Phosphoinositide 3-kinase signaling in the vertebrate retina

Rajala, Raju V S

doi:10.1194/jlr.r000232

Cited by 35 publications

(45 citation statements)

References 290 publications

(327 reference statements)

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“…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).…”

mentioning

confidence: 99%

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

Rajala

Tanito

Neel

et al. 2010

Journal of Biological Chemistry

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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,...

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confidence: 99%

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

Rajala

Tanito

Neel

et al. 2010

Journal of Biological Chemistry

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“…37,39,103,[128][129][130] These studies have described various complications such as pericyte loss, acellular capillaries, basement membrane thickening, activated glial cells and inflammation occurring within the neurosensory retina. 37,39,103,129,130 Unfortunately, work in animal models do not progress to the proliferative phase of diabetic retinopathy. 125 The exact mechanism of how high glucose levels contribute to the vascular and neuronal complications seen in diabetic retinopathy are not well understood, needing additional investigations to fully understand the pathology of this disease from the onset to visual loss.…”

Section: Chapter 5 General Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…39,59,103,122,[125][126][127] At a 2007 summer meeting of the Association for Research in Vision and Ophthalmology, it was suggested that diabetic retinopathy be defined as "structural and functional changes in the retina due to diabetes." The hyperglycemic environment caused by diabetes produces a number of vascular and neuronal changes in the retina, making the disease very difficult to describe and develop treatments.…”

Section: Chapter 5 General Discussionmentioning

confidence: 99%

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