Abstract

Jab1/CSN5, a Component of the COP9 Signalosome, Regulates Transforming Growth Factor β Signaling by Binding to Smad7 and Promoting Its Degradation Byung-Chul Kim 1 , 2 , † , Ho-Jae Lee 1 , † , Seok Hee Park 3 , † , Sae Ra Lee 1 , Tatiana S. Karpova 4 , James G. McNally 4 , Angelina Felici 1 , Dug Keun Lee 1 and Seong-Jin Kim 1 , * 1 Laboratory of Cell Regulation and Carcinogenesis 4 Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5055 2 Division of Life Science, College of Natural Science, Kangwon National University, Chuncheon, Kangwon-do 3 Inha University College of Medicine, Incheon, Korea ABSTRACT Smad7 inhibits responses mediated by transforming growth factor β (TGF-β) and acts in a negative-feedback loop to regulate the intensity or duration of the TGF-β signal. However, the aberrant expression and continued presence of Smad7 may cause TGF-β resistance. Here we report that Jab1/CSN5, which is a component of the COP9 signalosome complex, associates constitutively with Smad7 and that overexpression of Jab1/CSN5 causes the translocation of Smad7 from the nucleus to the cytoplasm, promoting its degradation. Overexpression of Jab1/CSN5 increases Smad2 phosphorylation and enhances TGF-β-induced transcriptional activity. The inhibition of endogenous Jab1/CSN5 expression by small interfering RNA (siRNA) induces Smad7 expression. This study thus defines Jab1/CSN5 as an adapter that targets Smad7 for degradation, thus releasing Smad7-mediated suppression of TGF-β signaling.