title: Injury-triggered Akt phosphorylation of Cx43: a ZO-1-driven molecular switch that regulates gap junction size.
abstract: The proteins that form vertebrate gap junctions, the connexins, are highly regulated and have short (<2 hour) half-lives. Phosphorylation of connexin43 (Cx43) affects gap junction assembly, channel gating and turnover. After finding dramatic effects on gap junctions with Akt inhibitors, we created an antibody specific for Cx43 phosphorylated on S373, a potential Akt substrate. We found S373 phosphorylation in cells and skin or heart almost exclusively in larger gap-junctional structures that increased dramatically after wounding or hypoxia. We were able to mechanistically show that Akt-dependent phosphorylation of S373 increases gap junction size and communication by completely eliminating the interaction between Cx43 and ZO-1. Thus, phosphorylation on S373 acts as a molecular 'switch' to rapidly increase gap-junctional communication, potentially leading to initiation of activation and migration of keratinocytes or ischemic injury response in the skin and the heart, respectively.
authors.affiliation: Translational Research Program, Human Biology and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
authors.forename: Clarence A
authors.initials: CA
authors.lastname: Dunn
authors.forename: Paul D
authors.initials: PD
authors.lastname: Lampe
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000187:drug effects; D018031:Connexin 43 / Q000378:metabolism*; D004285:Dogs; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012867:Skin / Q000187:drug effects / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D062826:Zonula Occludens-1 Protein / Q000378:metabolism*
chemical_list: D018031:Connexin 43; D061988:Proteasome Inhibitors; D062826:Zonula Occludens-1 Protein; D010768:Phosphoserine; D051057:Proto-Oncogene Proteins c-akt; D013755:Tetradecanoylphorbol Acetate
keywords: Akt; Connexin43; Gap junctions; Hypoxia; Wounding