title: Phosphorylation of Carma1, but not Bcl10, by Akt regulates TCR/CD28-mediated NF-κB induction and cytokine production.
abstract: Previous studies from our group and others have shown that the Akt kinase can contribute to induction of NF-κB by antigen receptor signaling. However, the direct targets of Akt in this pathway are not known. Here we show that Akt-mediated NF-κB activation is mediated at least in part through direct phosphorylation of the adaptor protein Carma1, which we previously demonstrated could interact with Akt in a TCR ligation-dependent manner. The putative Akt phosphorylation sites in Carma1 are distinct from known PKC consensus sites. Mutation of S551, S637 and S645 in Carma1 to non-phosphorylatable residues decreased phosphorylation of GST-Carma1-linker construct by Akt in vitro. In addition, Carma1 S637A/S645A mutants were significantly impaired in their ability to restore TCR-mediated NF-κB activation and IL-2 expression in Carma1-deficient T cells. Thus, our data reveal Carma1 as a novel target for Akt phosphorylation and suggest that Akt-mediated phosphorylation of Carma1 is an additional regulatory mechanism tuning the NF-κB response downstream of antigen receptor and co-stimulatory signaling.
authors.affiliation: University of Pittsburgh, Department of Immunology, BST E-1056, 200 Lothrop Street, Pittsburgh, PA 15261, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Cheng
authors.affiliation: University of Pittsburgh, Department of Immunology, BST E-1056, 200 Lothrop Street, Pittsburgh, PA 15261, United States; Graduate Program in Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, United States.
authors.forename: Kristia S
authors.initials: KS
authors.lastname: Hamilton
authors.affiliation: University of Pittsburgh, Department of Immunology, BST E-1056, 200 Lothrop Street, Pittsburgh, PA 15261, United States. Electronic address: lkane@pitt.edu.
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Kane
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism; D000595:Amino Acid Sequence; D000074018:B-Cell CLL-Lymphoma 10 Protein; D015153:Blotting, Western; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D006162:Guanylate Cyclase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D009154:Mutation; D016328:NF-kappa B / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D034622:RNA Interference; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism
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; D017252:CD3 Complex; D016207:Cytokines; D007376:Interleukin-2; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; D051057:Proto-Oncogene Proteins c-akt; C426242:CARD11 protein, human; D006162:Guanylate Cyclase
keywords: Akt; NF-κB; Phosphorylation; Signal transduction; T cells