Transglutaminase down-regulates the dimerization of epidermal growth factor receptor in rat perivenous and periportal hepatocytes.
OBJECTIVE
Recently, we found that transglutaminase 2 (TG2) might be involved in the difference in proliferative capacities between periportal hepatocytes (PPH) and perivenous hepatocytes (PVH) through down-regulation of high-affinity epidermal growth factor receptor (EGFR). However, it is uncertain whether this high-affinity EGFR contributes to the hepatocyte growth signalling pathway. Here, we have investigated the influence of TG2 on EGF-induced EGFR dimerization and its phosphorylation, which are important steps in the hepatocyte proliferative/growth signalling pathway, in PPH and PVH.


METHODS
PPH and PVH were isolated using the digitonin/collagenase perfusion technique. Amounts of TG2, EGFR dimerization and its phosphorylation were determined by Western blot analysis.


RESULTS
Pretreatment with monodansylcadaverine, an inhibitor of TG2, greatly increased EGF-induced EGFR dimerization and its phosphorylation in PVH compared with PPH. Conversely, treatment with retinoic acid, an inducer of TG2, significantly decreased EGF-induced EGFR dimerization and its phosphorylation with a significant increase in TG2 expression and its catalysed products, isopeptide bonds, in both subpopulations. It was found that EGFR served as a substrate for TG2.


CONCLUSIONS
The present data showed good correlation with our previous data on EGF-induced DNA synthesis and EGFR-binding affinity to EGF. These results suggest that zonal difference in cell growth between PPH and PVH may be caused by down-regulation of EGFR dimerization and subsequent autophosphorylation through TG2-mediated cross-linking of EGFR.
Maruko
A
A
Department of Radiopharmacy, Tohoku Pharmaceutical University, Aoba-ku, Sendai, Miyagi, Japan.
Ohtake
Y
Y
Katoh
S
S
Ohkubo
Y
Y
D000818:Animals; D002103:Cadaverine / Q000031:analogs & derivatives / Q000494:pharmacology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D019281:Dimerization; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006503:Hepatic Veins; D022781:Hepatocytes / Q000166:cytology* / Q000201:enzymology*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011169:Portal Vein; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D013379:Substrate Specificity; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology
D004791:Enzyme Inhibitors; C000717609:Tgm2 protein, rat; D014212:Tretinoin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D066246:ErbB Receptors; D019204:GTP-Binding Proteins; C008542:monodansylcadaverine; D002103:Cadaverine