title: CEACAM1 regulates Fas-mediated apoptosis in Jurkat T-cells via its interaction with β-catenin.
abstract: CEACAM1 (Carcinoembryonic Antigen Cell Adhesion molecule 1), an activation induced cell surface marker of T-cells, modulates the T-cell immune response by inhibition of the T-cell and IL-2 receptors. Since T-cells undergo activation induced cell death via Fas activation, it was of interest to determine if this pathway was also affected by CEACAM1. Previously, we identified a novel biochemical interaction between CEACAM1 and the armadillo repeats of β-catenin in Jurkat cells, in which two critical residues, H469 and K470 of the cytoplasmic domain of CEACAM1-4L played an essential role; while in other studies, β-catenin was shown to regulate Fas-mediated apoptosis in Jurkat cells. CEACAM1 expression in Jurkat cells leads to the re-distribution of β-catenin to the actin cytoskeleton as well as inhibition of β-catenin tyrosine phosphorylation and its degradation after Fas stimulation. As a result, Fas-mediated apoptosis in these cells was inhibited. The K470A mutation of CEACAM1 partially rescued the inhibitory effect, in agreement with the prediction that a CEACAM1-β-catenin interaction pathway is involved. Although CEACAM1 has two ITIMs, they were not tyrosine-phosphorylated upon Fas ligation, indicating an ITIM independent mechanism; however, mutation of the critical residue S508, located between the ITIMs, to aspartic acid and a prerequisite for ITIM activation, abrogates the inhibitory activity of CEACAM1 to Fas-mediated apoptosis. Since Fas-mediated apoptosis is a major form of activation-induced cell death, our finding supports the idea that CEACAM1 is a general inhibitory molecule for T-cell activation utilizing a variety of pathways.
authors.affiliation: City of Hope Irell & Manella Graduate School of Biological Sciences, Duarte, CA 91010, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: John E
authors.initials: JE
authors.lastname: Shively
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017209:Apoptosis / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics; D008954:Models, Biological; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism* / Q000502:physiology; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; C491901:FAS protein, human; D051176:beta Catenin; D019014:fas Receptor