Roles of superoxide radical anion in signal transduction mediated by reversible regulation of protein-tyrosine phosphatase 1B

William C. Barrett, Jon P. DeGnore, Yen Fang Keng, Zhong Yin Zhang, Moon B. Yim, P. Boon Chock

Research output: Contribution to journalArticle

303 Scopus citations

Abstract

Growth factors induce intracellular production of reactive oxygen species in non-phagocytic cells and elevation of their phosphorylated protein tyrosine level. The latter can be achieved by activating protein-tyrosine kinases and/or inactivating protein-tyrosine phosphatases (PTPs). A highly abundant PTP, PTP-1B, is known to be inactivated by oxidation of its catalytic site Cys-215. We show that O2- is kinetically more efficient and chemically more specific oxidant than H2O2 for inactivating PTP-1B. The second-order rate constant for the O2-- and H2O2-mediated inactivation is 334 ± 45 M-1 s-1 and 42.8 ± 3.8 M-1 s-1, respectively. PTP-1B oxidized by H2O2 exhibits significantly more oxidized methionine residues and shows a lower degree of reversibility. The initial oxidative product, the Cys-215 sulfenic derivative, can easily be oxidized further to its irreversible sulfinic and sulfonic derivatives. This step is prevented by glutathionylation of the sulfenic derivative to form a S-glutathionylated PTP-1B, which can be reactivated by dithiothreitol or thioltransferase. Thus, a signal transduction mechanism mediated by the O2- and the participation of glutathione is proposed for the regulation of PTP-1B. This mechanism is supported by the in vivo demonstration that glutathionylated PTP-1B at Cys-215 is formed in A431 cells when they were treated with epidermal growth factor.

Original languageEnglish (US)
Pages (from-to)34543-34546
Number of pages4
JournalJournal of Biological Chemistry
Volume274
Issue number49
DOIs
StatePublished - Dec 3 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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