Phosphorylation of ARD1 by IKKbeta contributes to its destabilization and degradation.
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.
Kuo
Hsu-Ping
HP
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Lee
Dung-Fang
DF
Xia
Weiya
W
Lai
Chien-Chen
CC
Li
Long-Yuan
LY
Hung
Mien-Chie
MC
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
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