Chronic ethanol consumption disrupts complexation between EGF receptor and phospholipase C-γ1:: Relevance to impaired hepatocyte proliferation

We have previously shown that chronic ethanol consumption inhibits liver regeneration by impairing EGF receptor (EGFR)-operated phospholipase C-gamma 1 (PLC-gamma 1) activation and resultant intracellular Ca2+ signalling. Activation of PLC-gamma 1 by EGFR requires the EGFR to bind to PLC-gamma 1 after its translocation from cytosol to cytoskeleton. In order to understand the mechanism by which ethanol impairs PLC-gamma 1 activation, we examined the effect of alcohol on interactions between EG;FR and PLC-gamma 1. In cultured hepatocytes from control rats, EGF rapidly induced tyrosine phosphorylation of both the EGFR and of PLC-gamma 1. EGF also stimulated PLC-gamma 1 translocation from cytosol to a cytoskeletal compartment where PLC-gamma 1 interacted with EGFR. In hepatocytes from rats fed ethanol for 16 weeks, the above reactions were substantially inhibited. Tyrphostin AG1478, an EGFR-specific tyrosine kinase inhibitor, mimicked the effects of chronic ethanol on EGFR phosphorylation, PLC-gamma 1 translocation and interactions between EGFR and PLC-, in the cytoskeleton. Further, tyrphostin AG1478 also inhibited EGF-induced DNA synthesis. These results indicate that ethanol impairs EGFR-operated [Ca2+]i signaling by disrupting the interactions between EGFR and PLC-gamma 1. (C) 1999 Academic Press.