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  • Original Paper
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Negative regulation of transforming growth factor-β (TGF-β) signaling by WW domain-containing protein 1 (WWP1)

Oncogene volume 23, pages 6914–6923 (2004)Cite this article

Abstract

Smad7 negatively regulates transforming growth factor (TGF)-β superfamily signaling by binding to activated type I receptors, thereby preventing the phosphorylation of receptor-regulated Smads (R-Smads), as well as by recruiting HECT-type E3 ubiquitin ligases to degrade type I receptors through a ubiquitin-dependent mechanism. To elucidate the regulatory mechanisms of TGF-β signaling, we searched for novel members of proteins that interact with Smad7 using a yeast two-hybrid system. One of the proteins identified was the WW domain-containing protein 1 (WWP1) that is structurally related to Smad ubiquitin regulatory factors (Smurfs), E3 ubiquitin ligases for Smads and TGF-β superfamily receptors. Using a TGF-β-responsive reporter in mammalian cells, we found that WWP1 inhibited transcriptional activities induced by TGF-β. Similar to Smurfs, WWP1 associated with Smad7 and induced its nuclear export, and enhanced binding of Smad7 to TGF-β type I receptor to cause ubiquitination and degradation of the receptor. Consistent with these results, WWP1 inhibited phosphorylation of Smad2 induced by TGF-β. WWP1 thus negatively regulates TGF-β signaling in cooperation with Smad7. However, unlike Smurfs, WWP1 failed to ubiquitinate R-Smads and SnoN. Importantly, WWP1 and Smurfs were expressed in distinct patterns in human tissues and carcinoma cell lines, suggesting unique pathophysiological roles of WWP1 and Smurfs.

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Acknowledgements

We are grateful to Yuri Inada and Aki Hanyu, Ken Shirakawa for technical help. This study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sport, Science, and Technology of Japan, and by the Viral Hepatitis Research Foundation of Japan.

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Authors and Affiliations

  1. Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Akiyoshi Komuro, Masao Saitoh, Kohei Miyazono & Keiji Miyazawa

  2. Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, 226-8501, Nagatsuta, Japan

    Akiyoshi Komuro & Takeshi Imamura

  3. Department of Biochemistry,

    Takeshi Imamura & Kohei Miyazono

  4. Cancer Chemotherapy Center, The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo, 170-8455, Japan

    Yoko Yoshida & Takao Yamori

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  1. Akiyoshi Komuro
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Correspondence to Keiji Miyazawa.

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Komuro, A., Imamura, T., Saitoh, M. et al. Negative regulation of transforming growth factor-β (TGF-β) signaling by WW domain-containing protein 1 (WWP1). Oncogene 23, 6914–6923 (2004). https://doi.org/10.1038/sj.onc.1207885

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