title: Epidermal growth factor receptor is involved in enterocyte anoikis through the dismantling of E-cadherin-mediated junctions.
abstract: Enterocytes of the intestinal epithelium are continually regenerated. They arise from precursor cells in crypts, migrate along villi, and finally die, 3-4 days later, when they reach the villus apex. Their death is thought to occur by anoikis, a form of apoptosis induced by cell detachment, but the mechanism of this process remains poorly understood. We have previously shown that a key event in the onset of anoikis in normal enterocytes detached from the basal lamina is the disruption of adherens junctions mediated by E-cadherin (Fouquet S, Lugo-Martinez VH, Faussat AM, Renaud F, Cardot P, Chambaz J, Pincon-Raymond M, Thenet S. J Biol Chem 279: 43061-43069, 2004). Here we have further investigated the mechanisms underlying this disassembly of the adherens junctions. We show that disruption of the junctions occurs through endocytosis of E-cadherin and that this process depends on the tyrosine-kinase activity of the epidermal growth factor receptor (EGFR). Activation of EGFR was detected in detached enterocytes before E-cadherin disappearance. Specific inhibition of EGFR by tyrphostin AG-1478 maintained E-cadherin and its cytoplasmic partners beta- and alpha-catenin at cell-cell contacts and decreased anoikis. Finally, EGFR activation was evidenced in the intestinal epithelium in vivo, in rare individual cells, which were shown to lose their interactions with the basal lamina. We conclude that EGFR is activated as enterocytes become detached from the basal lamina, and that this mechanism contributes to the disruption of E-cadherin-dependent junctions leading to anoikis. This suggests that EGFR participates in the physiological elimination of the enterocytes.
authors.affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, UMR S872, Paris, France.
authors.forename: Verónica-Haydée
authors.initials: VH
authors.lastname: Lugo-Martínez
authors.forename: Constance S
authors.initials: CS
authors.lastname: Petit
authors.forename: Stéphane
authors.initials: S
authors.lastname: Fouquet
authors.forename: Johanne
authors.initials: J
authors.lastname: Le Beyec
authors.forename: Jean
authors.initials: J
authors.lastname: Chambaz
authors.forename: Martine
authors.initials: M
authors.lastname: Pinçon-Raymond
authors.forename: Philippe
authors.initials: P
authors.lastname: Cardot
authors.forename: Sophie
authors.initials: S
authors.lastname: Thenet
mesh_terms: D000818:Animals; D023102:Anoikis / Q000187:drug effects; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D004705:Endocytosis; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020032:Tyrphostins / Q000494:pharmacology; D051178:alpha Catenin / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D015820:Cadherins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D020032:Tyrphostins; D051178:alpha Catenin; D051176:beta Catenin; C101044:RTKI cpd; D066246:ErbB Receptors