OXIDIZED GLUTATHIONE INDUCES ACTIVATION OF THE EPIDERMAL GROWTH FACTOR RECEPTOR AND EXTRACELLULAR SIGNAL-REGULATED
KINASES ERK 1,2
K. P. Vasilenko,1 * E. B. Burova,1 V. G. Antonov,2
N. N. Nikolsky 1
1 Institute of Cytology RAS and 2 Military Medical Academy, St. Petersburg;
* e-mail: shambala@mail.cytspb.rssi.ru
Ligand-independent activation ("transactivation") of the epidermal growth factor receptor (EGFR) was demonstrated
upon cell stimulation with cytokines, activators of G-protein-coupled receptors and various stressors. Recently, we
showed transactivation of EGFR and activation of transcription factor STAT3, rather than STAT1, induced by
glutathione disulfide (GSSG) and glutoxim in epidermoid carcinoma A431 cells (Burova et al., Dokl. Akad. Nauk., 2005,
404 : 1-3). Glutoxim® (PHARMA-VAM, Moscow) is a pharmacological synthetic analogue of GSSG, whose
therapeutic use as an immunomodulator has been permitted. In this study, we investigated dynamics of EGFR activation
upon A431 cell stimulation with GSSG and glutoxim. The time course of activation has a sinuous pattern. It has been
shown that the intrinsic EGFR tyrosine kinase is responsible for the receptor phosphorylation induced by GSSG and
glutoxim. Here, we also demonstrated the activation of ERK 1,2 upon treatment of A431 cells and HER14 cells (HIN 3T3
fibroblasts transfected with full-length EGFR) with these drugs. ERK 1,2 activation was abolished by AG1478, a
pharmacological inhibitor of EGFR tyrosine kinase, implicating intrinsic EGFR tyrosine kinase in this process.
Key words: signal transduction, epidermal growth factor receptor, transactivation, glutathione
disulfide, MAP-kinase ERK 1,2, tyrosine phosphorylation
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