Arkadia Induces Degradation of SnoN and c-Ski to Enhance Transforming Growth Factor-β Signaling

• Published in: The Journal of biological chemistry 2007-07, Vol.282 (28), p.20492
• Main Authors: Yoshiko Nagano, Konstantinos J. Mavrakis, Kian Leong Lee, Tomoko Fujii, Daizo Koinuma, Hitoshi Sase, Keiko Yuki, Kazunobu Isogaya, Masao Saitoh, Takeshi Imamura, Vasso Episkopou, Kohei Miyazono, Keiji Miyazawa
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M701294200

Transforming growth factor-β (TGF-β) signaling is controlled by a variety of regulators that target either signaling receptors or activated Smad complexes. Among the negative regulators, Smad7 antagonizes TGF-β 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-β 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-β 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-β family signaling in target cells.