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A redox-linked novel pathway for arsenic-mediated RET tyrosine kinase activation

Authors

  • Masashi Kato,

    Corresponding author
    1. Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi 487-8501, Japan
    2. Voluntary Body for International Health Care, Chubu University, Kasugai-shi, Aichi 487-8501, Japan
    • Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences (Building No. 50, 11F), Chubu University, 1200 Matsumoto-cho, Kasugai-shi, Aichi 487-8501, Japan.
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  • Kozue Takeda,

    1. Voluntary Body for International Health Care, Chubu University, Kasugai-shi, Aichi 487-8501, Japan
    2. Unit of Immunology, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi 487-8501, Japan
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  • Khaled Hossain,

    1. Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi 487-8501, Japan
    2. Voluntary Body for International Health Care, Chubu University, Kasugai-shi, Aichi 487-8501, Japan
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  • Nguyen D. Thang,

    1. Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi 487-8501, Japan
    2. Department of Dermatology, Aichi Medical University School of Medicine, Nagakute-cho, Aichi-gun, Aichi 480-1195, Japan
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  • Yu Kaneko,

    1. Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi 487-8501, Japan
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  • Mayuko Kumasaka,

    1. Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi 487-8501, Japan
    2. Voluntary Body for International Health Care, Chubu University, Kasugai-shi, Aichi 487-8501, Japan
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  • Osamu Yamanoshita,

    1. Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi 487-8501, Japan
    2. Voluntary Body for International Health Care, Chubu University, Kasugai-shi, Aichi 487-8501, Japan
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  • Noriyuki Uemura,

    1. Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi 487-8501, Japan
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  • Masahide Takahashi,

    1. Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
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  • Nobutaka Ohgami,

    1. Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi 487-8501, Japan
    2. Voluntary Body for International Health Care, Chubu University, Kasugai-shi, Aichi 487-8501, Japan
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  • Yoshiyuki Kawamoto

    1. Unit of Immunology, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi 487-8501, Japan
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Abstract

We examined the biochemical effects of arsenic on the activities of RET proto-oncogene (c-RET protein tyrosine kinases) and RET oncogene (RET-MEN2A and RET-PTC1 protein tyrosine kinases) products. Arsenic activated c-RET kinase with promotion of disulfide bond-mediated dimerization of c-RET protein. Arsenic further activated RET-MEN2A kinase, which was already 3- to 10-fold augmented by genetic mutation compared with c-RET kinase activity, with promotion of disulfide bond-mediated dimerization of RET-MEN2A protein (superactivation). Arsenic also increased extracellular domain-deleted RET-PTC1 kinase activity with promotion of disulfide bond-mediated dimerization of RET-PTC1 protein. Arsenic increased RET-PTC1 kinase activity with cysteine 365 (C365) replaced by alanine with promotion of dimer formation but not with cysteine 376 (C376) replaced by alanine. Our results suggest that arsenic-mediated regulation of RET kinase activity is dependent on conformational change of RET protein through modulation of a special cysteine sited at the intracellular domain in RET protein (relevant cysteine of C376 in RET-PTC1 protein). Moreover, arsenic enhanced the activity of immunoprecipitated RET protein with increase in thiol-dependent dimer formation. As arsenic (14.2 µM) was detected in the cells cultured with arsenic (100 µM), direct association between arsenic and RET in the cells might modulate dimer formation. Thus, we demonstrated a novel redox-linked mechanism of activation of arsenic-mediated RET proto-oncogene and oncogene products. J. Cell. Biochem. 110: 399–407, 2010. © 2010 Wiley-Liss, Inc.

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