ERK1/2-mediated EGFR-signaling is required for TGFβ-induced lens epithelial-mesenchymal transition.
Epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) plays a critical role in the pathogenesis of fibrotic cataract. Transforming growth factor-beta (TGFβ) is a potent inducer of this fibrotic process in lens. Recent studies in cancer progression have shown that in addition to activating the canonical Smad signaling pathway, TGFβ can also transactivate the epidermal growth factor receptor (EGFR) to enhance invasive cell migration. The present study aims to elucidate the involvement of EGFR-signaling in TGFβ-induced EMT in LECs. Treatment with TGFβ2 induced transdifferentiation of LECs into myofibroblastic cells, typical of an EMT. TGFβ2 induced the phosphorylation of the EGFR and upregulation of Egfr and Hb-egf gene expression. Pharmacologic inhibition of EGFR-signaling using PD153035 inhibited TGFβ-induced EMT, including the upregulation of mesenchymal markers and downregulation of epithelial markers. Crosstalk between TGFβ2-induced EGFR and ERK1/2 was evident, with both pathways impacting on Smad2/3-signaling. Our finding that TGFβ2 transactivates downstream EGFR-signaling reveals a previously unknown mechanism in the pathogenesis of cataract. Understanding the complex interplay between divergent canonical and non-canonical signaling pathways, as well as downstream target genes involved in TGFβ-induced EMT, will enable the development of more effective targeted therapies in the pharmacological treatment of cataract.
['Shu|Daisy Y|DY|', 'Wojciechowski|Magdalena|M|', 'Lovicu|Frank J|FJ|']
D000199:Actins D000818:Animals D015153:Blotting, Western D002465:Cell Movement D004591:Electrophoresis, Polyacrylamide Gel D004791:Enzyme Inhibitors D004847:Epithelial Cells D058750:Epithelial-Mesenchymal Transition D066246:ErbB Receptors D019084:Fluorescent Antibody Technique, Indirect D007908:Lens, Crystalline D020935:MAP Kinase Signaling System D010766:Phosphorylation D011799:Quinazolines D051381:Rats D017208:Rats, Wistar D060888:Real-Time Polymerase Chain Reaction D015398:Signal Transduction D051899:Smad2 Protein D051900:Smad3 Protein D053781:Transforming Growth Factor beta2 D051176:beta Catenin
Epithelial-mesenchymal transition (EMT) Cataract Transforming growth factor-beta (TGFβ) Smad EGFR Myofibroblast ERK1/2 Fibrosis