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Published on: September 19, 2018

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

Masashi Kato1, Kozue Takeda, Khaled Hossain

  • 1Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi, Japan. katomasa@isc.chubu.ac.jp

Journal of Cellular Biochemistry
|March 18, 2010
PubMed

Insights

Arsenic activates RET proto-oncogene and oncogene products by promoting protein dimerization. This redox-linked mechanism involves specific cysteine residues, revealing a novel pathway for arsenic-mediated RET kinase regulation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • The RET proto-oncogene and its oncogenic forms (RET-MEN2A, RET-PTC1) are critical protein tyrosine kinases.
  • Dysregulation of RET signaling is implicated in various cancers, including thyroid carcinoma.

Purpose of the Study:

  • To investigate the biochemical effects of arsenic on the activity of c-RET, RET-MEN2A, and RET-PTC1 protein tyrosine kinases.
  • To elucidate the mechanism by which arsenic modulates RET kinase activity and dimerization.

Main Methods:

  • Biochemical assays to measure protein tyrosine kinase activity.
  • Disulfide bond formation and dimerization studies.
  • Site-directed mutagenesis of cysteine residues in RET-PTC1.
  • Immunoprecipitation and Western blotting.

Main Results:

  • Arsenic activated c-RET kinase by promoting disulfide bond-mediated dimerization.
  • Arsenic superactivated RET-MEN2A kinase activity, also via disulfide bond-mediated dimerization.
  • Arsenic increased RET-PTC1 kinase activity and dimerization, dependent on specific cysteine residues (C376).
  • Arsenic directly associated with RET proteins in cells, enhancing thiol-dependent dimer formation.

Conclusions:

  • Arsenic modulates RET kinase activity through a redox-linked mechanism involving conformational changes and disulfide bond formation.
  • The intracellular cysteine residue C376 in RET-PTC1 is crucial for arsenic-mediated activation.
  • These findings reveal a novel mechanism of arsenic-induced activation of RET proto-oncogene and oncogene products.

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