EGF Receptor Signaling Modulates YAP Activation and Promotes Experimental Proliferative Vitreoretinopathy

PURPOSE: Both epidermal growth factor receptor (EGFR) and the Yes-associated protein (YAP) signaling pathway are implicated in cell proliferation and differentiation. In this study, we explored whether the formation of proliferative vitreoretinopathy (PVR) depends on the interaction of the EGFR receptor and YAP pathway. METHODS: We studied the effects of EGFR and YAP activation on retinal fibrosis in a PVR mouse model as well as in knockout mice (conditional deletion of EGFR or YAP specifically in RPE cells). Reversal and knockdown experiments were performed to induce a model of ARPE-19 cells treated with TGF-β2 in vitro. The effect of EGFR/YAP signaling blockade on the PVR-induced cell cycle and TGF-β2–induced ARPE-19 cell activation was determined. RESULTS: The EGFR inhibitor erlotinib or conditional deletion of EGFR attenuated YAP activation and decreased the expression of YAP and its downstream target Cyr61 and of connective tissue growth factor in vivo and in vitro. EGFR-PI3K-PDK1 signaling induced by PVR promoted YAP activation and cell cycle progression. Furthermore, activated EGFR signaling bypassed RhoA to increase the protein levels of YAP, C-Myc, CyclinD1, and Bcl-xl. CONCLUSIONS: Our work highlights that EGFR-PI3K-PDK1–dependent YAP activation plays a crucial role in the formation of PVR. Targeting EGFR and the YAP pathway provides promising therapeutic treatments for PVR.