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Ana I. Arroba, Jesús Revuelta-Cervantes, Lorena Menes, Águeda González-Rodríguez, Virginia Pardo, Pedro de la Villa, Deborah J. Burks, Ángela M. Valverde; Loss of Protein Tyrosine Phosphatase 1B Increases IGF-I Receptor Tyrosine Phosphorylation but Does Not Rescue Retinal Defects in IRS2-Deficient Mice. Invest. Ophthalmol. Vis. Sci. 2013;54(6):4215-4225. doi: https://doi.org/10.1167/iovs.12-11438.
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Mice with deletion of insulin receptor substrate (IRS) 2 develop type 2 diabetes and photoreceptor degeneration. Loss of protein tyrosine phosphatase 1B (PTP1B) in diabetic IRS2−/− mice restores insulin sensitivity and normalizes glucose homeostasis. Since insulin-like growth factor (IGF)–IR promotes survival of photoreceptors and is a substrate of PTP1B, we investigated IGF-IR–mediated survival signaling and visual function in PTP1B−/− and double mutant IRS2−/−/PTP1B−/− mice.
IGF-IR–mediated Akt signaling was evaluated in IGF-I–stimulated retinal explants. Histologic and electroretinogram analysis was performed in wild-type (WT), IRS2−/−, PTP1B−/−, and the double mutant IRS2−/−/PTP1B−/− mice.
IGF-I stimulated the tyrosine phosphorylation of its receptor and Akt activation in retinal explants of WT mice. In PTP1B−/− retinal explants, these responses were enhanced. Conversely, in retinas from IRS2−/− mice, expression of PTP1B was increased, coincident with decreased IGF-I–mediated Akt serine 473 phosphorylation. PTP1B deletion in IRS2−/− mice also enhanced IGF-IR tyrosine phosphorylation but, unexpectedly, did not rescue Akt activation in response to IGF-I. One potential explanation is that PTEN was increased in retinas of IRS2−/− and IRS2−/−/PTP1B−/− mice. Histologic evaluation revealed alterations in various structures of the retina in IRS2−/− and IRS2−/−/PTP1B−/− mice, specifically in the outer nuclear layer (ONL) and retinal outer segments (ROS). Electroretinogram (ERG) analysis confirmed that PTP1B deficiency did not restore visual function in IRS2−/− mice.
Although loss of PTP1B enhances tyrosine phosphorylation of the IGF-IR in retinal explants of IRS2−/− mice, Akt activation remains defective owing to elevated PTEN levels and, thus, structural and functional visual defects persist in this model.
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