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Raju V. Rajala, Dustin T. Allen, Radhika Dighe, Ammaji Rajala; PTP1B Is A Novel Molecular Therapy Target For Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1609.
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© ARVO (1962-2015); The Authors (2016-present)
Retinitis Pigmentosa (RP) is a type of inherited retinal degeneration and it is currently untreatable and usually leads to blindness. Systemic administration of insulin which activates the insulin receptor (IR) signaling has been shown to delay the death of cone photoreceptors in a mouse model of RP. Unfortunately prolonged treatment with insulin did not maintain the survival effect and this could be due to the activation of an IR specific phosphatase, PTP1B that works to turn of the IR signaling. We previously reported enhanced IR signaling in mice lacking PTP1B in rods. We recently identified a rhodopsin-mediated novel signaling pathway that inhibits PTP1B in the healthy retina by an adapter protein, Grb14. In this study we examined the regulation of PTP1B in mouse model of both dominant and recessive RP.
Rhodopsin mutant VPP-transgenic mice (a mouse model of dominant RP), wild type, Grb14-/- and Rpe65-/- (account for ≈2% of cases of recessive RP) mice were used to study the regulation of PTP1B activity. We measured the retinal PTP1B activity in wild type, Grb14-/-, VPP-transgenic and Rpe65-/- mice. Grb14 and Src-kinase phosphorylation was examined in wild type, VPP-transgenic and Rpe65-/- mice.
We found that Grb14 competitively inhibits PTP1B activity in a phosphorylation-regulated manner. We also found that rhodopsin-regulated Src kinase activation in retina leads to the phosphorylation of Grb14. Further, ablation of Grb14 resulted in significantly elevated retinal PTP1B activity in vivo. We found that Src kinase activation and Grb14 phosphorylation is absent in VPP-transgenic and Rpe65-/- mice compared to wild type mice. The results also indicate significantly elevated levels of PTP1B activity in VPP-transgenic and Rpe65-/- mice compared to wild type mice.
Our results provide the first evidence that enhanced PTP1B activity in mouse models of RP is due to dysregulation of Src-mediated Grb14 phosphorylation. Activators of Src-kinase or PTP1B antagonists could be potential therapeutic agents to treat RP.
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