Oncotarget

Research Papers: Gerotarget (Focus on Aging):

Activation of oncogenic tyrosine kinase signaling promotes insulin receptor-mediated cone photoreceptor survival

Ammaji Rajala, Yuhong Wang and Raju V.S. Rajala _

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Oncotarget. 2016; 7:46924-46942. https://doi.org/10.18632/oncotarget.10447

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Abstract

Ammaji Rajala1,4, Yuhong Wang1,4 and Raju V.S. Rajala1,2,3,4

1 Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

2 Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

3 Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

4 Dean McGee Eye Institute, Oklahoma City, OK, USA

Correspondence to:

Raju V.S. Rajala, email:

Keywords: age-related retinal degeneration; insulin receptor; Src kinase; cone photoreceptors; tyrosine phosphorylation; Gerotarget

Received: May 24, 2016 Accepted: June 26, 2016 Published: July 06, 2016

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.


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