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Published 10 December 2001. doi:10.1083/jcb.200106023
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© The Rockefeller University Press, 0021-9525/2001/12/1017 $5.00
The Journal of Cell Biology, Volume 155, Number 6, December 10, 2001 1017-1028

Article

The N domain of Smad7 is essential for specific inhibition of transforming growth factor-ß signaling



Aki Hanyu1, Yasuhiro Ishidou1, Takanori Ebisawa1, Tomomasa Shimanuki1, Takeshi Imamura1 and Kohei Miyazono1,2

1 Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), Tokyo 170-8455, Japan
2 Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan

Address correspondence to Kohei Miyazono, Department of Biochemistry, The JFCR Cancer Institute, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan. Tel.: 81-35-394-3866. Fax: 81-33-918-0342. E-mail: miyazono-ind{at}umin.ac.jp

Inhibitory Smads (I-Smads) repress signaling by cytokines of the transforming growth factor-ß (TGF-ß) superfamily. I-Smads have conserved carboxy-terminal Mad homology 2 (MH2) domains, whereas the amino acid sequences of their amino-terminal regions (N domains) are highly divergent from those of other Smads. Of the two different I-Smads in mammals, Smad7 inhibited signaling by both TGF-ß and bone morphogenetic proteins (BMPs), whereas Smad6 was less effective in inhibiting TGF-ß signaling. Analyses using deletion mutants and chimeras of Smad6 and Smad7 revealed that the MH2 domains were responsible for the inhibition of both TGF-ß and BMP signaling by I-Smads, but the isolated MH2 domains of Smad6 and Smad7 were less potent than the full-length Smad7 in inhibiting TGF-ß signaling. The N domains of I-Smads determined the subcellular localization of these molecules. Chimeras containing the N domain of Smad7 interacted with the TGF-ß type I receptor (TßR-I) more efficiently, and were more potent in repressing TGF-ß signaling, than those containing the N domain of Smad6. The isolated N domain of Smad7 physically interacted with the MH2 domain of Smad7, and enhanced the inhibitory activity of the latter through facilitating interaction with TGF-ß receptors. The N domain of Smad7 thus plays an important role in the specific inhibition of TGF-ß signaling.

Key Words: TGF-ß; bone morphogenetic protein; Smad; receptor; signaling


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