title: The adaptor protein CIN85 assembles intracellular signaling clusters for B cell activation.
abstract: The adaptor molecule Cbl-interacting protein of 85 kD (CIN85) regulates signaling from a number of cell surface receptors, such as growth factor receptors and antigen receptors on lymphocytes. Because of its multidomain structure, CIN85 is thought to act as a classical adaptor protein that connects functionally distinct components of a given signaling pathway through diverse protein domains. However, we found that in B lymphocytes, CIN85 functions to oligomerize SLP-65, which is the central effector protein of the B cell receptor (BCR). Therefore, CIN85 trimerizes through a carboxyl-terminal, coiled-coil domain. The multiple Src homology 3 (SH3) domains of trimeric CIN85 molecules associated with multiple SLP-65 molecules, which recruited further CIN85 trimers, thereby perpetuating the oligomerization process. Formation of this oligomeric signaling complex in resting B cells rendered the cells poised for the efficient initiation of intracellular signaling upon BCR stimulation. Our data suggest that the functionality of signaling cascades does not rely solely on the qualitative linkage of their various components but requires a critical number of effectors to become concentrated in signaling complexes.
authors.affiliation: Institute of Cellular and Molecular Immunology, Georg August University of Göttingen, Humboldtallee 34, 37073 Göttingen, Germany.
authors.forename: Julius
authors.initials: J
authors.lastname: Kühn
authors.affiliation: Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Leo E
authors.initials: LE
authors.lastname: Wong
authors.affiliation: Institute of Cellular and Molecular Immunology, Georg August University of Göttingen, Humboldtallee 34, 37073 Göttingen, Germany.
authors.forename: Sona
authors.initials: S
authors.lastname: Pirkuliyeva
authors.affiliation: Institute of Cellular and Molecular Immunology, Georg August University of Göttingen, Humboldtallee 34, 37073 Göttingen, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schulz
authors.affiliation: Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schwiegk
authors.affiliation: Department for Cellular Logistic, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Kevser Gencalp
authors.initials: KG
authors.lastname: Fünfgeld
authors.affiliation: Lymphocyte Interaction Laboratory, London Research Institute, Cancer Research UK, Lincoln's Inn Fields 44, London WC2A 3LY, UK.
authors.forename: Selina
authors.initials: S
authors.lastname: Keppler
authors.affiliation: Lymphocyte Interaction Laboratory, London Research Institute, Cancer Research UK, Lincoln's Inn Fields 44, London WC2A 3LY, UK.
authors.forename: Facundo D
authors.initials: FD
authors.lastname: Batista
authors.affiliation: Bioanalytical Mass Spectrometry, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany. Bioanalytics Group, Institute for Clinical Chemistry, University Medical Center, Robert-Koch-Strasse 40, 37075 Göttingen, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.affiliation: Statistical Inverse Problems in Biophysics, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Habeck
authors.affiliation: Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.affiliation: Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany. jwienan@gwdg.de cigr@nmr.mpibpc.mpg.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Griesinger
authors.affiliation: Institute of Cellular and Molecular Immunology, Georg August University of Göttingen, Humboldtallee 34, 37073 Göttingen, Germany. jwienan@gwdg.de cigr@nmr.mpibpc.mpg.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wienands
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D008213:Lymphocyte Activation; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D011947:Receptors, Antigen, B-Cell; C433810:SH3KBP1 protein, human