Chronic ethanol consumption disrupts complexation between EGF receptor and phospholipase C-gamma1: relevance to impaired hepatocyte proliferation.
We have previously shown that chronic ethanol consumption inhibits liver regeneration by impairing EGF receptor (EGFR)-operated phospholipase C-gamma1 (PLC-gamma1) activation and resultant intracellular Ca2+ signalling. Activation of PLC-gamma1 by EGFR requires the EGFR to bind to PLC-gamma1 after its translocation from cytosol to cytoskeleton. In order to understand the mechanism by which ethanol impairs PLC-gamma1 activation, we examined the effect of alcohol on interactions between EGFR and PLC-gamma1. In cultured hepatocytes from control rats, EGF rapidly induced tyrosine phosphorylation of both the EGFR and of PLC-gamma1. EGF also stimulated PLC-gamma1 translocation from cytosol to a cytoskeletal compartment where PLC-gamma1 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-gamma1 translocation and interactions between EGFR and PLC-gamma1 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-gamma1.
Zhang
B H
BH
Department of Medicine, University of Sydney at Westmead Hospital, Westmead, NSW 2145, Australia.
Farrell
G C
GC
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism*; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051966:Phospholipase C gamma; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011799:Quinazolines; D051381:Rats; D017208:Rats, Wistar; D010738:Type C Phospholipases / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology
D007527:Isoenzymes; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D019000:Phosphotyrosine; D000431:Ethanol; D004815:Epidermal Growth Factor; D004247:DNA; D066246:ErbB Receptors; D010738:Type C Phospholipases; D051966:Phospholipase C gamma