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Vol. 15, Issue 3, 963-972, March 2004

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Interaction with Smad4 Is Indispensable for Suppression of BMP Signaling by c-Ski

Masafumi Takeda ^* , Masafumi Mizuide , Masako Oka ^*, Tetsuro Watabe ^*, Hirofumi Inoue , Hiroyuki Suzuki ^*, Toshiro Fujita , Takeshi Imamura , Kohei Miyazono ^*  , and Keiji Miyazawa ^*

^* Department of Molecular Pathology; Department of Endocrinology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; and Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan

Submitted July 8, 2003; Revised December 3, 2003; Accepted December 5, 2003
Monitoring Editor: Carl-Henrik Heldin

c-Ski is a transcriptional corepressor that interacts strongly with Smad2, Smad3, and Smad4 but only weakly with Smad1 and Smad5. Through binding to Smad proteins, c-Ski suppresses signaling of transforming growth factor- (TGF-) as well as bone morphogenetic proteins (BMPs). In the present study, we found that a mutant of c-Ski, termed c-Ski (ARPG) inhibited TGF-/activin signaling but not BMP signaling. Selectivity was confirmed in luciferase reporter assays and by determination of cellular responses in mammalian cells (BMP-induced osteoblastic differentiation of C2C12 cells and TGF-–induced epithelial-to-mesenchymal transdifferentiation of NMuMG cells) and Xenopus embryos. The ARPG mutant recruited histone deacetylases 1 (HDAC1) to the Smad3-Smad4 complex but not to the Smad1/5-Smad4 complex. c-Ski (ARPG) was unable to interact with Smad4, and the selective loss of suppression of BMP signaling by c-Ski (ARPG) was attributed to the lack of Smad4 binding. We also found that c-Ski interacted with Smad3 or Smad4 without disrupting Smad3-Smad4 heteromer formation. c-Ski (ARPG) would be useful for selectively suppressing TGF-/activin signaling.

Corresponding author. E-mail address: miyazono-ind{at}umin.ac.jp.

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