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Gudiseva Chandrasekher, Dasetty Sailaja; Differential Activation of Phosphatidylinositol 3-Kinase Signaling during Proliferation and Differentiation of Lens Epithelial Cells. Invest. Ophthalmol. Vis. Sci. 2003;44(10):4400-4411. doi: 10.1167/iovs.03-0136.
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purpose. To investigate whether phosphatidylinositol 3-kinase (PI-3K) signaling is involved in lens epithelial cell proliferation and differentiation promoted by growth factors.
methods. Proliferation of rabbit lens epithelial cells grown in culture was measured with a DNA-binding fluorescent dye in a proliferation assay. Primary cultures of embryonic chicken lens epithelial cells that develop lentoids were used for differentiation-related studies, and δ-crystallin synthesis in these cultures was determined by metabolic labeling with [35S]methionine. Immunoprecipitation and immunoblot analyses were also used.
results. The PI-3K inhibitors wortmannin and LY294002 blocked the insulin-, insulin-like growth factor (IGF)-1-, and fibroblast growth factor (FGF)-2-promoted cell proliferation in rabbit lens epithelial cells. Inhibition of PI-3K activity by these inhibitors unexpectedly increased the synthesis of early differentiation marker protein δ-crystallin in chicken lens epithelial cells. Insulin and IGF-1 stimulated activation of PI-3K in proliferating and differentiating cultures. FGF-2 showed no direct effect on PI-3K activation. Platelet-derived growth factor (PDGF) did not induce significant proliferation or increased expression of δ-crystallin, but stimulated PI-3K. The presence of FGF-2 in proliferating rabbit lens epithelial cells enhanced the IGF-1-, but not the PDGF-mediated PI-3K activation, suggesting a possible integration of FGF-2 signals with IGF-1. Whereas there was a gradual decrease in insulin/IGF-1-mediated activation of PI-3K and its downstream target Akt, with progression of differentiation in chicken lens epithelial cells, Erk2 phosphorylation induced by these growth factors was not decreased; rather, it remained increased in early stages of differentiation.
conclusions. The results reveal significant differences in the modulation of PI-3K signaling by different growth factors during proliferation in rabbit lens epithelial cells and differentiation in chicken lens epithelial cells and demonstrate that regulation of the PI-3K pathway plays a key role in these processes. A balance between the nonactivation of PI-3K and the activation of Erk2 may be necessary during early stages of epithelial cell transformation.
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