors.forename: Thomas
authors.initials: T
authors.lastname: Oellerich
authors.forename: Kai
authors.initials: K
authors.lastname: Dittmann
authors.forename: He-Hsuan
authors.initials: HH
authors.lastname: Hsiao
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
authors.forename: Christian
authors.initials: C
authors.lastname: Griesinger
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wienands
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D000941:Antigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002460:Cell Line; D002645:Chickens; D025461:Feedback, Physiological; D006801:Humans; D008213:Lymphocyte Activation; D009154:Mutation / Q000235:genetics; D051966:Phospholipase C gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics; D015202:Protein Engineering; D017434:Protein Structure, Tertiary / Q000235:genetics; D019076:Transgenes / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000941:Antigens; C113939:B cell linker protein; D051966:Phospholipase C gamma; D002118:Calcium