Growth factor receptor-bound protein 14 (Grb14) is an adapter protein implicated in receptor tyrosine kinase signaling. Grb14 ؊/؊ studies highlight both the positive and negative roles of Grb14 in receptor tyrosine kinase signaling in a tissue-specific manner. In this study, we made a novel finding that Grb14 inhibits the activity of PTP1B, the major negative regulator of insulin receptor (IR) signaling, in a phosphorylationregulated manner. Phosphorylation of Tyr-347 in the BPS domain of Grb14 is critical for interaction with PTP1B, resulting in the competitive inhibition of PTP1B activity. 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. PTP1B is known to be regulated by oxidation, glutathionylation, phosphorylation, and SUMOlyation, and our study for the first time demonstrates the inhibition of PTP1B activity in vivo by protein molecule Grb14 in a tissue-specific manner.

Background: Insulin receptor (IR)-phosphoinositide 3-kinase (PI3K) signaling pathway provides neuroprotection to cones. Results: Loss of PI3K in cones triggers cone degeneration that is not protected by rod derived cone survival factors. Conclusion: Cones have their own endogenous PI3K-mediated neuroprotective pathway. Significance: The IR-PI3K signaling pathway may be a target for neuroprotective therapeutic intervention.

The results suggest that melatonin, acting through Mel(1c) receptors on rod photoreceptor membranes, directly stimulates the responsiveness of rod photoreceptors to light. This supports the hypothesis that melatonin acts both as an intracrine and paracrine circadian signal of darkness, and binds to specific receptors in photoreceptors and other retinal cells to increase visual sensitivity.