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.

The Warburg Effect Mediator Pyruvate Kinase M2 Expression and Regulation in the Retina

“…This may be due to the activation of tyrosine kinase signaling proteins that promote PKM2 phosphorylation. Consistent with this idea, our laboratory previously reported a light-dependent activation of several oncogenic signaling proteins, including insulin receptor, non-receptor tyrosine kinases, phosphoinositide 3-kinase, and Akt in photoreceptor cells183037. We have observed no effect of light on the activation of oncogenic receptor and non-receptor tyrosine kinases in mouse retinas that are deficient in rhodopsin photobleaching303839, further establishing the role of photobleachable visual pigments in this process.…”

“…We previously reported light-dependent PI3K activation in both rods and cones1830. To identify early pathways that are both stimulated by light and are PI3K-dependent, we treated retinal ex vivo implants with PI3K inhibitor (LY294002) or DMSO (vehicle), followed by light exposure.…”

“…Further, pharmacological inhibition of PTP1B increased Y105-PKM2 phosphorylation and decreased PKM2 activity47. We previously reported that either pharmacological inhibition of PTP1B48 or conditional ablation of PTP1B in a mouse model of cone degeneration is neuroprotective30. Studies to establish the link between the activation of PKM2 phosphorylation and protection of photoreceptor degeneration are ongoing in our laboratories.…”

“…Very recently, we reported that activation of oncogenic tyrosine kinase signaling promotes cone photoreceptor survival mediated through insulin receptor activation30. In terms of energy utilization and activation of tyrosine kinase signaling pathways, photoreceptors behave like cancer cells.…”

Constitutive Activation Mutant mTOR Promote Cone Survival in Retinitis Pigmentosa Mice

“…Deletion of IR from cones resulted in age-related cone degeneration. We found a ligand-independent IR activation in both rod and cone photoreceptor cells (Rajala et al, 2016; Rajala et al, 2002). This activation occurs through inhibition of a protein tyrosine phosphatase by phosphorylated Grb14.…”