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Modulation of the functional binding sites for TGF-β on the type II receptor leads to suppression of TGF-β signaling

Oncogene volume 26, pages 3311–3320 (2007)Cite this article

Abstract

Transforming growth factor-β (TGF-β) binds to two different types of serine/threonine kinase receptors termed type II (TβR-II) and type I (TβR-I). TGF-β is unable to bind to TβR-I in the absence of TβR-II, and initiates receptor assembly by binding with high affinity to TβR-II. Previous structural analysis of the TGF-β3–TβR-II complex has suggested that two charged amino acid residues, D55 and E142 of TβR-II, are binding sites of TGF-β. In the present study, we have shown that mutations of the amino-acid residues, D55 and E142 of TβR-II, resulted in loss of TGF-β binding and downstream signaling activity. Moreover, we found that 3,5,7,2′,4′-pentahydroxyflavone (Morin) inhibits TGF-β binding to TβR-II, and suppresses phosphorylation of Smad2 and expression of a TGF-β target gene Smad7 induced by TGF-β. Our findings may thus provide useful information for designing therapeutic agents for various diseases induced by TGF-β, including advanced cancers.

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Acknowledgements

We thank T Era for providing pCAG 20-1 and pUHD 10-3 puro vectors and M Laiho and J Massagué for DR-mutant Mv1Lu cells. We are grateful to the members of our group for their helpful discussions. This work was supported by grants from the Ministry of Education, Culture, Science, Sports, and Technology of Japan.

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Authors and Affiliations

  1. Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    T Shimanuki & K Miyazono

  2. The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), Koto-ku, Tokyo, Japan

    T Shimanuki, T Imamura & K Miyazono

  3. Cutaneous Drug Research Laboratories, POLA Chemical Industries, Inc., Totsuka-ku, Kanagawa, Japan

    T Shimanuki

  4. PharmaDesign Inc., Chuo-ku, Tokyo, Japan

    T Hara & T Furuya

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  1. T Shimanuki
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Correspondence to K Miyazono.

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Shimanuki, T., Hara, T., Furuya, T. et al. Modulation of the functional binding sites for TGF-β on the type II receptor leads to suppression of TGF-β signaling. Oncogene 26, 3311–3320 (2007). https://doi.org/10.1038/sj.onc.1210123

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