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Processing of CD109 by furin and its role in the regulation of TGF-β signaling

Oncogene volume 29, pages 2181–2191 (2010)Cite this article

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Abstract

CD109 is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein, whose expression is upregulated in squamous cell carcinomas of the lung, esophagus, uterus and oral cavity. CD109 negatively regulates transforming growth factor (TGF)-β signaling in keratinocytes by directly modulating receptor activity. In this study, we further characterized CD109 regulation of TGF-β signaling and cell proliferation. We found that CD109 is produced as a 205 kDa glycoprotein, which is then processed in the Golgi apparatus into 180 kDa and 25 kDa proteins by furin (furinase). 180 kDa CD109 associated with GPI-anchored 25 kDa CD109 on the cell surface and was also secreted into the culture medium. To investigate whether furinase cleavage of CD109 is necessary for its biological activity, we mutated arginine 1273 in the CD109 furinase cleavage motif (amino acid 1270-RRRR-1273) to serine (R1273S). Interestingly, CD109 R1273S neither significantly impaired TGF-β signaling nor affected TGF-β-mediated suppression of cell growth, although it was expressed on the cell surface as a 205 kDa protein. Consistent with this finding, the 180 kDa and 25 kDa CD109 complex, but not CD109 R1273S, associated with the type I TGF-β receptor. These findings indicate that processing of CD109 into 180 kDa and 25 kDa proteins by furin, followed by complex formation with the type I TGF-β receptor is required for the regulation of TGF-β signaling in cancer cells and keratinocytes.

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Acknowledgements

This work was supported by Grants-in-Aid for Global Center of Excellence (GCOE) research, Scientific Research (A) and Scientific Research on Priority Area ‘Cancer’ commissioned by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (to MT).

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Authors and Affiliations

  1. Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    S Hagiwara, Y Murakumo, S Mii & M Takahashi

  2. Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan

    S Hagiwara, T Shigetomi, N Yamamoto, H Furue & M Ueda

  3. Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan

    M Takahashi

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  1. S Hagiwara
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Correspondence to M Takahashi.

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Hagiwara, S., Murakumo, Y., Mii, S. et al. Processing of CD109 by furin and its role in the regulation of TGF-β signaling. Oncogene 29, 2181–2191 (2010). https://doi.org/10.1038/onc.2009.506

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