title: The B-cell antigen receptor signals through a preformed transducer module of SLP65 and CIN85.
abstract: Spleen tyrosine kinase Syk and its substrate SLP65 (also called BLNK) are proximal signal transducer elements of the B-cell antigen receptor (BCR). Yet, our understanding of signal initiation and processing is limited owing to the incomplete list of SLP65 interaction partners and our ignorance of their association kinetics. We have now determined and quantified the in vivo interactomes of SLP65 in resting and stimulated B cells by mass spectrometry. SLP65 orchestrated a complex signal network of about 30 proteins that was predominantly based on dynamic interactions. However, a stimulation-independent and constant association of SLP65 with the Cbl-interacting protein of 85 kDa (CIN85) was requisite for SLP65 phosphorylation and its inducible plasma membrane translocation. In the absence of a steady SLP65/CIN85 complex, BCR-induced Ca(2+) and NF-κB responses were abrogated. Finally, live cell imaging and co-immunoprecipitation experiments further confirmed that both SLP65 and CIN85 are key components of the BCR-associated primary transducer module required for the onset and progression phases of BCR signal transduction.
authors.affiliation: Institute of Cellular and Molecular Immunology, Georg-August-University Göttingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Oellerich
authors.forename: Vanessa
authors.initials: V
authors.lastname: Bremes
authors.forename: Konstantin
authors.initials: K
authors.lastname: Neumann
authors.forename: Hanibal
authors.initials: H
authors.lastname: Bohnenberger
authors.forename: Kai
authors.initials: K
authors.lastname: Dittmann
authors.forename: He-Hsuan
authors.initials: HH
authors.lastname: Hsiao
authors.forename: Michael
authors.initials: M
authors.lastname: Engelke
authors.forename: Tim
authors.initials: T
authors.lastname: Schnyder
authors.forename: Facundo D
authors.initials: FD
authors.lastname: Batista
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wienands
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000072377:Syk Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011947:Receptors, Antigen, B-Cell; C433810:SH3KBP1 protein, human; C498782:Sh3kbp1 protein, mouse; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D002118:Calcium