title: The Dok-3/Grb2 adaptor module promotes inducible association of the lipid phosphatase SHIP with the BCR in a coreceptor-independent manner.
abstract: The SH2 domain-containing inositol 5'-phosphatase (SHIP) plays a key role in preventing autoimmune phenomena by limiting antigen-mediated B cell activation. SHIP function is thought to require the dual engagement of the BCR and negative regulatory coreceptors as only the latter appear capable of recruiting SHIP from the cytosol to the plasma membrane by the virtue of phosphorylated immunoreceptor tyrosine-based inhibitory motifs. Here, we demonstrate a coreceptor-independent membrane recruitment and function of SHIP in B cells. In the absence of coreceptor ligation, SHIP translocates to sites of BCR activation through a concerted action of the protein adaptor unit Dok-3/Grb2 and phosphorylated BCR signaling components. Our data reveal auto-inhibitory SHIP activation by the activated BCR and suggest an unexpected negative-regulatory capacity of immunoreceptor tyrosine-based activation motifs in Igα and Igβ.
authors.affiliation: Georg August University of Göttingen, Institute of Cellular and Molecular Immunology, Göttingen, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Manno
authors.affiliation: Department of Hematology and Oncology, Johann Wolfgang Goethe University of Frankfurt, Frankfurt, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Oellerich
authors.affiliation: Lincoln's Inn Fields Laboratory, The Francis Crick Institute London, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Schnyder
authors.affiliation: Bioanalytical Mass Spectrometry, Max Planck Institute of Biophysical Chemistry, Göttingen.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Corso
authors.affiliation: Georg August University of Göttingen, Institute of Cellular and Molecular Immunology, Göttingen, Germany.|Vivo Science GmbH, Gronau, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Lösing
authors.affiliation: Georg August University of Göttingen, Institute of Cellular and Molecular Immunology, Göttingen, Germany.|Institute of Clinical Chemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Neumann
authors.affiliation: Bioanalytical Mass Spectrometry, Max Planck Institute of Biophysical Chemistry, Göttingen.|Bioanalytics Department of Clincal Chemistry, University Medical Center Goettingen, Göttingen, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.affiliation: Lincoln's Inn Fields Laboratory, The Francis Crick Institute London, UK.
authors.forename: Facundo D
authors.initials: FD
authors.lastname: Batista
authors.affiliation: Georg August University of Göttingen, Institute of Cellular and Molecular Immunology, Göttingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Engelke
authors.affiliation: Georg August University of Göttingen, Institute of Cellular and Molecular Immunology, Göttingen, Germany. jwienan@gwdg.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wienands
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D002645:Chickens; D051380:GRB2 Adaptor Protein / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D011947:Receptors, Antigen, B-Cell; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
keywords: BCR; B cell inhibition; Dok-3; Grb2; Plasma membrane recruitment; SHIP