title: Activation of oncogenic tyrosine kinase signaling promotes insulin receptor-mediated cone photoreceptor survival.
abstract: In humans, daylight vision is primarily mediated by cone photoreceptors. These cells die in age-related retinal degenerations. Prolonging the life of cones for even one decade would have an enormous beneficial effect on usable vision in an aging population. Photoreceptors are postmitotic, but shed 10% of their outer segments daily, and must synthesize the membrane and protein equivalent of a proliferating cell each day. Although activation of oncogenic tyrosine kinase and inhibition of tyrosine phosphatase signaling is known to be essential for tumor progression, the cellular regulation of this signaling in postmitotic photoreceptor cells has not been studied. In the present study, we report that a novel G-protein coupled receptor-mediated insulin receptor (IR) signaling pathway is regulated by non-receptor tyrosine kinase Src through the inhibition of protein tyrosine phosphatase IB (PTP1B). We demonstrated the functional significance of this pathway through conditional deletion of IR and PTP1B in cones, in addition to delaying the death of cones in a mouse model of cone degeneration by activating the Src. This is the first study demonstrating the molecular mechanism of a novel signaling pathway in photoreceptor cells, which provides a window of opportunity to save the dying cones in retinal degenerative diseases.
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Dean McGee Eye Institute, Oklahoma City, OK, USA.
authors.forename: Ammaji
authors.initials: A
authors.lastname: Rajala
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Dean McGee Eye Institute, Oklahoma City, OK, USA.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Dean McGee Eye Institute, Oklahoma City, OK, USA.
authors.forename: Raju V S
authors.initials: RV
authors.lastname: Rajala
mesh_terms: D000367:Age Factors; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002470:Cell Survival / Q000502:physiology*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology; D012162:Retinal Degeneration / Q000473:pathology*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D011972:Receptor, Insulin; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse
keywords: Gerotarget; Src kinase; age-related retinal degeneration; cone photoreceptors; insulin receptor; tyrosine phosphorylation