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Transforming Growth Factor-β Suppresses the Ability of Ski to Inhibit Tumor Metastasis by Inducing Its Degradation

¹ Department of Molecular and Cell Biology, University of California Berkeley; ² Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California; ³ Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas; and ⁴ Institut National de la Sante et de la Recherche Medicale, U697, Paris, France

Requests for reprints: Kunxin Luo, Department of Molecular Cell Biology, University of California, 16 Barker Hall, MC3204, Berkeley, CA 94720. Phone: 510-643-3183; Fax: 510-643-6334; E-mail: kluo{at}berkeley.edu.

Key Words: Ski • Arkadia • TGF-β • Metastasis • Degradation

c-Ski is an important corepressor of transforming growth factor-β (TGF-β) signaling through its ability to bind to and repress the activity of the Smad proteins. It was initially identified as an oncogene that promotes anchorage-independent growth of chicken and quail embryo fibroblasts when overexpressed. Although increased Ski expression is detected in many human cancer cells, the roles of Ski in mammalian carcinogenesis have yet to be defined. Here, we report that reducing Ski expression in breast and lung cancer cells does not affect tumor growth but enhances tumor metastasis in vivo. Thus, in these cells, Ski plays an antitumorigenic role. We also showed that TGF-β, a cytokine that is often highly expressed in metastatic tumors, induces Ski degradation through the ubiquitin-dependent proteasome in malignant human cancer cells. On TGF-β treatment, the E3 ubiquitin ligase Arkadia mediates degradation of Ski in a Smad-dependent manner. Although Arkadia interacts with Ski in the absence of TGF-β, binding of phosphorylated Smad2 or Smad3 to Ski is required to induce efficient degradation of Ski by Arkadia. Our results suggest that the ability of TGF-β to induce degradation of Ski could be an additional mechanism contributing to its protumorigenic activity. [Cancer Res 2008;68(9):3277–85]