Quinone-induced Cdc25A inhibition causes ERK-dependent connexin phosphorylation.
Gap junctional intercellular communication (GJC) varies during progression of the cell cycle. We propose here that Cdc25A, a dual specificity phosphatase crucial for cell cycle progression, is linked to connexin (Cx) phosphorylation and the modulation of GJC. Inhibition of Cdc25 phosphatases in rat liver epithelial cells employing a 1,4-naphthoquinone-based inhibitor, NSC95397, induced cell cycle arrest, tyrosine phosphorylation of the epidermal growth factor receptor (EGFR), and activation of extracellular signal-regulated kinases ERK-1 and -2. ERK activation was blocked by specific inhibitors of MAPK/ERK kinases 1/2 or of the EGFR tyrosine kinase. An EGFR-dephosphorylation assay suggested that Cdc25A interacts with the EGFR, with inhibition by NSC95397 resulting in activation of the receptor. As a consequence of ERK activation, Cx43 was phosphorylated, resulting in a downregulation of GJC. Loss of GJC was prevented by inhibition of ERK activation. In summary, cell cycle and GJC are connected via Cdc25A and the EGFR-ERK pathway.
Melchheier
Ira
I
Institut für Biochemie und Molekularbiologie I, Heinrich-Heine-Universität Düsseldorf, D-40225 Düsseldorf, Germany.
von Montfort
Claudia
C
Stuhlmann
Dominik
D
Sies
Helmut
H
Klotz
Lars-Oliver
LO
D000818:Animals; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D015394:Molecular Structure; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism
C451261:2,3-bis(2-hydroxyethylsulfanyl)-(1,4)naphthoquinone; D018031:Connexin 43; D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C517007:Cdc25a protein, rat; D020687:cdc25 Phosphatases