Transglutaminase down-regulates the dimerization of epidermal growth factor receptor in rat perivenous and periportal hepatocytes |
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Authors: | A Maruko Y Ohtake S Katoh† Y Ohkubo |
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Institution: | Department of Radiopharmacy, Tohoku Pharmaceutical University, Komatsushima, Aoba-ku, Sendai, Miyagi, Japan;, Department of Life Science, Laboratory of Radiophysiology, Yokohama College of Pharmacy, Matano-cho, Totsuka-ku, Yokohama, Japan |
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Abstract: | 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. Materials and 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. Conclusion: 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. |
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