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Raju V. Rajala, Vivek K. Gupta, Ammaji Rajala, Radhika Dighe, Devaraj K. Basavarajappa; Loss of Grb14 Leads to Photoreceptor Degeneration due to Increased Protein Tyrosine Phosphatase-1B Activity. Invest. Ophthalmol. Vis. Sci. 2011;52(14):46.
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Growth factor receptor bound-protein 14 (Grb14) is an adapter protein implicated in receptor tyrosine kinase signaling. In the retina, Grb14 protects the retinal IR activation, which is an important element of photoreceptor neuroprotection and consistent with these studies the Grb14-deficient mice exhibit age-related photoreceptor degeneration. In this study we made a novel finding that Grb14 inhibits PTP1B activity, the major negative regulator of insulin receptor signaling (IR), in a phosphorylation-regulated manner. We have also identified the molecular mechanism of photoreceptor degeneration in Grb14-deficeint mice.
Grb14, rod-specific PTP1B, and Rpe65 knockout mice were used to study molecular mechanism of Grb14-mediated inhibition of PTP1B activity. We measured the retinal PTP1B activity in wild type, Grb14-/- and Rpe65-/- mice. Electroretinography (ERG) was used to assess retinal rod and cone function at one, three and seven months of age. Outer nuclear thickness was used as a function of photoreceptor degeneration. Deletion analysis and site-directed mutagenesis techniques were used to study the molecular interaction between Grb14 and PTP1B. Retinal ex vivo organ cultures were used to study the Grb14 phosphorylation in the presence and absence of Src kinase inhibitors.
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 Grb14-/- mice experience an age-dependent retinal degeneration and a significant decrease in the function of both scotopic a- and b-waves and photopic b-wave ERG amplitudes. We further found that Src kinase is a not a substrate of PTP1B.
This is the first study demonstrating the molecular mechanism underlying the Grb14-mediated inhibition of PTP1B activity. We have shown previously that inhibition of PTP1B activity is neuroprotective and the observed retinal degeneration phenotype in Grb14-deficient mice is due to increased PTP1B activity.
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