title: CD28 stimulation triggers NF-kappaB activation through the CARMA1-PKCtheta-Grb2/Gads axis.
abstract: CD28 stimulation contributes to activation of the IL-2 promoter by up-regulating the activity of several transcription factors, including nuclear factor kappaB (NF-kappaB)/Rel family members. However, the signal-transducing cascades linking the CD28 molecule and activation of NF-kappaB remain unclear. Protein kinase C (PKC) , CARMA1 and Bcl10 have recently been reported to integrate TCR-mediated NF-kappaB activation. However, since the data in these studies were drawn from experiments in which T cells were usually stimulated with both TCR and CD28, the relative contributions of TCR- and CD28-mediated signals to initiation of the NF-kappaB pathway remain elusive. To examine the role of these molecules in NF-kappaB activation through CD28-mediated stimulation, Bcl10 was over-expressed in Jurkat cells and their NF-kappaB activation by CD28- or TCR-cross-linking was evaluated. We found that CD28 stimulation alone can induce NF-kappaB activation in Bcl10-over-expressing Jurkat cells, whereas TCR stimulation alone has only little effect. In addition, we found that Bcl10-induced NF-kappaB activation through CD28-mediated stimulation could be blocked by the dominant-negative form of PKC or CARMA1. Furthermore, genetic studies revealed that Grb2/Gads binding, but not phosphatidylinositol 3-kinase binding, is important in CD28-mediated NF-kappaB activation. These findings indicate that the PKC-CARMA1-Bcl10 signaling pathway participates in the CD28 co-stimulatory signal independently of the TCR-signaling pathway, which leads us to propose that the activation of the NF-kappaB-signaling pathway via PKC-CARMA1-Bcl10 may be markedly dependent on CD28 stimulation rather than TCR stimulation.
authors.affiliation: Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Takeda
authors.forename: Yohsuke
authors.initials: Y
authors.lastname: Harada
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Watanabe
authors.forename: Yuu
authors.initials: Y
authors.lastname: Inutake
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ogawa
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Onuki
authors.forename: Saori
authors.initials: S
authors.lastname: Kagaya
authors.forename: Kazunari
authors.initials: K
authors.lastname: Tanabe
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Kishimoto
authors.forename: Ryo
authors.initials: R
authors.lastname: Abe
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000276:immunology / Q000378:metabolism*; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016466:CHO Cells; D002458:Cell Fractionation; D006224:Cricetinae; D003412:Cricetulus; D051380:GRB2 Adaptor Protein / Q000276:immunology / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000276:immunology / Q000378:metabolism*; D019169:Jurkat Cells; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000276:immunology / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D021381:Protein Transport; D015398:Signal Transduction / Q000276:immunology; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D053468:CARD Signaling Adaptor Proteins; D018106:CD28 Antigens; D051380:GRB2 Adaptor Protein; D007527:Isoenzymes; D016328:NF-kappa B; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; C426242:CARD11 protein, human; D006162:Guanylate Cyclase