title: The Dok-3/Grb2 protein signal module attenuates Lyn kinase-dependent activation of Syk kinase in B cell antigen receptor microclusters.
abstract: Recruitment of the growth factor receptor-bound protein 2 (Grb2) by the plasma membrane-associated adapter protein downstream of kinase 3 (Dok-3) attenuates signals transduced by the B cell antigen receptor (BCR). Here we describe molecular details of Dok-3/Grb2 signal integration and function, showing that the Lyn-dependent activation of the BCR transducer kinase Syk is attenuated by Dok-3/Grb2 in a site-specific manner. This process is associated with the SH3 domain-dependent translocation of Dok-3/Grb2 complexes into BCR microsignalosomes and augmented phosphorylation of the inhibitory Lyn target SH2 domain-containing inositol 5' phosphatase. Hence, our findings imply that Dok-3/Grb2 modulates the balance between activatory and inhibitory Lyn functions with the aim to adjust BCR signaling efficiency.
authors.affiliation: Georg August University of Göttingen, Institute of Cellular and Molecular Immunology, Humboldtallee 34, 37073 Göttingen, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Lösing
authors.forename: Ingo
authors.initials: I
authors.lastname: Goldbeck
authors.forename: Birgit
authors.initials: B
authors.lastname: Manno
authors.forename: Thomas
authors.initials: T
authors.lastname: Oellerich
authors.forename: Tim
authors.initials: T
authors.lastname: Schnyder
authors.forename: Hanibal
authors.initials: H
authors.lastname: Bohnenberger
authors.forename: Björn
authors.initials: B
authors.lastname: Stork
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.forename: Facundo D
authors.initials: FD
authors.lastname: Batista
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wienands
authors.forename: Michael
authors.initials: M
authors.lastname: Engelke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002645:Chickens; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation; D013058:Mass Spectrometry / Q000379:methods; D018613:Microscopy, Confocal / Q000379:methods; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; C518789:DOK3 protein, human; D051380:GRB2 Adaptor Protein; D011947:Receptors, Antigen, B-Cell; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D002118:Calcium