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H. Lei, A. Kazlauskas; Growth Factors Outside of the Pdgf Family Employ Ros/sfks to Activate Pdgf Receptor and Thereby Promote Proliferation and Survival of Cells. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2704.
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© ARVO (1962-2015); The Authors (2016-present)
Platelet-derived growth factor receptor (PDGFR) plays a key role in experimental proliferative vitreoretinopathy (PVR). We previously observed that while platelet-derived growth factor (PDGF) was present in the vitreous, vitreal growth factors outside of the PDGF family activated the PDGF receptor (PDGFR), and promoted disease progression in a rabbit model of PVR. The purpose of this study was to investigate the mechanism by which non-PDGFs activated PDGFR.
Activation of PDGFR was monitored by anti-phosphotyrosine Western blotting of PDGFR immunoprecipitates. Intracellular H2O2 generation was measured indirectly using the fluorescent dye, 2',7'-dichlorofluorescein diacetate. Cell proliferation was assessed directly by counting the cell number. Apoptosis was determined by flow cytometry.
Non-PDGF-s increased the cellular level of reactive oxygen species (ROS), and this event was necessary and sufficient for phosphorylation of PDGFR. Furthermore, non-PDGFs promoted tyrosine phosphorylation of catalytically inactive PDGFR, and thereby indicated that at least one additional tyrosine kinase was involved. Indeed, preventing expression or blocking the kinase activity of Src family kinases (SFKs), suppressed non-PDGF-dependent tyrosine phosphorylation of PDGFR. Thus non-PDGFs increased the level of ROS, which activated SFKs and resulted in phosphorylation of PDGFR. Finally, while non-PDGFs induced only modest phosphorylation of PDGFR, proliferation and survival of cells in response to non-PDGFs was significantly enhanced by expression of PDGFR.
These studies reveal a novel mechanism for activation of PDGFR that appears capable of enhancing the responsiveness of cells to vitreal growth factors outside of the PDGF family. Signaling enzymes required for activation of PDGFR by this pathway (SFKs and enzymes that generate ROS) are potential therapeutic targets for PVR.
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