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R. V. Rajala, A. Rajala, Y. Z. Le, B. G. Neel, M. Tanito; Enhanced Insulin Receptor Activated Neuroprotective Survival Signal in Mice Lacking the Protein Tyrosine Phosphatase-1B Gene in Rod Photoreceptor Cells. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1688.
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© ARVO (1962-2015); The Authors (2016-present)
We have previously demonstrated the light-induced tyrosine phosphorylation of retinal insulin receptor (IR) that results in the activation of PI3K/Akt survival pathway in rod photoreceptor cells. The state of IR phosphorylation is tightly regulated by protein tyrosine phosphatase 1b (PTP1b). We have observed an increase in PTP1b activity in dark adapted mouse retinas compared to light-adapted mouse retinas. These observations led to the hypothesis that light-induced IR phosphorylation is due to reduced PTP1b activity and the reduced IR phosphorylation in the dark is due to increased PTP1b activity. To investigate the effect of PTP1b on the state of IR phosphorylation, we studied the IR phosphorylation in global PTP1b knockout mouse retinas. To investigate the neuroprotective role of PTP1b on rod photoreceptors, we disrupted PTP1b gene specifically in mouse rod photoreceptors using cre-lox technology and challenged these mice to bright light stress.
Rod-specific PTP1b knockout mice were generated by mating mouse opsin promoter controlled Cre mice with floxed PTP1b mice. Loss of PTP1b in rod photoreceptor was confirmed by Western blot analysis. Immunoprecipitation and Western blot analysis were carried out to examine the state of IR and Akt activation in global PTP1b and rod-specific PTP1b knockout mice. Mice were exposed to constant bright light stress. Photoreceptor structural and functional integrity was measured by quantitative morphometry (outer nuclear layer (ONL) thickness) and electroretinography (ERG).
IR and Akt activation was observed in both light and dark-adapted PTP1b knockout mouse retinas compared to wild type (activation only in light) retinas. Disruption of PTP1b specifically in rods caused decreased PTP1b expression. Mice lacking PTP1b in rods were protected from bright light-induced retinal degeneration. Photoreceptor structure and functional integrity was well-preserved in PTP1b knockout mice (normal ERG and normal ONL thickness) compared to wild type controls.
Our studies clearly demonstrate that PTP1b regulates the state of IR phosphorylation in the retina, which in turn regulates the IR/PI3K/Akt survival pathway. These studies suggest that PTP1b antagonists could be potential therapeutic agents to treat stress-induced retinal degenerations.
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