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

Masashi Kato, Kozue Takeda, Khaled Hossain, Nguyen D. Thang, Yu Kaneko, Mayuko Kumasaka, Osamu Yamanoshita, Noriyuki Uemura, Masahide Takahashi, Nobutaka Ohgami, Yoshiyuki Kawamoto

研究成果: Article査読

11 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)399-407
ページ数9
ジャーナルJournal of Cellular Biochemistry
110
2
DOI
出版ステータスPublished - 15-05-2010
外部発表はい

All Science Journal Classification (ASJC) codes

  • 生化学
  • 分子生物学
  • 細胞生物学

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