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

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11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)399-407
Number of pages9
JournalJournal of Cellular Biochemistry
Volume110
Issue number2
DOIs
Publication statusPublished - 15-05-2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Kato, M., Takeda, K., Hossain, K., Thang, N. D., Kaneko, Y., Kumasaka, M., Yamanoshita, O., Uemura, N., Takahashi, M., Ohgami, N., & Kawamoto, Y. (2010). A redox-linked novel pathway for arsenic-mediated RET tyrosine kinase activation. Journal of Cellular Biochemistry, 110(2), 399-407. https://doi.org/10.1002/jcb.22550