Phosphorylation of ARD1 by IKK beta contributes to its destabilization and degradation

摘要

I kappa B kinase beta (IKK beta), 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 IKK beta substrate. We provided evidence showing that ARD1 is indeed a bona. de substrate of IKK beta. IKK beta physically associated with ARD1 and phosphorylated it at Ser209. Phosphorylation by IKK beta 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 IKK beta may enable further understanding of the upstream regulation mechanisms of ARD1 and of the diverse functions of IKK beta. (C) 2009 Elsevier Inc. All rights reserved.