title: Phosphorylation of ARD1 by IKKbeta contributes to its destabilization and degradation.
abstract: IkappaB kinase beta (IKKbeta), a major kinase downstream of various proinflammatory signals, mediates multiple cellular functions through phosphorylation and regulation of its substrates. On the basis of protein sequence analysis, we identified arrest-defective protein 1 (ARD1), a protein involved in apoptosis and cell proliferation processes in many human cancer cells, as a new IKKbeta substrate. We provided evidence showing that ARD1 is indeed a bona fide substrate of IKKbeta. IKKbeta physically associated with ARD1 and phosphorylated it at Ser209. Phosphorylation by IKKbeta destabilized ARD1 and induced its proteasome-mediated degradation. Impaired growth suppression was observed in ARD1 phosphorylation-mimic mutant (S209E)-transfected cells as compared with ARD1 non-phosphorylatable mutant (S209A)-transfected cells. Our findings of molecular interactions between ARD1 and IKKbeta may enable further understanding of the upstream regulation mechanisms of ARD1 and of the diverse functions of IKKbeta.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hsu-Ping
authors.initials: HP
authors.lastname: Kuo
authors.forename: Dung-Fang
authors.initials: DF
authors.lastname: Lee
authors.forename: Weiya
authors.initials: W
authors.lastname: Xia
authors.forename: Chien-Chen
authors.initials: CC
authors.lastname: Lai
authors.forename: Long-Yuan
authors.initials: LY
authors.lastname: Li
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017124:Conserved Sequence; D004795:Enzyme Stability; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D063209:N-Terminal Acetyltransferase A; D063213:N-Terminal Acetyltransferase E; D010766:Phosphorylation / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism
chemical_list: D000123:Acetyltransferases; D063209:N-Terminal Acetyltransferase A; C504824:NAA10 protein, human; D063213:N-Terminal Acetyltransferase E; D051550:I-kappa B Kinase; D046988:Proteasome Endopeptidase Complex