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Osmotic stress-mediated activation of RET kinases involves intracellular disulfide-bonded dimer formation.

Authors
  • Takeda, K
  • Kato, M
  • Wu, J
  • Iwashita, T
  • Suzuki, H
  • Takahashi, M
  • Nakashima, I
Type
Published Article
Journal
Antioxidants and Redox Signaling
Publisher
Mary Ann Liebert
Publication Date
Jun 01, 2001
Volume
3
Issue
3
Pages
473–482
Identifiers
PMID: 11491658
Source
Medline
License
Unknown

Abstract

We showed that osmotic stress induces activation of c-RET and second-set activation of constitutively activated RET-MEN2B. A few percentage of RET proteins normally formed disulfide-bonded dimers in the cell, and osmotic stress promoted formation of these dimers. The disulfide-bonded dimers displayed higher levels of autophosphorylation and catalytic activity per molecule than did monomers. Osmotic stress also promoted activation and disulfide-bonded dimerization of the extracellular domain-depleted mutant RET (RET-PTC-1), suggesting that the target amino acid(s) for dimerization is located intracellularly rather than in the cysteine-rich region of the extracellular domain. In the mutant c-RET and RET-PTC-1 in which Cys987 of c-RET or Cys376 of RET-PTC-1 was replaced with Ala, the levels of intrinsic kinase activity were greatly reduced and barely increased in response to osmotic stress. Correspondingly, the Cys376-defective RET-PTC-1 did not form any demonstrable levels of dimers even after exposure to osmotic stress. In contrast, another RET-PTC-1 mutant that had a replacement of Cys365 with Ala mostly behaved like parental RET-PTC-1. These results suggest that Cys987 of c-RET or Cys376 of RET-PTC-1 plays a crucial role in maintenance and promotion of dimerization and activation of the RET kinases.

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