Nagano Yoshiko, Mavrakis Konstantinos J, Lee Kian Leong, Fujii Tomoko, Koinuma Daizo, Sase Hitoshi, Yuki Keiko, Isogaya Kazunobu, Saitoh Masao, Imamura Takeshi, Episkopou Vasso, Miyazono Kohei, Miyazawa Keiji
Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
J Biol Chem. 2007 Jul 13;282(28):20492-501. doi: 10.1074/jbc.M701294200. Epub 2007 May 16.
Transforming growth factor-beta (TGF-beta) signaling is controlled by a variety of regulators that target either signaling receptors or activated Smad complexes. Among the negative regulators, Smad7 antagonizes TGF-beta signaling mainly through targeting the signaling receptors, whereas SnoN and c-Ski repress signaling at the transcriptional level through inactivation of Smad complexes. We previously found that Arkadia is a positive regulator of TGF-beta signaling that induces ubiquitin-dependent degradation of Smad7 through its C-terminal RING domain. We report here that Arkadia induces degradation of SnoN and c-Ski in addition to Smad7. Arkadia interacts with SnoN and c-Ski in their free forms as well as in the forms bound to Smad proteins, and constitutively down-regulates levels of their expression. Arkadia thus appears to effectively enhance TGF-beta signaling through simultaneous down-regulation of two distinct types of negative regulators, Smad7 and SnoN/c-Ski, and may play an important role in determining the intensity of TGF-beta family signaling in target cells.
转化生长因子-β（TGF-β）信号传导受多种靶向信号受体或活化的Smad复合物的调节因子控制。在负调节因子中，Smad7主要通过靶向信号受体拮抗TGF-β信号传导，而SnoN和c-Ski则通过使Smad复合物失活在转录水平抑制信号传导。我们先前发现Arkadia是TGF-β信号传导的正调节因子，它通过其C末端RING结构域诱导Smad7的泛素依赖性降解。我们在此报告，Arkadia除了诱导Smad7降解外，还诱导SnoN和c-Ski降解。Arkadia以其游离形式以及与Smad蛋白结合的形式与SnoN和c-Ski相互作用，并持续下调它们的表达水平。因此，Arkadia似乎通过同时下调两种不同类型的负调节因子Smad7和SnoN/c-Ski有效地增强TGF-β信号传导，并可能在确定靶细胞中TGF-β家族信号传导的强度方面发挥重要作用。
