Abstract
Epithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells is a major pathologic change in the development of proliferative vitreoretinopathy (PVR), which leads to severe visual impairment. ERK1/2 pathway has been reported to play a key role in the carcinogenesis, cancer metastasis, and multiple fibrotic diseases. We hypothesized that ERK1/2 signaling could cross-interact with transforming growth factor β2 (TGFβ2)/Smad and Notch signaling pathways in the regulation of EMT in RPE cells. Here, we demonstrated that ERK1/2 signaling was activated in TGFβ2-induced EMT in human RPE cells, while blockade of the canonical TGFβ2/Smad2/3 signaling with SB431542 could not inhibit TGFβ2-induced the activation of ERK1/2. Meanwhile, blockade of ERK1/2 signaling with a specific MEK/ERK1/2 inhibitor U0126 strongly prevented TGFβ2-induced the downregulation of P-cadherin, and the upregulation of α-SMA, collagen type IV, N-cadherin and fibronectin in RPE cells. In addition, we also identified that blockade of ERK1/2 signaling could inhibit not only the canonical TGFβ/Smad signaling, but also the Jagged/Notch pathway. Finally, we found that blockade of Notch pathway with a specific inhibitor DAPT could inhibit TGFβ2-induced the activation of ERK1/2 pathway conversely. Therefore, our study provides evidence that ERK1/2 signaling can cross-interact with the canonical TGFβ/Smad and the Jagged/Notch signaling pathways in RPE cells EMT. ERK1/2 inhibitor may have therapeutic value in the prevention and treatment of PVR and other fibrotic diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Benzamides / pharmacology
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Blotting, Western
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Butadienes / pharmacology
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism*
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Cell Line
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Dioxoles / pharmacology
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Enzyme Inhibitors / pharmacology
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Epithelial Cells / drug effects*
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Epithelial Cells / metabolism
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Epithelial-Mesenchymal Transition / drug effects*
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Gene Expression / drug effects
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Jagged-1 Protein
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MAP Kinase Signaling System / drug effects*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / metabolism
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Multiprotein Complexes / metabolism
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Nitriles / pharmacology
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Receptor, Notch3
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Receptors, Notch / genetics
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Receptors, Notch / metabolism*
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Retinal Pigment Epithelium / cytology
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Reverse Transcriptase Polymerase Chain Reaction
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Serrate-Jagged Proteins
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Signal Transduction / drug effects
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Smad Proteins / metabolism*
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Smad2 Protein / metabolism
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Smad3 Protein / metabolism
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Transforming Growth Factor beta2 / pharmacology*
Substances
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4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
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Benzamides
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Butadienes
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Calcium-Binding Proteins
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Dioxoles
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Enzyme Inhibitors
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Intercellular Signaling Peptides and Proteins
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JAG1 protein, human
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Jagged-1 Protein
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Membrane Proteins
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Multiprotein Complexes
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NOTCH3 protein, human
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Nitriles
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Receptor, Notch3
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Receptors, Notch
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Serrate-Jagged Proteins
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Smad Proteins
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Smad2 Protein
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Smad3 Protein
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Transforming Growth Factor beta2
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U 0126
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MAPK1 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
Grants and funding
The research was funded by the National Nature and Science Grant (81370994) and the Guangdong Province Nature and Science Grant (S2013010015960). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.