Enhanced Retinal Insulin Receptor-activated Neuroprotective Survival Signal in Mice Lacking the Protein-tyrosine Phosphatase-1B Gene

Abstract

Protein-tyrosine phosphatase 1B (PTP1B) has been implicated in the negative regulation of insulin signaling. We previously demonstrated that light-induced tyrosine phosphorylation of the retinal insulin receptor (IR) results in the activation of phosphoinositide 3-kinase/Akt survival pathway in rod photoreceptor cells. The molecular mechanism behind light-induced activation of IR is not known. We investigated the in vivo mechanism of IR activation and found that PTP1B activity in dark-adapted retinas was significantly higher than in lightadapted retinas. We made a novel finding in this study that the light-dependent regulation of PTP1B activity is signaled through photobleaching of rhodopsin. Conditional deletion of PTP1B in rod photoreceptors by the Cre-loxP system resulted in enhanced IR signaling. Further PTP1B activity negatively regulated the neuroprotective survival signaling in the retina. One of the challenging questions in the retina research is how mutations in human rhodopsin gene slowly disable and eventually disrupt photoreceptor functions. Our studies suggest that a defect in the photobleaching of rhodopsin and mutation in rhodopsin gene enhances the activity of PTP1B, and this activated activity could down-regulate the IR survival signaling. Our studies suggest that PTP1B antagonists could be potential therapeutic agents to treat stress-induced photoreceptor degenerations and provide further evidence that rhodopsin photoexcitation may trigger signaling events alternative to the classic phototransduction. Insulin receptors (IRs)3 and insulin signaling proteins are widely distributed throughout the central nervous system (1). Dysregulation of insulin signaling in the central nervous system has been linked to the pathogenesis of neurodegenerative disorders such as Alzheimer and Parkinson diseases (2, 3). Cells of bovine and rat retinas contain high affinity receptors for insulin (1). IR signaling provides a trophic signal for transformed retinal neurons in culture (4). We recently reported that IR is functionally important for photoreceptor survival (5). IR deletion in photoreceptor cells caused increased sensitivity to light-induced photoreceptor degeneration (5). We previously reported that light induces tyrosine phosphorylation of the retinal IR and that this activation leads to the binding of phosphoinositide 3-kinase (PI3K) to rod outer segment (ROS) membranes (6) and the subsequent activation of Akt (7, 8). More recently, we demonstrated that IR activation is mediated through the photobleaching of the G-protein-coupled receptor, rhodopsin, but not signaling through the phototransduction cascade (9).The extent of tyrosyl phosphorylation on a given protein is controlled by the reciprocal action of protein-tyrosine kinase and protein-tyrosine phosphatase (PTP) activities. Specific PTPs, including LAR, SHP-2, and PTP1B, have been implicated in the regulation of normal IR signaling (10 -23). Of these, PTP1B has received significant attention due to its abundance in all insulin-sensitive tissues (24,...

Phosphorylated Grb14 Is an Endogenous Inhibitor of Retinal Protein Tyrosine Phosphatase 1B, and Light-Dependent Activation of Src Phosphorylates Grb14

“…Consistent with this idea, in retina significantly increased tyrosine phosphorylation of IR and the activation of its downstream effectors were observed in light compared to dark-adapted conditions (27,30). Under these conditions, we found decreased PTP1B activity in light compared to dark-adapted conditions (34), and the decreased PTP1B activity in light correlates with the higher Grb14 phosphorylation observed in the current study. The phosphorylation-dependent affinity shift of Grb14 toward PTP1B is further evident from our finding that an increased amount of Grb14 associates with IR in the dark.…”

“…Photobleaching of rhodopsin regulates Src-mediated phosphorylation of Grb14. We previously reported significantly higher levels of PTP1B activity in retinal pigment epithelium 65-knockout mice (Rpe65 Ϫ/Ϫ ) than in wild-type mice under light-adapted conditions (34). Rpe65 Ϫ/Ϫ mice have opsin in their photoreceptor outer segments but do not form photobleachable rhodopsin (activated form) due to the absence of regeneration of the chromophore 11-cis-retinal (37).…”

H2O2 Signalling Pathway: A Possible Bridge between Insulin Receptor and Mitochondria

“…A decrease in hypothalamic PTP1B lowers food intake, reducing body weight and improving insulin action and signalling in the hypothalamus [36]. A conditional deletion of PTP1B in the retina was shown to enhance insulin receptor signalling and cell survival [37]. Mice lacking PTP1B demonstrate increased tyrosine phosphorylation of the insulin receptor, improved systemic insulin sensitivity and obesity resistance [38,39].…”

Beta-2-Adrenergic Receptor Regulates Insulin Signaling to Reduce Cell Death in Müller Cells

“…101 While our findings confirm our hypothesis of TNF-modulation in insulin receptor signaling, we also recognize that our findings could be the result of phosphatases such as PTP1B that were previously suggested by Rajala et al 2010 which would decrease insulin receptor activity leading to a decrease in Akt activity. 102,103 It is well know that insulin receptor mediates activation of caspase-3 by signaling through the PI3K/Akt pathway as well as the MAPK pathway. 102,103 Our future studies will focus more in detail on the relationship of the PI3K and MAPK pathways in retinal Müller cells.…”

“…102,103 It is well know that insulin receptor mediates activation of caspase-3 by signaling through the PI3K/Akt pathway as well as the MAPK pathway. 102,103 Our future studies will focus more in detail on the relationship of the PI3K and MAPK pathways in retinal Müller cells.…”