METALLOPROTEASE-MEDIATED HB-EGF RELEASE REGULATES EGF RECEPTOR TRANSACTIVATION IN A431 CELLS UNDER OXIDATIVE STRESS
I. S. Smirnova, I. V. Gonchar, A. N. Shatrova, N. N. Nikolsky, E. B. Burova 1
Institute of Cytology RAS, St. Petersburg;
1 e-mail: lenbur87@mail.ru
We have shown earlier that H2O2 induces EGF receptor transactivation in different cells overexpressing
EGF receptor. Mechanism of H2O2-induced EGF receptor transactivation in A431 human epidermoid carcinoma
cells was examined in this work. We have demonstrated autophosphorylation of Tyr1045, 1068, 1148, 1173 as
well as phosphorylation of Tyr845 of EGF receptor in response to H2O2, as assessed by autophosphorylation
specific antibody. Tyrosine phosphorylation of EGF receptor by H2O2 did not involve receptor autophosphorylation
at Tyr992. Blocking functions of metalloproteases by broad-spectrum inhibitor GM6001 suppressed
H2O2-induced phosphorylation of EGF receptor, suggesting dependence of the transactivation on metalloproteases
activity. To elucidate the possible role of EGF receptor agonists in its activation we used HB-EGF and
TGF-a neutralizing antibody. H2O2-induced EGF receptor phosphorylation was inhibited by HB-EGF, but not
TGF-a, neutralizing antibody. Taken together, our data suggest that, in human epidermoid carcinoma A431
cells, H2O2 stimulates EGF receptor transactivation via metalloprotease-dependent HB-EGF release and autophosphorylation.
Key words: epidermal growth factor receptor, H2O2, transactivation, HB-EGF, metalloprotease, autophosphorylation, A431
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