title: Activation of Epstein-Barr virus/C3d receptor (gp140, CR2, CD21) on human B lymphoma cell surface triggers Cbl tyrosine phosphorylation, its association with p85 subunit, Crk-L and Syk and its dissociation with Vav.
abstract: It is well established that CD21 activation on human B cell surface triggers B cell proliferation. We previously demonstrated that CD21 activation also triggers tyrosine phosphorylation of two components, p95 and p120, both interacting with SH2 domains of the p85 subunit of PI 3-kinase. We successively identified p95 as the nucleolin and the first signal transduction pathway specifically triggered by CD21 activation, i.e.: pp60Src activation, tyrosine phosphorylation of p95 nucleolin, its interaction with SH2 domains of p85 subunit and PI 3-kinase activation, followed by AKT-GSK-3 activations. We herein identified the p120 component as the protooncoprotein Cbl and the first steps associated to its activation. First, CD21 activation triggered Cbl tyrosine phosphorylation, which required c-Src kinase but not PI 3-kinase or Syk kinase activities. Involvement of Src kinase in this step was supported by inhibition of Cbl phosphorylation and its interactions with other components when cells were either preincubated with specific Src inhibitor or transfected with dominant-negative c-Src form. Second, once tyrosine phosphorylated, Cbl interacts with SH2 domains of p85 subunit, SH2 domains of Crk-L and with tyrosine phosphorylated Syk kinase. The third and unexpected feature was to found that, at the contrary of BCR or of CD19 (herein also analyzed for the first time), CD21 activation triggers dissociation of Cbl-Vav complex. Thus, these results provide the first molecular basis of a new signal transduction pathway specifically triggered by CD21 activation.
authors.affiliation: INSERM U.672 (ex U.354), Immunochimie des Régulations Cellulaires et des Interactions Virales, Bâtiment G8, Campus 1, 5 rue Henri Desbruères, Génopole d'Evry, 91030, EVRY Cedex, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Lottin-Divoux
authors.forename: Didier
authors.initials: D
authors.lastname: Jean
authors.forename: Murielle
authors.initials: M
authors.lastname: Le Romancer
authors.forename: Raymond
authors.initials: R
authors.lastname: Frade
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008223:Lymphoma / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism*; D017464:Receptors, Complement 3d / Q000276:immunology / Q000378:metabolism*; D000072377:Syk Kinase; D014775:Virus Activation / Q000187:drug effects; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D051567:Proto-Oncogene Proteins c-vav; D017464:Receptors, Complement 3d; D019000:Phosphotyrosine; D050721:Proto-Oncogene Proteins c-cbl; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase