title: Phosphorylation/inactivation of PTEN by Akt-independent PI3K signaling in retinal pigment epithelium.
abstract: Retinal pigment epithelium (RPE) plays a critical role in vertebrate vision by providing functional and structural support to the retina. Degeneration of RPE by cumulative oxidative stresses or acute injury frequently results in retinal degenerative diseases, notably age-related macular degeneration (AMD). Moreover, it has been shown that phosphorylation-mediated inactivation of PTEN (phosphatase and tensin homolog) in RPE is closely linked to AMD-like retinal degeneration in mice [1]. In this study, we used AMD mouse models, in which chemokine (C-C motif) ligand 2 (Ccl2) or chemokine (C-C motif) receptor 2 (Ccr2) were genetically ablated, to examine mechanisms linking reactive oxygen species (ROS) to phosphorylation/inactivation of PTEN in RPE. We found that ROS levels were increased in these RPE cells in association with phosphorylation/inactivation of PTEN. Both PTEN phosphorylation/inactivation and consequent Akt activation in the RPE of AMD model mice were inhibited by antioxidant treatment, indicating a functional role for elevated intracellular ROS. We further discovered that PTEN phosphorylation in oxidatively stressed RPE was repressed by a phosphoinositide 3-kinase (PI3K) inhibitor, but not by an Akt inhibitor. Taken together, these results suggest that ROS-activated PI3K potentiates AMD-related RPE pathogenesis through phosphorylation/inactivation of PTEN.
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, South Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Lee
authors.forename: Namsuk
authors.initials: N
authors.lastname: Kim
authors.forename: Kyung Hwa
authors.initials: KH
authors.lastname: Kang
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Kim
mesh_terms: D000818:Animals; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D008268:Macular Degeneration / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D054390:Receptors, CCR2 / Q000235:genetics; D055213:Retinal Pigment Epithelium / Q000201:enzymology* / Q000473:pathology
chemical_list: C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D017382:Reactive Oxygen Species; D054390:Receptors, CCR2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse