title: ERK is involved in EGF-mediated protection of tight junctions, but not adherens junctions, in acetaldehyde-treated Caco-2 cell monolayers.
abstract: The role of mitogen-activated protein kinases (MAPK) in the mechanism of EGF-mediated prevention of acetaldehyde-induced tight junction disruption was evaluated in Caco-2 cell monolayers. Pretreatment of cell monolayers with EGF attenuated acetaldehyde-induced decrease in resistance and increase in inulin permeability and redistribution of occludin, zona occludens-1 (ZO-1), E-cadherin, and β-catenin from the intercellular junctions. EGF rapidly increased the levels of phospho-ERK1/2, phospho-p38 MAPK, and phospho-JNK1. Pretreatment of cell monolayers with U-0126 (inhibitor of ERK activation), but not SB-202190 and SP-600125 (p38 MAPK and JNK inhibitors), significantly attenuated EGF-mediated prevention of acetaldehyde-induced changes in resistance, inulin permeability, and redistribution of occludin and ZO-1. U-0126, but not SB-202190 and SP-600125, also attenuated EGF-mediated prevention of acetaldehyde effect on the midregion F-actin ring. However, EGF-mediated preservation of junctional distribution of E-cadherin and β-catenin was unaffected by all three inhibitors. Expression of wild-type or constitutively active MEK1 attenuated acetaldehyde-induced redistribution of occludin and ZO-1, whereas dominant-negative MEK1 prevented EGF-mediated preservation of occludin and ZO-1 in acetaldehyde-treated cells. MEK1 expression did not alter E-cadherin distribution in acetaldehyde-treated cells in the presence or absence of EGF. Furthermore, EGF attenuated acetaldehyde-induced tyrosine-phosphorylation of occludin, ZO-1, claudin-3, and E-cadherin. U-0126, but not SB-202190 and SP-600125, prevented EGF effect on tyrosine-phosphorylation of occludin and ZO-1, but not claudin-3, E-cadherin, or β-catenin. These results indicate that EGF-mediated protection of tight junctions from acetaldehyde requires the activity of ERK1/2, but not p38 MAPK or JNK1/2, and that EGF-mediated protection of adherens junctions is independent of MAPK activities.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, 38163, USA.
authors.forename: G
authors.initials: G
authors.lastname: Samak
authors.forename: S
authors.initials: S
authors.lastname: Aggarwal
authors.forename: R K
authors.initials: RK
authors.lastname: Rao
mesh_terms: D000079:Acetaldehyde / Q000494:pharmacology*; D000199:Actins / Q000378:metabolism; D022005:Adherens Junctions / Q000187:drug effects*; D000873:Anthracenes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D018938:Caco-2 Cells; D015820:Cadherins / Q000378:metabolism; D062465:Claudin-3; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007444:Inulin / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D062793:Occludin; D010539:Permeability / Q000187:drug effects; D010750:Phosphoproteins / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D019108:Tight Junctions / Q000187:drug effects*; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000199:Actins; D000873:Anthracenes; D002070:Butadienes; C568122:CLDN3 protein, human; D015820:Cadherins; D062465:Claudin-3; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008565:Membrane Proteins; D009570:Nitriles; C568985:OCLN protein, human; D062793:Occludin; D010750:Phosphoproteins; D011725:Pyridines; C569042:TJP1 protein, human; C113580:U 0126; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin; C432165:pyrazolanthrone; D004815:Epidermal Growth Factor; D007444:Inulin; D048049:Extracellular Signal-Regulated MAP Kinases; D000079:Acetaldehyde; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole