Metalloprotease-mediated HB-EGF release regulates EGF receptor transactivation in A431 cells at oxidative stress |
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Authors: | I S Smirnova I V Gonchar A N Shatrova N N Nikolskii E B Burova |
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Institution: | 1.Institute of Cytology,Russian Academy of Sciences,St. Petersburg,Russia |
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Abstract: | Previously, we showed that hydrogen peroxide (H2O2) induces the ligand-independent activation (transactivation) of EGF receptor in various cells overexpressing EGF receptor.
In the present work, the mechanism of H2O2-induced EGF receptor transactivation was studied in A431 human epidermoid carcinoma cells. The autophosphorylation of the
EGF receptor at tyrosine residues 1045, 1068, 1148, 1173, as well as the phosphorylation of tyrosine 845, was demonstrated.
It has been shown that the tyrosine phosphorylation of the EGF receptor does not involve autophosphorylation at tyrosine 992.
The blockage of the function of metalloproteases with broad-spectrum inhibitor GM6001 suppressed H2O2-induced phosphorylation of EGF receptor, which suggests the dependence of the transactivation on metalloprotease activity.
To elucidate the possible role of EGF receptor agonists in its activation, antibodies against HB-EGF and TGF-α were used.
H2O2-induced EGF receptor phosphorylation was inhibited by HB-EGF, but not TGF-α, a neutralizing antibody. We believe that the
mechanism of transactivation of EGF receptor during oxidative stress is realized via autophosphorylation and includes HB-EGF
as a necessary component of signal transduction mediated by metalloprotease activity. |
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