title: EGF regulates claudin-2 and -4 expression through Src and STAT3 in MDCK cells.
abstract: Epidermal Growth Factor (EGF) is a key regulator of epithelial paracellular permeability, a property that depends on tight junctions (TJ) and can be evaluated through the measurement of the transepithelial electrical resistance (TER). EGF increases the TER of MDCK monolayers by inducing ERK1/2-dependent downregulation of claudin-2 (CLDN-2) and upregulation of claudin-4 (CLDN-4). Because either increments or decrements in TER often involve Src activation and epithelial cell differentiation occasionally depends on STAT3, here we investigated whether EGF might control CLDN-2 downregulation and CLDN-4 upregulation through those proteins. We found that EGF induces Src activation necessary for the reduction of CLDN-2 at the TJ, the degradation of this CLDN, the reduction of the cellular levels of its mRNA and the resulting increase of TER. EGF-induced changes on CLDN-2 protein and mRNA also depend on STAT3 activity. This growth factor increases the levels of STAT3 phosphorylated at Y705 in the nucleus, a process that depends on Src activation. Interestingly, Src and STAT3 activation do not exclusively mediate the EGF-induced downregulation of CLDN-2, but they are also implicated in the EGF-induced CLDN-4 transcription, translation, and exocytic fusion into TJ. Our results indicate that EGF controls the levels of CLDN-2 and -4 proteins and mRNAs through Src and STAT3 activity.
authors.affiliation: Department of Physiology, Biophysics and Neurosciences, Center for Research and Advanced Studies (Cinvestav), México City, México.
authors.forename: Vicky
authors.initials: V
authors.lastname: García-Hernández
authors.forename: Catalina
authors.initials: C
authors.lastname: Flores-Maldonado
authors.forename: Ruth
authors.initials: R
authors.lastname: Rincon-Heredia
authors.forename: Odette
authors.initials: O
authors.lastname: Verdejo-Torres
authors.forename: José
authors.initials: J
authors.lastname: Bonilla-Delgado
authors.forename: Ivan
authors.initials: I
authors.lastname: Meneses-Morales
authors.forename: Patricio
authors.initials: P
authors.lastname: Gariglio
authors.forename: Rubén G
authors.initials: RG
authors.lastname: Contreras
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D062446:Claudin-2 / Q000096:biosynthesis* / Q000235:genetics; D062506:Claudin-4 / Q000096:biosynthesis* / Q000235:genetics; D004285:Dogs; D015536:Down-Regulation; D017097:Electric Impedance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells; D008301:Maleimides / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000378:metabolism*; D019108:Tight Junctions / Q000502:physiology; D014158:Transcription, Genetic; D015854:Up-Regulation; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: C465664:2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide; C412373:AG 1879; D002070:Butadienes; D062446:Claudin-2; D062506:Claudin-4; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C113580:U 0126; D004815:Epidermal Growth Factor; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases