Abstract
Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that play a critical role in transmitting signals from cell-surface molecules to intracellular protein effectors. Key PI3Ks include PI3Kα, PI3Kβ, and PI3Kδ, which are regulated by receptors. The signaling pathway comprising the PI3Ks, along with a Ser/Thr kinase (AKT), a proto-oncogene product (mouse double minute (MDM)2), and a tumor suppressor protein (p53), plays an essential role in experimental proliferative vitreoretinopathy (PVR), which is a fibrotic blinding eye disorder. However, which PI3K isoforms are involved in PVR is unknown. A major characteristic of PVR is the formation of epi (or sub)-retinal membranes that consist of extracellular matrix and cells, including retinal pigment epithelium (RPE) cells, glial cells, and macrophages. RPE cells are considered key players in PVR pathogenesis. Using immunoblotting and immunofluorescence analyses, we herein provide the evidence that PI3Kδ is highly expressed in human RPEs when it is primarily expressed in leukocytes. We also found that PI3Kδ inactivation through two approaches, CRISPR/Cas9-mediated depletion and a PI3Kδ-specific inhibitor (idelalisib), not only blocks vitreous-induced activation of AKT and MDM2 but also abrogates a vitreous-stimulated decrease in p53. Furthermore, we demonstrate that PI3Kδ inactivation prevents vitreous-induced proliferation, migration, and contraction of human RPEs. These results suggest that PI3Kδ may represent a potential therapeutic target for RPE-related eye diseases, including PVR.
Highlights
Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that play a critical role in transmitting signals from cellsurface molecules to intracellular protein effectors
We found that PI3K␦ is highly expressed in human retinal pigment epithelium (RPE), and inactivation of PI3K␦ with its specific inhibitor idelalisib or clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated depletion suppresses vitreous-induced activation of AKT and MDM2 and degradation of p53, proliferation, migration, as well as contraction of human RPEs
Previous studies have demonstrated that PI3Ks play a central role in experimental proliferative vitreoretinopathy (PVR) [14, 16], but which PI3K isoform contributes to the pathogenesis of PVR is still a mystery
Summary
Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that play a critical role in transmitting signals from cellsurface molecules to intracellular protein effectors. Key PI3Ks include PI3K␣, PI3K, and PI3K␦, which are regulated by receptors. The signaling pathway comprising the PI3Ks, along with a Ser/Thr kinase (AKT), a proto-oncogene product (mouse double minute (MDM)2), and a tumor suppressor protein (p53), plays an essential role in experimental proliferative vitreoretinopathy (PVR), which is a fibrotic blinding eye disorder. RPE cells are considered key players in PVR pathogenesis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The expressional pattern and function of PI3K␦ in retinal pigment epithelial cells (RPEs) have not been explored
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