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J. L. Walker, L. Zhang, I. M. Wolff, A. Menko; Activation of a PI-3K-Akt Pathway Promotes Migration and Emt During Pco. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5643.
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Posterior capsule opacification (PCO) is a complication of cataract surgery that results from the proliferation, migration and epithelial-mesenchymal transition (EMT) of lens epithelial cells that remain attached to the lens capsule. Lens cells undergoing EMT become myofibroblast-like. Their contractile phenotype can lead to diminished visual acuity due to the wrinkling and fibrosis of the lens capsule. We are interested in identifying mechanisms involved in regulating EMT during PCO to aid in the development of therapeutic interventions to prevent loss of visual acuity. Recently we have identified a role for Src Family Kinases (SFKs) in the induction of proliferation, migration and EMT during PCO. Since phosphatidyl-inositol-3 kinase (PI-3K) is a known effector of SFKs and the PI-3K-Akt pathway is implicated in regulating EMT processes during development and cancer we investigated the role of the PI3K-Akt pathway during PCO.
Following mock cataract surgery, chick lens capsular bags are pinned to the culture dish and grown in the presence and absence of the PI-3K inhibitor, LY294002. The chick lens capsular bag model mimics PCO: lens epithelial cells proliferate, migrate across the posterior capsule and undergo EMT. Cell migration and morphology were monitored by photo-microscopy and changes in PI-3K-Akt signaling cascade and EMT markers were evaluated by western blotting.
During the development of PCO following mock cataract surgery Akt activation increased at its two PI-3K-dependent phosphorylation sites, Thr 308 (located in the activation loop) and Ser 473 (located in the carboxyl tail). The increase in Akt activation was accompanied by an increase in phosphorylation of its downstream effector, GSK-3. Treatment with an inhibitor of PI-3K, LY294002, diminished activation of Akt, reduced migration of lens cells across the posterior capsule and blocked expression of EMT markers, α- smooth muscle actin and fibronectin.
Activation of the PI-3K-Akt pathway is involved in regulating lens cell migration across the posterior capsule and induction of EMT. Inhibition of the PI3K-Akt pathway represents a possible pharmaceutical target for prevention of PCO following cataract surgery.
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