ERK1/2-mediated EGFR-signaling is required for TGFβ-induced lens epithelial-mesenchymal transition

Abstract

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.