Role of EGF receptor tyrosine kinase activity in antiapoptotic effect of EGF on mouse hepatocytes

The apoptotic Fas pathway is potentially involved in the pathogenesis of li ver diseases. Growth factors, such as epidermal growth factor (EGF), can pr otect cells against apoptosis induced by a variety of stimuli, including Fa s receptor stimulation. However, the underlying mechanisms of this protecti on have yet to be determined. We investigated the involvement of EGF recept or (EGFR) tyrosine kinase (TK) activity in the antiapoptotic effect of EGF on primary mouse hepatocyte cultures. Cells undergoing apoptosis after trea tment with anti-Fas antibody were protected by EGF treatment. This protecti on was significantly but partially decreased when cells were treated with t wo specific inhibitors of the TK activity of EGFR. Evaluation of the effica cy of these compounds indicated that they were able to abolish EGFR autopho sphorylation and postreceptor events such as activation of mitogen-activate d protein kinases and the phosphatidylinositol 3'-kinase pathways as well a s increases in Bcl-x(L) mRNA and protein levels. This leads us to postulate that EGF exerts its antiapoptotic action partially through the TK activity of EGFR. In addition, our results suggest that Bcl-x(L) protein upregulati on caused by EGF is linked to the TK activity of its receptor.